Multiple sclerosis is at a checkpoint: advancing the program

Multiple sclerosis(MS) is a chronic inflammatory and demyelinating disease of the central nervous system(CNS). Patients with MS experience sensory and motor function loss due to myelin and/or axon damage perpetuated by infiltrating immune cells(Hauser and Cree, 2020).

Generation of brain vascular heterogeneity:recent advances from the perspective of angiogenesis

Heterogeneous proper t i es of vascular endothelial cells in the brain:The brain displays large energy dynamics and consumption,and this high level of metabolic demands is fulfilled by a continuous supply of glucose and oxygen through its vascular networks.Brain vasculature consists of highly divergent blood vessel branches,giving rise to a dense network of capillaries that supply blood to all cells across the brain.This elaborated vascular network is thought to develop via angiogenesis,a process in which new blood vessels grow from pre-existing vasculature.Brain capillaries exhibit organotypic features distinct from other tissues and are formed primarily by two major endothelial cell(EC)types:those that form the semi-permeable blood-brain barrier(BBB)and those that develop highly permeable pores known as fenestrae(Matsuoka et al.,2022).The structural and functional differences between BBB and fenestrated vascular ECs represent a fundamental feature of brain vasculature and form the foundation for both brain function and homeostasis.

Routine utilization of machine perfusion in liver transplantation:Ready for prime time?

The last decade has been notable for increasing high-quality research and dramatic improvement in outcomes with dynamic liver preservation.Robust evidence from numerous randomized controlled trials has been pooled by meta-analyses,providing the highest available evidence on the protective effect of machine perfusion(MP)over static cold storage in liver transplantation(LT).Based on a protective effect with less complications and improved graft survival,the field has seen a paradigm shift in organ preservation.This editorial focuses on the role of MP in LT and how it could become the new“gold standard”.Strong collaborative efforts are needed to explore its effects on long-term outcomes.

Revealing the contribution of basilar membrane's biological activity to the mechanism of the cochlear phonosensitive amplification

Explaining the mechanism of the cochlear active phonosensitive amplification has been a major problem in medicine.The basilar membrane(BM)is the key infrastructure.In 1960,Nobel Laureate von B′ek′esy first discovered BM's traveling wave motion.Since that time,BM's models only have considered the traveling wave but not the biological activity.Therefore,a new model considering changes of BM's stiffness in space and time is established based on the immersed boundary method to describe its biological activity.It not only reproduces the results of traveling wave motion but also explains the mechanization on the generation of traveling wave.An important discovery is that changes of BM's stiffness in space and time will cause the unstable global resonance,which will induce amplification of sounds in cochlea.An important inference is that biological activity shall be included in the application of mechanical principles to the analysis of life,which is the essential difference between biomechanics and general mechanics.

儿茶酚胺介导的多形性室速研究进展

儿茶酚胺介导的多形性室速是一种少见却严重的遗传性心律失常,表现为无器质性心脏病的个体在运动或激动时发生双向性、多形性室速导致发作性晕厥及进展为心室颤动导致猝死。心肌细胞肌浆网异常释放钙离子使细胞内钙离子超载引起的延迟后除极可能是儿茶酚胺介导的多形性室速发生的机制。目前已知的和儿茶酚胺介导的多形性室速相关的基因为常染色体显性遗传的RyR2(位于1q42.1-q43)和常染色体隐性遗传的CASQ2(位于1p13.3-p11)。治疗:β-阻断剂适用于所有临床症状的个体和可能有RyR2突变而没有心脏事件(晕厥)或运动试验诱发的室性心律失常等病史的个体。反复心脏骤停患者需植入式心律转复除颤器。每6至12个月随访以监测疗效。患者所有的一级亲属,都应予心脏评估。

