Soluble p75 neurotrophic receptor as a reliable biomarker in neurodegenerative diseases: what is the evidence?

Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve development and maturation.Its cleavable extracellular domain(ECD)is readily detectable in various biological fluids including plasma,serum and urine.There is evidence for increased p75NTR ECD levels in neurodegenerative diseases such as Alzheimer’s disease,amyotrophic lateral sclerosis,age-related dementia,schizophrenia,and diabetic neuropathy.Whether p75^(NTR) ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders,and whether it could potentially lead to the development of targeted therapies,remains an open question.In this review,we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases.We also highlight areas that require further investigation to better understand the role of p75^(NTR) ECD in the clinical diagnosis and management of neurodegenerative disorders.

Genetic identification and reiterated captures suggest that the Astyanax mexicanus El Pachón cavefish population is closed and declining

The sizes of Astyanax mexicanus blind cavefish populations of North-East Mexico are demographic parameters of great importance for investigating a variety of ecological,evolutionary,and conservation issues.However,few estimates have been obtained.For these mobile animals living in an environment difficult to explore as a whole,methods based on capture-mark-recapture are appropriate,but their feasibility and interpretation of results depend on several assumptions that must be carefully examined.Here,we provide evidence that minimally invasive genetic identification from captures at different time intervals(three days and three years)can give insights into cavefish population size dynamics as well as other important demographic parameters of interest.We also provide tools to calibrate sampling and genotyping efforts necessary to reach a given level of precision.Our results suggest that the El Pachón cave population is currently very small,of an order of magnitude of a few hundreds of individuals,and is distributed in a relatively isolated area.The probable decline in population size in the El Pachón cave since the last census in 1971 raises serious conservation issues.

Dental impact of anti-fibroblast growth factor 23 therapy in X-linked hypophosphatemia

Elevated fibroblast growth factor 23(FGF23)in X-linked hypophosphatemia(XLH)results in rickets and phosphate wasting,manifesting by severe bone and dental abnormalities.Burosumab,a FGF23-neutralizing antibody,an alternative to conventional treatment(phosphorus and active vitamin D analogs),showed significant improvement in the long bone phenotype.Here,we examined whether FGF23 antibody(FGF23-mAb)also improved the dentoalveolar features associated with XLH.Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg−1 of FGF23-mAb for 2 months and compared to wild-type(WT)and vehicle(PBS)treated Hyp mice(n=3–7 mice).Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice,the higher concentration resulting in a rescue similar to WT levels.FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones.Histology revealed improved mineralization of the dentoalveolar tissues,with a decreased amount of osteoid,predentin and cementoid.Better periodontal ligament attachment was also observed,evidenced by restoration of the acellular cementum.These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features.Taken together,our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment,heralding its benefit in clinics for dental abnormalities.

Involvement of toll-like receptor 5 in mouse model of colonic hypersensitivity induced by neonatal maternal separation

BACKGROUND Chronic abdominal pain is the most common cause for gastroenterology consultation and is frequently associated with functional gastrointestinal disorders including irritable bowel syndrome and inflammatory bowel disease. These disorders present similar brain/gut/microbiota trialogue alterations, associated with abnormal intestinal permeability, intestinal dysbiosis and colonic hypersensitivity(CHS). Intestinal dysbiosis can alter colon homeostasis leading to abnormal activation of the innate immunity that promotes CHS, perhaps involving the toll-like receptors(TLRs), which play a central role in innate immunity.AIM To understand the mechanisms between early life event paradigm on intestinal permeability, fecal microbiota composition and CHS development in mice with TLRs expression in colonocytes.METHODS Maternal separation model(NMS) CHS model, which mimics deleterious events in childhood that can induce a wide range of chronic disorders during adulthood were used. Colonic sensitivity of NMS mice was evaluated by colorectal distension(CRD) coupled with intracolonic pressure variation(IPV) measurement. Fecal microbiota composition was analyzed by 16S rRNA sequencing from weaning to CRD periods. TLR mRNA expression was evaluated in colonocytes.Additionally, the effect of acute intrarectal instillation of the TLR5 agonist flagellin(FliC) on CHS in adult naive wildtype mice was analyzed.RESULTS Around 50% of NMS mice exhibited increased intestinal permeability and CHS associated with intestinal dysbiosis, characterized by a significant decrease of species richness, an alteration of the core fecal microbiota and a specific increased relative abundance of flagellated bacteria. Only TLR5mRNA expression was increased in colonocytes of NMS mice with CHS. Acute intrarectal instillation of FliC induced transient increase of IPV, reflecting transient CHS appearance.CONCLUSION Altogether, these data suggest a pathophysiological continuum between intestinal dysbiosis and CHS, with a role for TLR5.

