The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke ...The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied.The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra.Our findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma concentrations.These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors.Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia.It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation.Thus,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury.Understanding these pathways co uld highlight new therapeutic targets to mitigate brain injury.展开更多
Introduction to human endogenous retrovirus type-W(HERV-W): Genomic inheritance from the past includes retroviral sequences that have been stably incorporated into our genomes and account for up to 8% of human DNA.
Multiple sclerosis(MS),the most common inflammatory condition of the central nervous system in young adults,is characterized by immunemediated demyelination and neurodegeneration that translate into heterogeneous clin...Multiple sclerosis(MS),the most common inflammatory condition of the central nervous system in young adults,is characterized by immunemediated demyelination and neurodegeneration that translate into heterogeneous clinical phenotypes and disease trajectories.展开更多
Cytochromes P450 s(CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks i...Cytochromes P450 s(CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms(CYP1 A1, CYP2 D6, CYP2 J2, CYP2 R1,CYP3 A5, CYP3 A7, CYP4 F3, CYP24 A1, CYP26 B1 and CYP27 B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.展开更多
Irritable bowel syndrome （IBS） and chronic pelvic pain （CPP） are both somatoform disorders with a high prevalence within the population in general. The objective was to compare both entities, to find the differenc...Irritable bowel syndrome （IBS） and chronic pelvic pain （CPP） are both somatoform disorders with a high prevalence within the population in general. The objective was to compare both entities, to find the differences and the similarities related to epidemiology and psychosocial aspects like stressful life events, physical and sexual abuse, illness behaviour and comorbidity. The technical literature was reviewed systematically from 1971 to 2006 and compared. According to literature, IBS and CPP seem to be one rather than two different entities with the same Iocalisation of pain. Both syndromes also are similar concerning prevalence, the coexistence of mental and somatoform disorders, the common history of sexual and physical abuse in the past and their health care utilization. It could be shown that there were many similarities between IBS and CPP. Nevertheless both are traded as different clinical pictures as far. Therefore it seems to be reasonable and necessary to generate a common diagnosis algorithm and to bring gynaecologists and gastroenterologists into dialogue.展开更多
Autologous bone marrow concentrate(BMC)and mesenchymal stem cells(MSCs)have beneficial effects on the healing of bone defects.To address the shortcomings associated with the use of primary MSCs,induced pluripotent ste...Autologous bone marrow concentrate(BMC)and mesenchymal stem cells(MSCs)have beneficial effects on the healing of bone defects.To address the shortcomings associated with the use of primary MSCs,induced pluripotent stem cell(iPSC)-derived MSCs(iMSCs)have been proposed as an alternative.The aim of this study was to investigate the bone regeneration potential of human iMSCs combined with calcium phosphate granules(CPG)in critical-size defects in the proximal tibias of mini-pigs in the early phase of bone healing compared to that of a previously reported autograft treatment and treatment with a composite made of either a combination of autologous BMC and CPG or CPG alone.iMSCs were derived from iPSCs originating from human fetal foreskin fibroblasts(HFFs).They were able to differentiate into osteoblasts in vitro,express a plethora of bone morphogenic proteins(BMPs)and secrete paracrine signaling-associated cytokines such as PDGF-AA and osteopontin.Radiologically and histomorphometrically,HFF-iMSC+CPG transplantation resulted in significantly better osseous consolidation than the transplantation of CPG alone and produced no significantly different outcomes compared to the transplantation of autologous BMC+CPG after 6 weeks.The results of this translational study imply that iMSCs represent a valuable future treatment option for load-bearing bone defects in humans.展开更多
Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence.Understanding the complex network of food intake and energy balance regulation is an essential prerequisite fo...Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence.Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity.G protein-coupled receptors(GPCRs)are among the main modulators of metabolism and energy balance.They,for instance,regulate appetite and satiety in certain hypothalamic neurons,as well as glucose and lipid metabolism and hormone secretion from adipocytes.Mutations in some GPCRs,such as the melanocortin receptor type 4(MC4R),have been associated with early-onset obesity.Here,we identified the adhesion GPCR latrophilin 1(ADGRL1/LPHN1)as a member of the regulating network governing food intake and the maintenance of energy balance.Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity,accompanied by dysregulation of glucose homeostasis.Consistently,we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity.Therefore,we propose that LPHN1 dysfunction is a risk factor for obesity development.展开更多
In a recent study published in Nature,Nobs and colleagues aimed to identify novel mechanisms that may explain why diabetes is associated with an increased susceptibility to viral respiratory infections.Their analyses ...In a recent study published in Nature,Nobs and colleagues aimed to identify novel mechanisms that may explain why diabetes is associated with an increased susceptibility to viral respiratory infections.Their analyses revealed a central role of lung dendritic cells(DC)which exhibited several functional defects induced by hyperglycaemia and consequently result in impaired antiviral immune responses.展开更多