转基因内皮细胞的构建及其在复合血管上种植的初步研究

目的:为了解决小口径(直径7mm以下)人造血管术后通畅率低下的问题,利用生物-人工复合血管,结合分子生物学手段,将转入血管内皮生长因子(VEGF165)基因的人脐静脉内皮细胞(HUVEC)种植于复合血管内腔面,为解决此临床难题提供新的思路和手段。材料方法:构建VEGF165真核表达质粒pCI-neo-VEGF165,获得正确的质粒用于转染HUVEC。从中科院购买HUVEC(代号:ECV-304),用脂质体介导法将pCI-neo-VEGF165转入细胞,经G418筛选后,计数阳性克隆,以比较脂质体和质粒在不同比例情况下转染效率的高低。实验组按质粒和脂质体比例的不同分为4组:1μg/3μl;2μg/6μl;2μg/8μl;3μg/12μl。ELISA检测瞬时转染后HUVEC培养上清中VEGF的表达。再将VEGF165基因瞬时转入HUVEC,利用自己设计的旋转培养装置,将细胞均匀地粘附、种植于复合血管内腔面。复合血管是人工材料(聚酯)和生物材料(成纤维细胞长入,胶原形成)有机结合而成,是将包有聚酯网的硅胶棒埋入绵羊背部皮下组织,3个月后取出,抽去硅胶棒而得到的。结果:脂质体转染效率以2μg/8μl组阳性克隆数最多;ELISA测定瞬时转染后HUVEC培养上清中VEGF的表达量为532·5±43·1pg/ml。使用旋转培养装置的细胞均匀地粘附于复合血管,未使用者细胞积聚于血管腔面下部;转入和未转入VEGF165基因的HUVEC在复合血管内腔面覆盖面积百分比分别为69·9%±3·5%、43·7%±2·5%,有明显改善。结论:转入VEGF后可促进HUVEC在复合血管上生长,旋转培养装置有利于细胞的均匀粘附。

Cellular and molecular mechanisms of intestinal fibrosis

Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelialand endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic proc-ess, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.

Anti-inflammatory pathways and alcoholic liver disease: Role of an adiponectin/interleukin-10/heme oxygenase-1 pathway

The development of alcoholic liver disease (ALD) is a complex process involving both the parenchymal and non-parenchymal cells in the liver. Enhanced inflammation in the liver during ethanol exposure is an important contributor to injury. Kupffer cells, the resident macrophages in liver, are particularly critical to the onset of ethanol-induced liver injury. Chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharide via Toll-like receptor 4. This sensitization enhances production of inflammatory mediators, such as tumor necrosis factor-α and reactive oxygen species, that contribute to hepatocyte dysfunction, necrosis, apoptosis, and fibrosis. Impaired resolution of the inflammatory process probably also contributes to ALD. The resolution of inflammation is an active, highly coordinated response that can potentially be manipulated via therapeutic interventions to treat chronic inflammatory diseases. Recent studies have identif ied an adiponectin/interleukin-10/heme oxygenase-1 (HO-1) pathway that is profoundly effective in dampening the enhanced activation of innate immune responses in primary cultures of Kupffer cells, as well as in an in vivo mouse model of chronic ethanol feeding. Importantly, induction of HO-1 also reduces ethanol-induced hepatocellular apoptosis in this in vivo model. Based on these data, we hypothesize that the development of therapeutic agents to regulate HO-1 and its downstream targets could be useful in enhancing the resolution of inflammation during ALD and preventing progression of early stages of liver injury.

From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world

Hepatocellular carcinoma(HCC) is the most frequent primary liver malignancy and the third cause of cancer-related death in the Western Countries. The well-established causes of HCC are chronic liver infections such as hepatitis B virus or chronic hepatitis C virus, nonalcoholic fatty liver disease, consumption of aflatoxins and tobacco smocking. Clinical presentation varies widely; patients can be asymptomatic while symptomatology extends from right upper abdominal quadrant paint and weight loss to obstructive jaundice and lethargy. Imaging is the first key and one of the most important aspects at all stages of diagnosis, therapy and follow-up of patients with HCC. The Barcelona Clinic Liver Cancer Staging System remains the most widely classification system used for HCC management guidelines. Up until now, HCC remains a challenge to early diagnose, and treat effectively; treating management is focused on hepatic resection, orthotopic liver transplantation, ablative therapies, chemoembolization and systemic therapies with cytotocix drugs, and targeted agents. This review article describes the current evidence on epidemiology, symptomatology, diagnosis and treatment of hepatocellular carcinoma.