A level line of the Gaussian free field with measure-valued boundary conditions

In this article, we construct samples of Schramm-Loewner-evolution-like curves out of samples ofthe conformal loop ensemble and Poisson point processes of Brownian excursions. We show that the laws of thesecurves depend continuously on the intensity measure of the Brownian excursions. Using such a construction ofcurves, we extend the notion of level lines of the Gaussian free field to the case where the boundary conditionis measure-valued.

Diabetes and pulmonary infection:how hyperglycaemia shapes the immune system

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.

Lipid-derived radical-trapping antioxidants suppress ferroptosis

Ferroptosis,characterized by lipid peroxidation-mediated cell demise,is governed by a nuanced interplay of lipid species influencing its vulnerability.Two recent publications in Nature discovered 7-dehydrocholesterol,a cholesterol precursor,as a radical-trapping antioxidant that can suppress ferroptosis,thereby presenting a novel metabolic target to improve ferroptosis-related cancer therapy.

Protein-S-100-beta is increased in patients with decompensated cirrhosis admitted to ICU

Background Hepatic encephalopathy(HE)is highly prevalent in patients with liver diseases.The pathophysiology of HE is centered on the synergic role of hyperammonemia and systemic inflammation.However,some data suggest altered functioning of the blood–brain barrier(BBB).Assessing BBB function is challenging in clinical practice and at the bedside.Protein-S-100 Beta(PS100-Beta)could be a useful peripheral marker of BBB permeability in HE.This study aimed to assess plasmatic PS100-Beta levels in a prospective cohort of patients admitted to the intensive care unit(ICU)with decompensated cirrhosis with and without overt HE.Methods We retrospectively evaluated a prospective cohort of cirrhotic patients admitted to the ICU from October 2013 to September 2015 that had an available plasmatic PS100-Beta measurement.Patients with previous neurological impairment or limitation of intensive or resuscitative measures were excluded.Overt HE was defined as West-Haven grades 2 to 4.The patients were compared to a control cohort of outpatient clinic cirrhotic and non-cirrhotic patients explored for isolated elevation of liver enzymes.After ICU discharge,the patients were followed for at least 3 months for the occurrence of overt HE.Adverse outcomes(liver transplantation or death)were collected.The ability of PS100-Beta–in combination with other factors–to predict overt HE was evaluated in a multivariate analysis using logistic regression.Likelihood ratios were used to determine the effects and calculate odds ratios(OR).Survival analysis was performed by using the Kaplan–Meier method and survival between groups was compared using a Log-rank test.Results A total of 194 ICU patients and 207 outpatients were included in the study.Increased levels of plasmatic PS100-Beta were detected in the ICU decompensated cirrhotic patients compared with the outpatients([0.15±0.01]mg/L vs.[0.08±0]mg/L,P<0.001).ICU patients with overt HE had higher levels of PS100-Beta([0.19±0.03]mg/L)compared with the ICU patients without overt HE([0.13±0.01]mg/L)(P=0.003).PS100-Beta levels did not differ in outpatients with F 0–3 compared to F 4 fibrosis(P=0.670).PS100-Beta values were correlated with Child-Pugh score(P<0.001),Model for End-Stage Liver Disease(MELD)score(P=0.004),C-reactive protein(P<0.001),ammonemia(P<0.001),and chronic liver failure consortium(CLIF-C)organ failure(P<0.001)and CLIF-C acute-on-chronic(P=0.038)scores,but not with leukocytes(P=0.053),procalcitonin(PCT)(P=0.107),or the lymphocyte-to-neutrophil ratio in ICU patients(P=0.522).In a multivariate model including age,ammonemia,PS100-Beta,PCT,MELD,presence of transjugular portosystemic shunt,and sodium level,the diagnostic performance was 0.765 for the diagnosis of overt HE.Patients with a PS100-Beta level<0.12 mg/L had a better overall survival(P=0.019)and a better survival without liver transplantation(P=0.013).Conclusions Serum levels of PS100-Beta are elevated in ICU patients with decompensated cirrhosis,and even more so in those displaying overt HE,and the levels are correlated with outcome.This suggests an increase in the permeability of the BBB in these patients.