Mismanaged plastics,upon entering the environment,undergo degradation through physicochemical and/or biological processes.This process often results in the formation of microplastics(MPs),the most prevalent form of pl...Mismanaged plastics,upon entering the environment,undergo degradation through physicochemical and/or biological processes.This process often results in the formation of microplastics(MPs),the most prevalent form of plastic debris(<1 mm).MPs pose severe threats to aquatic and terrestrial ecosystems,necessitating innovative strategies for effective remediation.Some photosynthetic microorganisms can degrade MPs but there lacks a comprehensive review.Here we examine the specific role of photoautotrophic microorganisms in water and soil environments for the biodegradation of plastics,focussing on their unique ability to grow persistently on diverse polymers under sunlight.Notably,these cells utilise light and CO_(2) to produce valuable compounds such as carbohydrates,lipids,and proteins,showcasing their multifaceted environmental benefits.We address key scientific questions surrounding the utilisation of photosynthetic microorganisms for MPs and nanoplastics(NPs)bioremediation,discussing potential engineering strategies for enhanced efficacy.Our review highlights the significance of alternative biomaterials and the exploration of strains expressing enzymes,such as polyethylene terephthalate(PET)hydrolases,in conjunction with microalgal and/or cyanobacterial metabolisms.Furthermore,we delve into the promising potential of photo-biocatalytic approaches,emphasising the coupling of plastic debris degradation with sunlight exposure.The integration of microalgal-bacterial consortia is explored for biotechnological applications against MPs and NPs pollution,showcasing the synergistic effects in wastewater treatment through the absorption of nitrogen,heavy metals,phosphorous,and carbon.In conclusion,this review provides a comprehensive overview of the current state of research on the use of photoautotrophic cells for plastic bioremediation.It underscores the need for continued investigation into the engineering of these microorganisms and the development of innovative approaches to tackle the global issue of plastic pollution in aquatic and terrestrial ecosystems.展开更多
MY China story,about the profound influence China has had on my life from childhood through to the present,is a long one that I hope will continue far into the future.I spent a great deal of my boyhood,more than 65 ye...MY China story,about the profound influence China has had on my life from childhood through to the present,is a long one that I hope will continue far into the future.I spent a great deal of my boyhood,more than 65 years ago,leafing through all kinds of books,admittedly drawn more to their vivid illustrations than texts.They included travel literature encompassing works by German zoologist Ernst Haeckel on Insulinde,the Latin name for what we call today Indonesia.Wonderstruck at their exotic images,especially of volcanoes,I vowed to see these distant outposts for myself.My dream was to venture beyond Southeast Asia to East Asia as a whole-to Japan and,of course,to China.展开更多
A study recently published in Nature reported a single-cell transcriptome map of human hematopoietic stem cells(HSCs)and a gene expression signature that distinguishes nascent HSCs from non-HSCs during prenatal develo...A study recently published in Nature reported a single-cell transcriptome map of human hematopoietic stem cells(HSCs)and a gene expression signature that distinguishes nascent HSCs from non-HSCs during prenatal development.1 This transcriptome map provides an important tool for further elucidation of human HSC ontogeny and could also serve as a guide for generation of transplantable HSCs ex vivo,1 to widen the therapeutic application of HSCs.展开更多
Acute liver failure(ALF)is a medical emergency due to massive hepatocyte loss.In such a harsh condition,maintaining transcriptional regulation in the remaining hepatocytes while activating similar transcription factor...Acute liver failure(ALF)is a medical emergency due to massive hepatocyte loss.In such a harsh condition,maintaining transcriptional regulation in the remaining hepatocytes while activating similar transcription factor networks in liver progenitor cells(LPCs)to ensure essential liver functions are two critical processes to rescue patients from liver failure and death.In this review,we discuss the formation and functions of transcription networks in ALF and liver development.We focus on a hierarchical network of transcription factors that responds to different pathophysiological circumstances:(1)Under normal circumstances,pioneer factor forkhead box protein A2(FOXA2)coordinates several constitutive hepatic transcription factors,such as hepatic nuclear factor 4 alpha(HNF4a)and CCAAT-enhancer binding protein a(C/EBPa),which ensure normal liver function;(2)When the expression of both HNF4a and C/EBPa in hepatocytes are disrupted by severe inflammation,retinoic acid receptor(RAR)is the alternative transcription factor that compensates for their absence;(3)When massive hepatic necrosis occurs,a similar transcription network including FOXA2 and HNF4a,is activated as a“rescue network”in LPCs to maintain vital liver functions when hepatocytes fail,and thus ensures survival.Expression of these master transcription factors in hepatocytes and LPCs is tightly regulated by hormone signals and inflammation.The performance of this hierarchical transcription network,in particularly the“rescue network”described above,significantly affects the clinical outcome of ALF.展开更多
Ratiometric luminescence thermometry with trivalent lanthanide ions and their 4f^(n) energy levels is an emerging technique for non-invasive remote temperature sensing with high spatial and temporal resolution.Convent...Ratiometric luminescence thermometry with trivalent lanthanide ions and their 4f^(n) energy levels is an emerging technique for non-invasive remote temperature sensing with high spatial and temporal resolution.Conventional ratiometric luminescence thermometry often relies on thermal coupling between two closely lying energy levels governed by Boltzmann’s law.Despite its simplicity,Boltzmann thermometry with two excited levels allows precise temperature sensing,but only within a limited temperature range.While low temperatures slow down the nonradiative transitions required to generate a measurable population in the higher excitation level,temperatures that are too high favour equalized populations of the two excited levels,at the expense of low relative thermal sensitivity.In this work,we extend the concept of Boltzmann thermometry to more than two excited levels and provide quantitative guidelines that link the choice of energy gaps between multiple excited states to the performance in different temperature windows.By this approach,it is possible to retain the high relative sensitivity and precision of the temperature measurement over a wide temperature range within the same system.We demonstrate this concept using YAl_(3)(BO_(3))_(4)(YAB):Pr^(3+),Gd^(3+)with an excited 6 PJ crystal field and spin-orbit split levels of Gd^(3+)in the UV range to avoid a thermal black body background even at the highest temperatures.This phosphor is easily excitable with inexpensive and powerful blue LEDs at 450 nm.Zero-background luminescence thermometry is realized by using blue-to-UV energy transfer upconversion with the Pr^(3+)−Gd^(3+)couple upon excitation in the visible range.This method allows us to cover a temperature window between 30 and 800 K.展开更多