Hepatic immune tolerance induced by hepatic stellate cells

The liver, which is a metabolic organ, plays a pivotal role in tolerance induction. Hepatic stellate cells(Hp SCs), which are unique non-parenchymal cells, exert potent immunoregulatory activity during cotransplantation with allogeneic islets effectively protecting the islet allografts from rejection. Multiple mechanisms participate in the immune tolerance induced by Hp SCs, including the marked expansion of myeloid-derived suppressor cells(MDSCs), attenuation of effector T cell functions and augmentation of regulatory T cells. Hp SC conditioned MDSC-based immunotherapy has been conducted in mice with autoimmune disease and the results show that this technique may be promising. This article demonstrates how Hp SCs orchestrate both innate immunity and adaptive immunity to build a negative network that leads to immune tolerance.

Mechanistic insights of rapid liver regeneration after associating liver partition and portal vein ligation for stage hepatectomy

AIM To highlight the potential mechanisms of regeneration in the Associating Liver Partition and Portal vein ligation for Stage hepatectomy models(clinical and experimental) that could unlock the myth behind the extraordinary capability of the liver for regeneration,which would help in designing new therapeutic options for the regenerative drive in difficult setup,such as chronic liver diseases. Associating Liver Partition and Portal vein ligation for Stage hepatectomy has been recently advocated to induce rapid future liver remnant hypertrophy that significantly shortens the time for the second stage hepatectomy. The introduction of Associating Liver Partition and Portal vein ligation for Stage hepatectomy in the surgical armamentarium of therapeutic tools for liver surgeons represented a real breakthrough in the history of liver surgery. METHODS A comprehensive literature review of Associating Liver Partition and Portal vein ligation for Stage hepatectomy and its utility in liver regeneration is performed. RESULTS Liver regeneration after Associating Liver Partition and Portal vein ligation for Stage hepatectomy is a combination of portal flow changes and parenchymal transection that generate a systematic response inducing hepatocyte proliferation and remodeling. CONCLUSION Associating Liver Partition and Portal vein ligation for Stage hepatectomy represents a real breakthrough in the history of liver surgery because it offers rapid liver regeneration potential that facilitate resection of liver tumors that were previously though unresectable. The jury is still out though in terms of safety,efficacy and oncological outcomes. As far as Associating Liver Partition and Portal vein ligation for Stage hepatectomy-induced liver regeneration is concerned,further research on the field should focus on the role of nonparenchymal cells in liver regeneration as well as on the effect of Associating Liver Partition and Portal vein ligation for Stage hepatectomy in liver regeneration in the setup of parenchymal liver disease.

Multiple hurdle mechanism and blood-brain barrier in epilepsy:glucocorticoid receptor-heat shock proteins on drug regulation

Epilepsy is a complex neurologic condition which affects over 50 million people worldwide.Pharmacotherapy,primarily involving the use of anti-seizure drugs(ASDs),is an essential part of controlling seizures.However,nearly 30%of patients develop drug-resistant epilepsy,clinically defined as the persistence of seizure following trials of two ASDs(Kwan et al.,2010).Although several hypotheses have been proposed to explain this phenomenon,the mechanism of drug-resistant epilepsy still remains unclear.

A 3D-printable device allowing fast and reproducible longitudinal preparation of mouse intestines

Accurate and reproducible analysis of murine small and large intestinal tissue is key for preclinical models involving intestinal pathology.Currently,there is no easily ac-cessible,standardized method that allows researchers of different skill levels to con-sistently dissect intestines in a time-efficient manner.Here,we describe the design and use of the 3D-printed“Mouse Intestinal Slicing Tool”(MIST),which can be used to longitudinally dissect murine intestines for further analysis.We benchmarked the MIST against a commonly used procedure involving scissors to make a longitudinal cut along the intestines.Use of the MIST halved the time per mouse to prepare the intestines and outperformed alternative methods in smoothness of the cutting edge and overall reproducibility.By sharing the plans for printing the MIST,we hope to contribute a uniformly applicable method for saving time and increasing consistency in studies of the mouse gastrointestinal tract.