Targeted therapy for capillary-venous malformations

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK,an endothelial transmembrane receptor signaling through PIK3CA.Venous malformations are associated with pain,bleedings,thrombosis,pulmonary embolism,esthetic deformities and,in severe cases,life-threatening situations.No authorized medical treatment exists for patients with venous malformations.Here,we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes.We showed that these malformations only partially signal through AKT proteins.We compared the efficacy of different drugs,including rapamycin,a mTORC1 inhibitor,miransertib,an AKT inhibitor and alpelisib,a PI3Kαinhibitor at improving the lesions seen in the mouse model.We demonstrated the effectiveness of alpelisib in preventing vascular malformations’occurrence,improving the already established ones,and prolonging survival.Considering these findings,we were authorized to treat 25 patients with alpelisib,including 7 children displaying PIK3CA(n=16)or TEK(n=9)-related capillary venous malformations resistant to usual therapies including sirolimus,debulking surgical procedures or percutaneous sclerotherapies.We assessed the volume of vascular malformations using magnetic resonance imaging(MRI)for each patient.Alpelisib demonstrated improvement in all 25 patients.Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated.MRI showed a decrease of 33.4%and 27.8%in the median volume of PIK3CA and TEK malformations respectively,over 6 months on alpelisib.In conclusion,this study supports PI3Kαinhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

超慢速扩张西南印度洋中脊硫化物成矿模型

洋中脊多金属硫化物已经成为人类重要的战略资源,科学的成矿模型是对其调查研究和勘探的重要依据.相较快速、慢速扩张洋中脊,超慢速扩张洋中脊在岩浆供给、构造和围岩等特征均存在明显差异,但目前对其热液循环及硫化物成矿模型缺乏系统梳理,制约了其资源勘探评价与研究的有效进程.本文系统总结了超慢速扩张西南印度洋中脊热液活动分布以及典型热液区的构造、热源、热液通道、围岩类型、流体性质和硫化物等特征,根据其成矿地质背景的差异性特点将该洋中脊赋存的热液系统分为局部强岩浆控制型、单向拆离/高角度大偏移距断层控制型以及双向拆离控制型三类,根据岩浆供给率(M值)的大小进一步将其划分为五种类型,从而建立了超慢速扩张西南印度洋中脊的局部强热供给-深大断裂控制硫化物成矿模型.超慢速扩张西南印度洋中脊扩张速率整体变化不大(14~18mm/a),岩浆供给呈分段不均匀性.通过近20年的调查研究,发现其发育类型多样的热液系统和硫化物.在岩浆供给充足的洋脊段,发育局部强岩浆供给条件下的深部岩浆房(4~9km).而在岩浆供给贫瘠的洋脊段,发育长期持续活动的深大拆离断层(可达13km),并沿拆离断层形成成矿带.因而超慢速扩张洋脊具备形成大型多金属硫化物矿床所需的持续热源和稳定热液通道的必要条件.已调查区探测到的热液活动区数量是传统扩张速率-岩浆通量模型预测的2~3倍,具有良好的硫化物资源前景.洋中脊热液循环系统的类型、循环深度、热液活动沿轴发育频率以及硫化物成矿规模可能是岩浆供给和构造活动均衡贡献的结果.通常认为扩张速率控制着热源、岩浆供给和构造过程.对于超慢速扩张西南印度洋中脊,本文认为局部强热供给和深大断裂构造是其热液循环和硫化物成矿更直接的控制因素.局部强热供给-深大断裂控制的硫化物成矿模型有望为超慢速扩张西南印度洋中脊多金属硫化物的勘探与成矿研究提供指示.

Roles of macrophages in tumor development: a spatiotemporalperspective

Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In bothprimary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we knowthat TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just beingunraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized rolesassociated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enablethe growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth.Finally, we speculate on the challenges that remain to be overcome in TAM research.