Knowledge of residence time is a critical aspect in developing control and material diversion strategies for continuous manufacturing processes in pharmaceutical manufacturing.Dry granulation is a promising continuous...Knowledge of residence time is a critical aspect in developing control and material diversion strategies for continuous manufacturing processes in pharmaceutical manufacturing.Dry granulation is a promising continuous granulation technique as it is fast and economical.In this study,a step-change method to determine residence time in roll compaction/dry granulation is introduced.The factors roll speed and rotational speed of the impeller in the powder inlet unit of the compactor were evaluated using a central composite circumscribed statistical design of experiments in order to optimize the residence time.The fill volume in the compactor was varied exemplarily.It was found that high roll speed,low rotational speed of the impeller and low fill volume in the compactor are beneficial to generate fast transition through the compactor.The impact of roll speed increase was estimated.It can be concluded that despite fast residence time in the process,high roll speed and its subsequent high material throughput can generate a large amount of material that has to be discarded if material diversion is required.展开更多
Microbial secondary metabolites represent a rich source of valuable compounds with a variety of applications in medicine or agriculture.Effective exploitation of this wealth of chemicals requires the functional expres...Microbial secondary metabolites represent a rich source of valuable compounds with a variety of applications in medicine or agriculture.Effective exploitation of this wealth of chemicals requires the functional expression of the respective biosynthetic genes in amenable heterologous hosts.We have previously established the TREX system which facilitates the transfer,integration and expression of biosynthetic gene clusters in various bacterial hosts.Here,we describe the yTREX system,a new tool adapted for one-step yeast recombinational cloning of gene clusters.We show that with yTREX,Pseudomonas putida secondary metabolite production strains can rapidly be constructed by random targeting of chromosomal promoters by Tn5 transposition.Feasibility of this approach was corroborated by prodigiosin production after yTREX cloning,transfer and expression of the respective biosynthesis genes from Serratia marcescens.Furthermore,the applicability of the system for effective pathway rerouting by gene cluster adaptation was demonstrated using the violacein biosynthesis gene cluster from Chromobacterium violaceum,producing pathway metabolites violacein,deoxyviolacein,prodeoxyviolacein,and deoxychromoviridans.Clones producing both prodigiosin and violaceins could be readily identified among clones obtained after random chromosomal integration by their strong color-phenotype.Finally,the addition of a promoter-less reporter gene enabled facile detection also of phenazine-producing clones after transfer of the respective phenazine-1-carboxylic acid biosynthesis genes from Pseudomonas aeruginosa.All compounds accumulated to substantial titers in the mg range.We thus corroborate here the suitability of P.putida for the biosynthesis of diverse natural products,and demonstrate that the yTREX system effectively enables the rapid generation of secondary metabolite producing bacteria by activation of heterologous gene clusters,applicable for natural compound discovery and combinatorial biosynthesis.展开更多
Expanded 5-(hetero)aryl-thien-2-yl substituted 3-ethynyl quinoxaline dyes with variable substitution pattern on the peripheral thiophene ring were synthesized in moderate to very good yields by Suzuki and Buchwald-Har...Expanded 5-(hetero)aryl-thien-2-yl substituted 3-ethynyl quinoxaline dyes with variable substitution pattern on the peripheral thiophene ring were synthesized in moderate to very good yields by Suzuki and Buchwald-Hartwig coupling of the corresponding brominated 3-ethynyl quinoxalines. Dumbbell-shaped bis(thienyl 3-ethynyl quinoxalines) are also accessible by the Suzuki protocol. The photophysical properties were investigated by UV and fluorescence spectroscopy. Most of the obtained compounds display fluorescence in solution and some of them also in the solid state. Additionally, tuning of the emission color of the quinoxaline based chromophores can be conveniently accomplished by the remote substituent group. The determined absorption and emission maximum as well as the Stokes shifts strongly correlate with Hammett σp+parameters. Besides,photophysical properties of selected derivatives in the solid state, biphasic solutions, and PMMA films, along with their relationships, are comparatively investigated. Moreover, two 5-(hetero)aryl-thien-2-yl substituted 3-ethynyl quinoxaline dyes are aggregation induced emission(AIE) chromophores indicated by restriction of molecular motions. A covalently restricted 3-ethynyl quinoxaline supports that the inhibition of molecular rotation is responsible for the significant enhancement of fluorescence in acetonitrile/water mixtures.展开更多
We study for a class of symmetric Levy processes with state space R^n the transition density pt（x） in terms of two one-parameter families of metrics, （dt）t〉o and （δt）t〉o. The first family of metrics describes...We study for a class of symmetric Levy processes with state space R^n the transition density pt（x） in terms of two one-parameter families of metrics, （dt）t〉o and （δt）t〉o. The first family of metrics describes the diagonal term pt （0）; it is induced by the characteristic exponent ψ of the Levy process by dr（x, y） = √tψ（x - y）. The second and new family of metrics 6t relates to √tψ through the formula exp（-δ^2t（x,y））=F[e^-tψ/pt（0）]（x-y）,where Y denotes the Fourier transform. Thus we obtain the following ＂Gaussian＂ representation of the tran- sition density： pt（x） = pt（O）e^-δ^2t（x,0） where pt（O） corresponds to a volume term related to √tψ and where an ＂exponential＂ decay is governed by 5t2. This gives a complete and new geometric, intrinsic interpretation of pt（x）.展开更多