Differential Proteome Analysis of <i>Chlamydomonas reinhardtii</i>Response to Arsenic Exposure

The fresh water unicellular green alga Chlamydomonas reinhardtii was used to explore whether it could function as a model system to identify proteins that are differentially expressed in response to arsenate exposure. Cells were treated with different concentrations of arsenate ranging from 100 - 400 μM. When exposed to 200 μM arsenate, the amount of live cells started to lessen on the second day and continued to diminish, indicating a toxic effect of arsenate. Proteomic analysis was used to investigate if these cells showed a specific response to arsenic-induced stress. Fifteen proteins were found that were over-expressed in the 200 μM arsenate-treated samples and two proteins were found to be very strongly over-expressed in samples treated with 400 μM. These were selected for identification using liquid chromatography coupled with tandem mass spectrometry. Oxidative stress and protein damage were the major effects as shown by the up-regulation of Mn-superoxide dismutase, an oxygen-evolving enhancer protein, a chaperonin-like protein and a heat shock protein.

Gut Microbiota Community Shift with Severity of Coronary Artery Disease

Gut microbiota community shift with coronary artery disease(CAD)has been reported in several limited cohorts during the past several years.However,whether the enriched or decreased microbiota taxa with CAD can be reproducible deserves further investigation and validation.In this study,78 human subjects were recruited.Of these,19 were diagnosed without stenosis in coronary artery(control group,referred to herein as Ctrl),14 with stenosis less than 50%(LT50),and 45 with stenosis greater than 50%(GT50).Fecal samples were collected and DNA was extracted to perform 16S ribosomal RNA(rRNA)gene sequencing.The operational taxonomic units(OTUs)were analyzed to identify taxa specific to different groups;next,multivariate logistic regression was employed to test whether the defined taxa could independently predict CAD risk.We found that Deltaproteobacteria,Fusobacterium,Bilophila,Actinomyces,and Clostridium XIX were enriched in Ctrl;Prevotellaceae,Parabacteriodes,and Butyricicoccus were enriched in LT50;and Roseburia and Butyricimonas were enriched in GT50.Further analysis revealed that increased populations of Deltaproteobacteria,Fusobacterium,Bilophila,and Desulfovibrionaceae were associated with a 0.26-fold,0.21-fold,0.18-fold,and 0.26-fold decreased risk of CAD,respectively(p<0.05),and an increased Prevotellaceae population was associated with a 5.63-fold increased risk of CAD(p<0.01).A combination of the 20 microbial taxa achieved an area under the receiver operating characteristic(ROC)curve of higher than 0.88 for all discriminations between LT50 vs Ctrl,GT50 vs Ctrl,LT50+GT50 vs Ctrl,and GT50 vs Ctrl+LT50.However,the microbial taxa previously reported as enriched in CAD patients or healthy controls could not be observed in our cohort except for Bacteroides.In conclusion,CAD patients showed a different microbial taxa signature than the healthy controls.However,the non-reproducibility of the microbiota taxa enriched in CAD across different cohorts limits the use of this signature in early diagnosis and prevention.Only decreased Bacteroides abundance was found to be a reliable marker to indicate CAD progression.

Type I interferon signaling facilitates resolution of acute liver injury by priming macrophage polarization

Due to their broad functional plasticity,myeloid cells contribute to both liver injury and recovery during acetaminophen overdose-induced acute liver injury(APAP-ALI).A comprehensive understanding of cellular diversity and intercellular crosstalk is essential to elucidate the mechanisms and to develop therapeutic strategies for APAP-ALI treatment.Here,we identified the function of IFN-I in the myeloid compartment during APAP-ALI.Utilizing single-cell RNA sequencing,we characterized the cellular atlas and dynamic progression of liver CD11b+cells post APAP-ALI in WT and STAT2 T403A mice,which was further validated by immunofluorescence staining,bulk RNA-seq,and functional experiments in vitro and in vivo.We identified IFN-I-dependent transcriptional programs in a three-way communication pathway that involved IFN-I synthesis in intermediate restorative macrophages,leading to CSF-1 production in aging neutrophils that ultimately enabled Trem2+restorative macrophage maturation,contributing to efficient liver repair.Overall,we uncovered the heterogeneity of hepatic myeloid cells in APAP-ALI at single-cell resolution and the therapeutic potential of IFN-I in the treatment of APAP-ALI.