Sulfide metallogenic model for the ultraslow-spreading Southwest Indian Ridge

Polymetallic sulfides present in mid-ocean ridges(MORs)have become important strategic resources for humans,and a scientific metallogenic model is necessary for the investigation and exploration of these resources.Compared to fast-and slow-spreading MORs,ultraslow-spreading MORs show substantial differences in magma supply,tectonic activity,and oceanic crust structures.However,information on hydrothermal circulation and a metallogenic model related to sulfides along the ultraslow-spreading ridges is still limited,which hinders further exploration of these resources.In this study,the distribution of hydrothermal activities,as well as the characteristics of the structures,heat sources,fluid pathways,host rock types,fluid properties,and sulfide assemblages in typical hydrothermal fields along the ultraslow-spreading Southwest Indian Ridge(SWIR),have been studied.It is concluded that the hydrothermal systems along the SWIR can be categorized into three types,including local enhanced magma-controlled,one-way detachment/high-angle large-offset fault-controlled,and flip-flop detachment-controlled types,which are further categorized into five subtypes based on their distinct geological backgrounds.Herein,we present a sulfide metallogenic model called Local Enhanced Heat Supply-Deep Faults(eHeat-dFault)for the SWIR.The overall spreading rate remains almost constant(14-18 mm/year),while the magma supply is heterogeneous in the segment scale along the SWIR.Over the past two decades,various hydrothermal systems and sulfide deposits have been identified along the SWIR.A deep magma chamber(4-9 km)is developed in the ridge segment with sufficient magma supply owing to the local enhanced magma supply,while long-lived active deep detachment faults(up to 13 km)with associated metallogenic belts are developed in ridge segments with poor magma supply.Hence,the ultraslow-spreading MORs fulfill the necessary conditions of a sustained heat source and stable hydrothermal pathway for the formation of large-scale polymetallic sulfide deposits.The number of hydrothermal fields detected in the investigation area is 2-3 times that predicted by the traditional Spreading Rate-Magma Flux model,demonstrating its significant endowment for sulfide resources.A balance between magma supply and faulting may influence the type and depth of hydrothermal circulation,the frequency of hydrothermal activity along the axis,and the scale of sulfide deposits.Spreading rate was previously believed to control heat sources,magma supply,and tectonic processes.However,for the SWIR,we suggest that local enhanced heat supply and deep detachment faults have a greater influence than the spreading rate on hydrothermal circulation and sulfide mineralization.The eHeat-dFault sulfide metallogenic model proposed herein could provide guidance for further exploration and research on polymetallic sulfides in ultraslow-spreading SWIR.

Immature and mature antibodies as defenders against cancer

Antibodies(Abs)are glycoprotein molecules that represent an essential component of the adaptative immune response.They are secreted in body fluids and act as a critical part of immune defense.Although recognition of self-antigens by Abs is normally selected against during B-cell development,autoreactive Abs can be generated as a result of pathological immune responses,as observed in autoimmune diseases.Autoantibodies can also be produced in cancer patients,where they may have beneficial roles[1].Indeed,the presence of intratumoral antibody-secreting cells(ASCs)and B-cell-rich tertiary lymphoid structures(TLSs)has been observed in many cancer types and generally correlates with a favorable clinical prognosis[2,3,4,5,6].The existence of specific antitumor antibody responses suggests that tumor cells express molecules that are recognized as nonself antigens by the immune system or that tolerance of self-antigens expressed on cancer cells is lost[1,4].The study of the origin of tumor-reactive Abs and their specificity and functions is of paramount importance for understanding the development of adaptive antitumor immune responses and for revealing novel therapeutic avenues.A recent publication in Cell by Mazor et al.[7]has provided an important advance in our understanding of antibody responses in cancer.In particular,this work paves the way for the distinction between antibody-reactive tumors and antibody-nonreactive tumors,which is reminiscent of the dichotomy of the noninfiltrated“cold”tumor microenvironment(TME)in contrast with the highly infiltrated with immune cells“hot”TME[8].Moreover,an important finding of the study was the demonstration that tumor-directed autoreactivity may be either preexisting or induced by somatic hypermutations,a mechanism related to the chronicity of cancer.

High-density single antibody electrochemical nanoarrays

The fabrication and electrochemical interrogation of very high density single-antibody nanoarrays is reported.Gold nanodots,15 nm in diameter,arranged in large(cm2)square arrays with a pitch of 200 nm,are used as carriers for primary antibodies(immunoglobulin G(IgG)),further recognized by secondary redox-labeled detection antibodies.Ensemble scale interrogation of the antibody array by cyclic voltammetry,and nanoscale interrogation of individual nanodots by mediator tethered atomic forcescanning electrochemical microscopy(Mt/AFM-SECM),enable the occupancy of nanodots by single antibody molecules to be demonstrated.Experiments involving the competitive adsorption of antibodies of different species onto the nanodots evidence the possibility of using single-antibody nanoarrays for digital electrochemical immunoassays.