Lanthanide-doped(nano)crystals are an important class of materials in luminescence thermometry.The working mechanism of these thermometers is diverse but most often relies on variation of the ratio of emission intensi...Lanthanide-doped(nano)crystals are an important class of materials in luminescence thermometry.The working mechanism of these thermometers is diverse but most often relies on variation of the ratio of emission intensities from two thermally coupled excited states with temperature.At low temperatures,nonradiative coupling between the states can be slow compared to radiative decay,but,at higher temperatures,the two states reach thermal equilibrium due to faster nonradiative coupling.In thermal equilibrium,the intensity ratio follows Boltzmann statistics,which gives a convenient model to calibrate the thermometer.Here,we investigate multiple strategies to shift the onset of thermal equilibrium to lower temperatures,which enables Boltzmann thermometry in a wider dynamic range.We use Eu^(3+)-doped microcrystals as a model system and find that the nonradiative coupling rates increase for host lattices with higher vibrational energies and shorter lanthanide-ligand distances,which reduces the onset temperature of thermal equilibrium by more than 400 K.We additionally reveal that thermometers with excited states coupled by electricdipole transitions have lower onset temperatures than those with magnetic-dipole-coupled states due to selection rules.These insights provide essential guidelines for the optimization of Boltzmann thermometers to operate in an extended temperature range.展开更多
Background:Early detection and treatment of neuropathy in leprosy is important to prevent disabilities.A recent study showed that the Nerve Conduction Studies(NCS)and Warm Detection Thresholds(WDT)tests can detect lep...Background:Early detection and treatment of neuropathy in leprosy is important to prevent disabilities.A recent study showed that the Nerve Conduction Studies(NCS)and Warm Detection Thresholds(WDT)tests can detect leprosy neuropathy the earliest.These two tests are not practical under field conditions,however,because they require climate-controlled rooms and highly trained staff and are expensive.We assessed the usefulness of alternative test methods and their sensitivity and specificity to detect neuropathy at an early stage.Methods:Through a literature search we identified five alternative devices that appeared user-friendly,more affordable,portable and/or battery-operated:the Neuropad^(■),Vibratip^(TM),NC-Stat^(■)DPNCheck^(TM),NeuroQuick and the Thermal Sensibility Tester(TST),assessing respectively sweat function,vibration sensation,nerve conduction,cold sensation and warm sensation.In leprosy patients in Bangladesh,the posterior tibial and sural nerves that tested normal for the monofilament test and voluntary muscle test were assessed with the NCS and WDT as reference standard tests.The alternative devices were then tested on 94 nerves with abnormal WDT and/or NCS results and on 94 unaffected nerves.Sensitivity and specificity were the main outcomes.Results:The NeuroQuick and the TST showed very good sensitivity and specificity.On the sural nerve,the NeuroQuick had both a sensitivity and a specificity of 86%.The TST had a sensitivity of 83%and a specificity of 82%.Both the NC-Stat^(■)DPNCheck^(TM)and Vibratip^(TM)had a high specificity(88%and 100%),but a low sensitivity(16%and 0%).On the posterior tibial nerve,the NeuroQuick and the TST also showed good sensitivity,but the sensitivity was lower than for the sural nerve.The Neuropad^(■)had a sensitivity of 56%and a specificity of 61%.Conclusions:The NeuroQuick and TST are good candidates for further field-testing for reliability and reproducibility.The feasibility of production on a larger scale should be examined.展开更多
Background: Inflammatory responses are implicated as crucial patho-mechanisms of vascular brain malformations. Inflammation is suggested to be a key contributor to aneurysm rupture; however it is unclear whether infla...Background: Inflammatory responses are implicated as crucial patho-mechanisms of vascular brain malformations. Inflammation is suggested to be a key contributor to aneurysm rupture; however it is unclear whether inflammation contributes similarly to bleeding of cerebral cavernous malformations (CCMs). Black blood MRI is a sequence which identifies inflammation in blood vessel walls and in the present study is used to detect inflammatory response in CCMs. Methods: Fifteen patients with 17 CCMs treated in our department in 2017 were retrospectively analysed. All patients received black blood MRIs and the results were analysed in correlation with, size and bleeding of CCMs. Results: Size and bleeding status of CCMs did not correlate with contrast enhancement in the CCM wall. One of 3 patients with bleeding displayed contrast enhancement in black blood MRI, whereas the others had non enhancing lesions. Because of the small number of cases a statistical analysis was not performed. Conclusion: In this limited cohort, inflammatory reactions in CCMs could not be detected by black blood MRI suggesting that the level of inflammation is minimal in these lesions and those different patho-mechanisms play a more important role in the rupture of CCMs.展开更多
基金supported by MICIU(grant number PID2021-128133NB-100/AEI/FEDER10.13039/501100011033 to JMHG)by the National Institutes of Health(grant number R01 NS083858 to SAK)+1 种基金the Intramural Grants Program IGPP00057(to SAK)VIC enjoys a FPU contract from the Comunidad de Madrid(PIPF-2022/SAL-GL-25948)。
文摘The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied.The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra.Our findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma concentrations.These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors.Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia.It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation.Thus,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury.Understanding these pathways co uld highlight new therapeutic targets to mitigate brain injury.
基金supported by the Christiane and Claudia Hempel Foundation for Regenerative Medicineby the James and Elisabeth Cloppenburg, Peek and Cloppenburg Düsseldorf Stiftung(to PK)。
文摘Introduction to human endogenous retrovirus type-W(HERV-W): Genomic inheritance from the past includes retroviral sequences that have been stably incorporated into our genomes and account for up to 8% of human DNA.