DEEP-squared:deep learning powered De-scattering with Excitation Patterning

Limited throughput is a key challenge in in vivo deep tissue imaging using nonlinear optical microscopy.Point scanning multiphoton microscopy,the current gold standard,is slow especially compared to the widefield imaging modalities used for optically cleared or thin specimens.We recently introduced“De-scattering with Excitation Patterning”or“DEEP”as a widefield alternative to point-scanning geometries.Using patterned multiphoton excitation,DEEP encodes spatial information inside tissue before scattering.However,to de-scatter at typical depths,hundreds of such patterned excitations were needed.In this work,we present DEEP2,a deep learning-based model that can de-scatter images from just tens of patterned excitations instead of hundreds.Consequently,we improve DEEP’s throughput by almost an order of magnitude.We demonstrate our method in multiple numerical and experimental imaging studies,including in vivo cortical vasculature imaging up to 4 scattering lengths deep in live mice.

Identification of marine natural product Pretrichodermamide B as a STAT3 inhibitor for efficient anticancer therapy

The Janus kinase(JAK)/signal transducer and activator of transcription 3(STAT3)regulates the expression of various critical mediators of cancer and is considered as one of the central communication nodes in cell growth and survival.Marine natural products(MNP)represent great resources for discovery of bioactive lead compounds,especially anti-cancer agents.Through the medium-throughput screening of our in-house MNP library,Pretrichodermamide B,an epidithiodiketopiperazine,was identified as a JAK/STAT3 signaling inhibitor.Further studies identified that Pretrichodermamide B directly binds to STAT3,preventing phosphorylation and thus inhibiting JAK/STAT3 signaling.Moreover,it suppressed cancer cell growth,in vitro,at low micromolar concentrations and demonstrated efficacy in vivo by decreasing tumor growth in a xenograft mouse model.In addition,it was shown that Pretrichodermamide B was able to induce cell cycle arrest and promote cell apoptosis.This study demonstrated that Pretrichodermamide B is a novel STAT3 inhibitor,which should be considered for further exploration as a promising anti-cancer therapy.

Gut microbiota derived metabolites in cardiovascular health and disease

Trillions of microbes inhabit the human gut, not only providing nutrients and energy to the host from the ingested food, but also producing metabolic bioactive signaling molecules to maintain health and elicit dis- ease, such as cardiovascular disease （CVD）. CVD is the leading cause of mortality worldwide. In this review, we presented gut microbiota derived metabolites involved in cardiovascular health and disease, including trimethylamine-N-oxide （TMAO）, uremic toxins, short chain fatty acids （SCFAs）, phytoestrogens, antho- cyanins, bile acids and lipopolysaccharide. These gut microbiota derived metabolites play critical roles in maintaining a healthy cardiovascular function, and if dysregulated, potentially causally linked to CVD. A bet- ter understanding of the function and dynamics of gut microbiota derived metabolites holds great promise toward mechanistic predicative CVD biomarker discoveries and precise interventions.

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

Glioblastomas(GBMs)are highly lethal primary brain tumors.Despite current therapeutic advances in other solid cancers,the treatment of these malignant gliomas remains essentially palliative.GBMs are extremely resistant to conventional radiation and chemotherapies.We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells(GSCs)promotes therapeutic resistance.We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth,which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs.Furthermore,stem cell-like cancer cells(cancer stem cells)have been shown to promote metastasis.Although GBMs rarely metastasize beyond the central nervous system,these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection,and GSCs display an aggressive invasive phenotype.These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment.Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells,but also display critical distinctions that provide important clues into useful therapeutic targets.In this review,we summarize the current understanding and advances in glioma stem cell research,and discuss potential targeting strategies for future development of anti-GSC therapies.