Two-photon photopolymerization directly initiated by spiropyran photochromic molecules

Here,we report the ability of spiropyrans to initiate two-photon polymerization(TPP)for the first time in the literature.The comparison and synergies between the spiropyran photochromic molecule of interest,namely 6-nitro-BIPS,and well-known photoinitiators of radical photopolymerization have been studied.The spiropyran(SPy)molecule can initiate TPP in the presence of trifunctional acrylic monomers and create true 3D structures.The comparison with Irgacure 819,a well-known Type-I photoinitiator,shows that SPy has a comparable capability for TPP.In addition,the combination of SPy with methyl diethanolamine increased the reactivity of both one-and two-photon polymerizations.In the last section,we discuss which SPy isomer is the active photochromic species capable of generating radicals for initiating two-photon polymerization.

Persistent X-ray-activated phosphors:mechanisms and applications

Trivalent lanthanides in wide bandgap fluoride or phosphate hosts can present persistent luminescence between 200 nm and 1.7 μm after charging by X-rays.Mechanisms are reviewed and applications envisioned.

HIV-induced membraneless organelles orchestrate post-nuclear entry steps

HIV integration occurs in chromatin sites that favor the release of high levels of viral progeny;alternatively, the virus is alsoable to discreetly coexist with the host. The viral infection perturbs the cellular environment inducing the remodelling of thenuclear landscape. Indeed, HIV-1 triggers the nuclear clustering of the host factor CPSF6, but the underlying mechanism ispoorly understood. Our data indicate that HIV usurps a recently discovered biological phenomenon, called liquid–liquid phaseseparation, to hijack the host cell. We observed CPSF6 clusters as part of HIV-induced membraneless organelles (HIV-1 MLOs) inmacrophages, one of the main HIV target cell types. We describe that HIV-1 MLOs follow phase-separation rules and representfunctional biomolecular condensates. We highlight HIV-1 MLOs as hubs of nuclear reverse transcription, while the double-strandedviral DNA, once formed, rapidly migrates outside these structures. Transcription-competent proviruses localize outside but nearHIV-1 MLOs in LEDGF-abundant regions, known to be active chromatin sites. Therefore, HIV-1 MLOs orchestrate viral events priorto the integration step and create a favorable environment for the viral replication. This study uncovers single functional host–viralcomplexes in their nuclear landscape, which is markedly restructured by HIV-1.

A numerical method to predict the membrane tension distribution of spreading cells based on the reconstruction of focal adhesions

Changes in membrane tension significantly affect the physiological functions of cells in various ways.However,directly measuring the spatial distribution of membrane tension remains an ongoing issue.In this study,an algorithm is proposed to determine the membrane tension inversely by executing a particle-based method and searching for the minimum deformation energy based on the cell images and focal adhesions.A standard spreading cell model is established using 3D reconstructions with images from structured illumination microscopy as the reference cell shape.The membrane tension distribution,forces across focal adhesions,and profile of the spread cell are obtained using this method,until the cell deformation energy function optimization converges.Qualitative and quantitative comparisons with previous experimental results validated the reliability of this method.The results show that in the standard spreading cell model,the membrane tension decreases from the bottom to the top of the membrane.This method can be applied to predict the membrane tension distribution of cells freely spreading into different shapes,which could improve the quantitative analysis of cellular membrane tension in various studies for cell mechanics.

T-lymphoid progenitor-based immunotherapies:clinical perspectives for one and all

Commentary of Moirangthem,R.D.,Ma,K.,Lizot,S.et al.A DL-4-and TNFα-based culture system to generate high numbers of non-modified or genetically modified immunotherapeutic human T-lymphoid progenitors.Cell Mol Immunol 18,1662–1676(2021).

Recent advances in electrochemiluminescence imaging analysis

Electrochemiluminescence(ECL)has been widely applied in imaging owing to features that distinguish it from other microscopic techniques and electrochemical methods,including its high signal-to-noise ratio,remarkable sensitivity,wide linear range,high spatiotemporal resolution,and near-zero background light.Imaging technology based on ECL has been used in the fields of immunosensing,pathological cell detection,and drug analysis.Additionally,its simple operation and ability to detect dynamic processes and catalytic sites strengthen its potential for research on material surfaces and interfaces,in vivo biological analysis,and cell visualization.At the same time,the emergence of a variety of nanomaterials and new microscopic analysis equipment has further promoted the development of high-resolution ECL imaging technology.This paper introduces the development of ECL technology and the mechanisms of the main ECL systems.It then describes various forms of ECL imaging methods,and reviews research progress on ECL imaging technology in the fields of single-particle imaging,fingerprint structure analysis,and single-cell microscopic imaging.Finally,the authors offer their views about the prospects for ECL imaging technology.