基金supported by the German Research Foundation(DFG)-SFB-TR-128the Boehringer Ingelheim Fonds BIF-03the State University of Medicine and Pharmacy“Nicolae Testemitanu”(project codes 20.80009.8007.40 and 21.80013.8007.2B)。
文摘Multiple sclerosis(MS),the most common inflammatory condition of the central nervous system in young adults,is characterized by immunemediated demyelination and neurodegeneration that translate into heterogeneous clinical phenotypes and disease trajectories.
文摘Cytochromes P450 s(CYPs) are terminal enzymes in CYP dependent monooxygenases, which constitute a superfamily of enzymes catalysing the metabolism of both endogenous and exogenous substances. One of their main tasks is to facilitate the excretion of these substances and eliminate their toxicities in most phase 1 reactions. Endogenous substrates of CYPs include steroids, bile acids, eicosanoids, cholesterol, vitamin D and neurotransmitters. About 80% of currently used drugs and environmental chemicals comprise exogenous substrates for CYPs. Genetic polymorphisms of CYPs may affect the enzyme functions and have been reported to be associated with various diseases and adverse drug reactions among different populations. In this review, we discuss the role of some critical CYP isoforms(CYP1 A1, CYP2 D6, CYP2 J2, CYP2 R1,CYP3 A5, CYP3 A7, CYP4 F3, CYP24 A1, CYP26 B1 and CYP27 B1) in the pathogenesis or aetiology of ulcerative colitis concerning gene polymorphisms. In addition, their significance in metabolism concerning ulcerative colitis in patients is also discussed showing a clear underestimation in genetic studies performed so far.
文摘Irritable bowel syndrome （IBS） and chronic pelvic pain （CPP） are both somatoform disorders with a high prevalence within the population in general. The objective was to compare both entities, to find the differences and the similarities related to epidemiology and psychosocial aspects like stressful life events, physical and sexual abuse, illness behaviour and comorbidity. The technical literature was reviewed systematically from 1971 to 2006 and compared. According to literature, IBS and CPP seem to be one rather than two different entities with the same Iocalisation of pain. Both syndromes also are similar concerning prevalence, the coexistence of mental and somatoform disorders, the common history of sexual and physical abuse in the past and their health care utilization. It could be shown that there were many similarities between IBS and CPP. Nevertheless both are traded as different clinical pictures as far. Therefore it seems to be reasonable and necessary to generate a common diagnosis algorithm and to bring gynaecologists and gastroenterologists into dialogue.
文摘Autologous bone marrow concentrate(BMC)and mesenchymal stem cells(MSCs)have beneficial effects on the healing of bone defects.To address the shortcomings associated with the use of primary MSCs,induced pluripotent stem cell(iPSC)-derived MSCs(iMSCs)have been proposed as an alternative.The aim of this study was to investigate the bone regeneration potential of human iMSCs combined with calcium phosphate granules(CPG)in critical-size defects in the proximal tibias of mini-pigs in the early phase of bone healing compared to that of a previously reported autograft treatment and treatment with a composite made of either a combination of autologous BMC and CPG or CPG alone.iMSCs were derived from iPSCs originating from human fetal foreskin fibroblasts(HFFs).They were able to differentiate into osteoblasts in vitro,express a plethora of bone morphogenic proteins(BMPs)and secrete paracrine signaling-associated cytokines such as PDGF-AA and osteopontin.Radiologically and histomorphometrically,HFF-iMSC+CPG transplantation resulted in significantly better osseous consolidation than the transplantation of CPG alone and produced no significantly different outcomes compared to the transplantation of autologous BMC+CPG after 6 weeks.The results of this translational study imply that iMSCs represent a valuable future treatment option for load-bearing bone defects in humans.
基金supported by scholarships for A.N.D.from the Medical Faculty,Leipzig University,and for L.L.from the Jürgen Manchot Foundation,and grants from the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)through CRC1423/2(project number 421152132,C04(S.P.,T.S.))CRC1052/3(project number 209933838,B06(T.S.)),B10(D.L.D.))FOR 2149(project number 246212759,P02(S.P.)and P04(T.S.)).
文摘Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence.Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity.G protein-coupled receptors(GPCRs)are among the main modulators of metabolism and energy balance.They,for instance,regulate appetite and satiety in certain hypothalamic neurons,as well as glucose and lipid metabolism and hormone secretion from adipocytes.Mutations in some GPCRs,such as the melanocortin receptor type 4(MC4R),have been associated with early-onset obesity.Here,we identified the adhesion GPCR latrophilin 1(ADGRL1/LPHN1)as a member of the regulating network governing food intake and the maintenance of energy balance.Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity,accompanied by dysregulation of glucose homeostasis.Consistently,we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity.Therefore,we propose that LPHN1 dysfunction is a risk factor for obesity development.
基金supported by a grant from Horizon Europe (INTERCEPT-T2D,101095433)supported by the German Diabetes Center (DDZ),which is funded by the German Federal Ministry of Health (Berlin,Germany)+1 种基金the Ministry of Culture and Science of the state North Rhine-Westphalia (Düsseldorf,Germany)receives additional funding from the German Federal Ministry of Education and Research (BMBF)through the German Center for Diabetes Research (DZD e.V.).
文摘In a recent study published in Nature,Nobs and colleagues aimed to identify novel mechanisms that may explain why diabetes is associated with an increased susceptibility to viral respiratory infections.Their analyses revealed a central role of lung dendritic cells(DC)which exhibited several functional defects induced by hyperglycaemia and consequently result in impaired antiviral immune responses.
基金financial support by the University of Graz(Open Access Publishing Agreement)ARS would like to acknowledge the support given through ED431C2021/46-GRC attributed to Universidade de Vigo by Xunta de Galicia and IJC2020-044197-I through the Universidade de Vigo,MCIN/AEI/10.13039/501100011033+2 种基金the European Union through“Next-GenerationEU/PRTR”This article/publication is based upon work from COST Action CA20101 Plastics monitoRIng detection RemedIaTion recoverY-PRIORITY,supported by COST(European Cooperation in Science and Technology),www.cost.euThis work was partially supported the University of Wolverhampton Research Investment Fund(RIF4).The figures were created with BioRender.com.
文摘Mismanaged plastics,upon entering the environment,undergo degradation through physicochemical and/or biological processes.This process often results in the formation of microplastics(MPs),the most prevalent form of plastic debris(<1 mm).MPs pose severe threats to aquatic and terrestrial ecosystems,necessitating innovative strategies for effective remediation.Some photosynthetic microorganisms can degrade MPs but there lacks a comprehensive review.Here we examine the specific role of photoautotrophic microorganisms in water and soil environments for the biodegradation of plastics,focussing on their unique ability to grow persistently on diverse polymers under sunlight.Notably,these cells utilise light and CO_(2) to produce valuable compounds such as carbohydrates,lipids,and proteins,showcasing their multifaceted environmental benefits.We address key scientific questions surrounding the utilisation of photosynthetic microorganisms for MPs and nanoplastics(NPs)bioremediation,discussing potential engineering strategies for enhanced efficacy.Our review highlights the significance of alternative biomaterials and the exploration of strains expressing enzymes,such as polyethylene terephthalate(PET)hydrolases,in conjunction with microalgal and/or cyanobacterial metabolisms.Furthermore,we delve into the promising potential of photo-biocatalytic approaches,emphasising the coupling of plastic debris degradation with sunlight exposure.The integration of microalgal-bacterial consortia is explored for biotechnological applications against MPs and NPs pollution,showcasing the synergistic effects in wastewater treatment through the absorption of nitrogen,heavy metals,phosphorous,and carbon.In conclusion,this review provides a comprehensive overview of the current state of research on the use of photoautotrophic cells for plastic bioremediation.It underscores the need for continued investigation into the engineering of these microorganisms and the development of innovative approaches to tackle the global issue of plastic pollution in aquatic and terrestrial ecosystems.
文摘MY China story,about the profound influence China has had on my life from childhood through to the present,is a long one that I hope will continue far into the future.I spent a great deal of my boyhood,more than 65 years ago,leafing through all kinds of books,admittedly drawn more to their vivid illustrations than texts.They included travel literature encompassing works by German zoologist Ernst Haeckel on Insulinde,the Latin name for what we call today Indonesia.Wonderstruck at their exotic images,especially of volcanoes,I vowed to see these distant outposts for myself.My dream was to venture beyond Southeast Asia to East Asia as a whole-to Japan and,of course,to China.
基金The work was supported by grants from the Forschungskommission of the Medical Faculty of the Heinrich Heine University of Düsseldorf and the Leukämie Lymphom Liga e.V.to E.Grinstein.Acknowledged is furthermore grant support from Deutsche Forschungsgemeinschaft to E.Grinstein.
文摘A study recently published in Nature reported a single-cell transcriptome map of human hematopoietic stem cells(HSCs)and a gene expression signature that distinguishes nascent HSCs from non-HSCs during prenatal development.1 This transcriptome map provides an important tool for further elucidation of human HSC ontogeny and could also serve as a guide for generation of transplantable HSCs ex vivo,1 to widen the therapeutic application of HSCs.
基金supported by the Deutsche For-schungsge meinschaft WE 5009/9e1,Chinese-German Cooperation Group projects GZ 1517(H.-L.Weng)BMBF through HiChol 01GM1904A(R.Liebe).R.Feng is supported by the Chinese Scholarship Council(Grant No.201706230256).
文摘Acute liver failure(ALF)is a medical emergency due to massive hepatocyte loss.In such a harsh condition,maintaining transcriptional regulation in the remaining hepatocytes while activating similar transcription factor networks in liver progenitor cells(LPCs)to ensure essential liver functions are two critical processes to rescue patients from liver failure and death.In this review,we discuss the formation and functions of transcription networks in ALF and liver development.We focus on a hierarchical network of transcription factors that responds to different pathophysiological circumstances:(1)Under normal circumstances,pioneer factor forkhead box protein A2(FOXA2)coordinates several constitutive hepatic transcription factors,such as hepatic nuclear factor 4 alpha(HNF4a)and CCAAT-enhancer binding protein a(C/EBPa),which ensure normal liver function;(2)When the expression of both HNF4a and C/EBPa in hepatocytes are disrupted by severe inflammation,retinoic acid receptor(RAR)is the alternative transcription factor that compensates for their absence;(3)When massive hepatic necrosis occurs,a similar transcription network including FOXA2 and HNF4a,is activated as a“rescue network”in LPCs to maintain vital liver functions when hepatocytes fail,and thus ensures survival.Expression of these master transcription factors in hepatocytes and LPCs is tightly regulated by hormone signals and inflammation.The performance of this hierarchical transcription network,in particularly the“rescue network”described above,significantly affects the clinical outcome of ALF.
基金D.Y.is grateful to Prof.Wei Wei from Nanjing University of Posts and Telecommunication for useful suggestions.Moreover,Q.Z.acknowledges funding from the National Science Foundation of China(U1601205,51472088,and 51125005)while D.Y.and A.M.acknowledge funding from the Nederlandse Organisatie voor Wetenschappelijk Onderzoek(NWO,Grant No.731.017.302)A.M.and M.S.additionally gratefully acknowledge funding from the EU-Horizon 2020 FET-Open project NanoTBTech(grant agreement no.:801305).
文摘Ratiometric luminescence thermometry with trivalent lanthanide ions and their 4f^(n) energy levels is an emerging technique for non-invasive remote temperature sensing with high spatial and temporal resolution.Conventional ratiometric luminescence thermometry often relies on thermal coupling between two closely lying energy levels governed by Boltzmann’s law.Despite its simplicity,Boltzmann thermometry with two excited levels allows precise temperature sensing,but only within a limited temperature range.While low temperatures slow down the nonradiative transitions required to generate a measurable population in the higher excitation level,temperatures that are too high favour equalized populations of the two excited levels,at the expense of low relative thermal sensitivity.In this work,we extend the concept of Boltzmann thermometry to more than two excited levels and provide quantitative guidelines that link the choice of energy gaps between multiple excited states to the performance in different temperature windows.By this approach,it is possible to retain the high relative sensitivity and precision of the temperature measurement over a wide temperature range within the same system.We demonstrate this concept using YAl_(3)(BO_(3))_(4)(YAB):Pr^(3+),Gd^(3+)with an excited 6 PJ crystal field and spin-orbit split levels of Gd^(3+)in the UV range to avoid a thermal black body background even at the highest temperatures.This phosphor is easily excitable with inexpensive and powerful blue LEDs at 450 nm.Zero-background luminescence thermometry is realized by using blue-to-UV energy transfer upconversion with the Pr^(3+)−Gd^(3+)couple upon excitation in the visible range.This method allows us to cover a temperature window between 30 and 800 K.
基金This work was supported by the Drug Delivery Innovation Center(DDIC),INVITE GmbH,Leverkusen.
文摘Knowledge of residence time is a critical aspect in developing control and material diversion strategies for continuous manufacturing processes in pharmaceutical manufacturing.Dry granulation is a promising continuous granulation technique as it is fast and economical.In this study,a step-change method to determine residence time in roll compaction/dry granulation is introduced.The factors roll speed and rotational speed of the impeller in the powder inlet unit of the compactor were evaluated using a central composite circumscribed statistical design of experiments in order to optimize the residence time.The fill volume in the compactor was varied exemplarily.It was found that high roll speed,low rotational speed of the impeller and low fill volume in the compactor are beneficial to generate fast transition through the compactor.The impact of roll speed increase was estimated.It can be concluded that despite fast residence time in the process,high roll speed and its subsequent high material throughput can generate a large amount of material that has to be discarded if material diversion is required.
基金The scientific activities of the Bioeconomy Science Center were financially supported by the Ministry of Innovation,Science and Research of the German federal state of North Rhine-Westphalia MIWF within the framework of the NRW Strategieprojekt BioSC(No.313/323-400-00213).
文摘Microbial secondary metabolites represent a rich source of valuable compounds with a variety of applications in medicine or agriculture.Effective exploitation of this wealth of chemicals requires the functional expression of the respective biosynthetic genes in amenable heterologous hosts.We have previously established the TREX system which facilitates the transfer,integration and expression of biosynthetic gene clusters in various bacterial hosts.Here,we describe the yTREX system,a new tool adapted for one-step yeast recombinational cloning of gene clusters.We show that with yTREX,Pseudomonas putida secondary metabolite production strains can rapidly be constructed by random targeting of chromosomal promoters by Tn5 transposition.Feasibility of this approach was corroborated by prodigiosin production after yTREX cloning,transfer and expression of the respective biosynthesis genes from Serratia marcescens.Furthermore,the applicability of the system for effective pathway rerouting by gene cluster adaptation was demonstrated using the violacein biosynthesis gene cluster from Chromobacterium violaceum,producing pathway metabolites violacein,deoxyviolacein,prodeoxyviolacein,and deoxychromoviridans.Clones producing both prodigiosin and violaceins could be readily identified among clones obtained after random chromosomal integration by their strong color-phenotype.Finally,the addition of a promoter-less reporter gene enabled facile detection also of phenazine-producing clones after transfer of the respective phenazine-1-carboxylic acid biosynthesis genes from Pseudomonas aeruginosa.All compounds accumulated to substantial titers in the mg range.We thus corroborate here the suitability of P.putida for the biosynthesis of diverse natural products,and demonstrate that the yTREX system effectively enables the rapid generation of secondary metabolite producing bacteria by activation of heterologous gene clusters,applicable for natural compound discovery and combinatorial biosynthesis.
基金supported by the Fonds der Chemischen Industrie and Deutsche Forschungsgemeinschaft (Mu 1088/9-1)
文摘Expanded 5-(hetero)aryl-thien-2-yl substituted 3-ethynyl quinoxaline dyes with variable substitution pattern on the peripheral thiophene ring were synthesized in moderate to very good yields by Suzuki and Buchwald-Hartwig coupling of the corresponding brominated 3-ethynyl quinoxalines. Dumbbell-shaped bis(thienyl 3-ethynyl quinoxalines) are also accessible by the Suzuki protocol. The photophysical properties were investigated by UV and fluorescence spectroscopy. Most of the obtained compounds display fluorescence in solution and some of them also in the solid state. Additionally, tuning of the emission color of the quinoxaline based chromophores can be conveniently accomplished by the remote substituent group. The determined absorption and emission maximum as well as the Stokes shifts strongly correlate with Hammett σp+parameters. Besides,photophysical properties of selected derivatives in the solid state, biphasic solutions, and PMMA films, along with their relationships, are comparatively investigated. Moreover, two 5-(hetero)aryl-thien-2-yl substituted 3-ethynyl quinoxaline dyes are aggregation induced emission(AIE) chromophores indicated by restriction of molecular motions. A covalently restricted 3-ethynyl quinoxaline supports that the inhibition of molecular rotation is responsible for the significant enhancement of fluorescence in acetonitrile/water mixtures.
文摘We study for a class of symmetric Levy processes with state space R^n the transition density pt（x） in terms of two one-parameter families of metrics, （dt）t〉o and （δt）t〉o. The first family of metrics describes the diagonal term pt （0）; it is induced by the characteristic exponent ψ of the Levy process by dr（x, y） = √tψ（x - y）. The second and new family of metrics 6t relates to √tψ through the formula exp（-δ^2t（x,y））=F[e^-tψ/pt（0）]（x-y）,where Y denotes the Fourier transform. Thus we obtain the following ＂Gaussian＂ representation of the tran- sition density： pt（x） = pt（O）e^-δ^2t（x,0） where pt（O） corresponds to a volume term related to √tψ and where an ＂exponential＂ decay is governed by 5t2. This gives a complete and new geometric, intrinsic interpretation of pt（x）.
基金The Netherlands Center for Multiscale Catalytic Energy Conversion(MCEC),an NWO Gravitation Program funded by the Ministry of Education,Culture,and Science of the government of The Netherlands.
文摘Lanthanide-doped(nano)crystals are an important class of materials in luminescence thermometry.The working mechanism of these thermometers is diverse but most often relies on variation of the ratio of emission intensities from two thermally coupled excited states with temperature.At low temperatures,nonradiative coupling between the states can be slow compared to radiative decay,but,at higher temperatures,the two states reach thermal equilibrium due to faster nonradiative coupling.In thermal equilibrium,the intensity ratio follows Boltzmann statistics,which gives a convenient model to calibrate the thermometer.Here,we investigate multiple strategies to shift the onset of thermal equilibrium to lower temperatures,which enables Boltzmann thermometry in a wider dynamic range.We use Eu^(3+)-doped microcrystals as a model system and find that the nonradiative coupling rates increase for host lattices with higher vibrational energies and shorter lanthanide-ligand distances,which reduces the onset temperature of thermal equilibrium by more than 400 K.We additionally reveal that thermometers with excited states coupled by electricdipole transitions have lower onset temperatures than those with magnetic-dipole-coupled states due to selection rules.These insights provide essential guidelines for the optimization of Boltzmann thermometers to operate in an extended temperature range.
基金The study was a sub-study of the TENLEP trial.The TENLEP trial was funded by the The American Leprosy Mission,the German Leprosy and TB Relief Association,the Netherlands Leprosy Relief,the Ordre de Malte,and the Turing Foundation.
文摘Background:Early detection and treatment of neuropathy in leprosy is important to prevent disabilities.A recent study showed that the Nerve Conduction Studies(NCS)and Warm Detection Thresholds(WDT)tests can detect leprosy neuropathy the earliest.These two tests are not practical under field conditions,however,because they require climate-controlled rooms and highly trained staff and are expensive.We assessed the usefulness of alternative test methods and their sensitivity and specificity to detect neuropathy at an early stage.Methods:Through a literature search we identified five alternative devices that appeared user-friendly,more affordable,portable and/or battery-operated:the Neuropad^(■),Vibratip^(TM),NC-Stat^(■)DPNCheck^(TM),NeuroQuick and the Thermal Sensibility Tester(TST),assessing respectively sweat function,vibration sensation,nerve conduction,cold sensation and warm sensation.In leprosy patients in Bangladesh,the posterior tibial and sural nerves that tested normal for the monofilament test and voluntary muscle test were assessed with the NCS and WDT as reference standard tests.The alternative devices were then tested on 94 nerves with abnormal WDT and/or NCS results and on 94 unaffected nerves.Sensitivity and specificity were the main outcomes.Results:The NeuroQuick and the TST showed very good sensitivity and specificity.On the sural nerve,the NeuroQuick had both a sensitivity and a specificity of 86%.The TST had a sensitivity of 83%and a specificity of 82%.Both the NC-Stat^(■)DPNCheck^(TM)and Vibratip^(TM)had a high specificity(88%and 100%),but a low sensitivity(16%and 0%).On the posterior tibial nerve,the NeuroQuick and the TST also showed good sensitivity,but the sensitivity was lower than for the sural nerve.The Neuropad^(■)had a sensitivity of 56%and a specificity of 61%.Conclusions:The NeuroQuick and TST are good candidates for further field-testing for reliability and reproducibility.The feasibility of production on a larger scale should be examined.
文摘Background: Inflammatory responses are implicated as crucial patho-mechanisms of vascular brain malformations. Inflammation is suggested to be a key contributor to aneurysm rupture; however it is unclear whether inflammation contributes similarly to bleeding of cerebral cavernous malformations (CCMs). Black blood MRI is a sequence which identifies inflammation in blood vessel walls and in the present study is used to detect inflammatory response in CCMs. Methods: Fifteen patients with 17 CCMs treated in our department in 2017 were retrospectively analysed. All patients received black blood MRIs and the results were analysed in correlation with, size and bleeding of CCMs. Results: Size and bleeding status of CCMs did not correlate with contrast enhancement in the CCM wall. One of 3 patients with bleeding displayed contrast enhancement in black blood MRI, whereas the others had non enhancing lesions. Because of the small number of cases a statistical analysis was not performed. Conclusion: In this limited cohort, inflammatory reactions in CCMs could not be detected by black blood MRI suggesting that the level of inflammation is minimal in these lesions and those different patho-mechanisms play a more important role in the rupture of CCMs.
