New unexpected role for Wolfram Syndrome protein WFS1:a novel therapeutic target for Alzheimer’s disease?

Selective vulnerability of excitatory neurons in Alzheimer’s disease(AD):AD is the most common form of dementia;however,the pathogenesis of AD is largely unknown.One of the characteristic features of AD is the formation of intracellular neurofibrillary tangles(NFTs).NFTs are abnormal accumulates of misfolded tau protein,which may eventually cause neuronal death and neurodegeneration(Jack et al.,2018).In the early stages of AD progression,not all neurons are equally vulnerable to tau aggregates.Previous studies have shown that large pyramidal neurons in the entorhinal cortex(EC)are specifically vulnerable to pathological tau accumulation(Fu et al.,2017).This selective vulnerability of excitatory neurons to tau pathology is one of the fundamental questions needed to be answered in AD research.

Targeting and exploitation of tumor-associated neutrophils to enhance immunotherapy and drug delivery for cancer treatment

Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-associated neutrophils(TAN)are classified into anti-tumor N1 and pro-tumor N2 subsets.One of the major mechanisms underlying the tumor-promoting function of N2-TANs is suppression of adaptive immune cells,in particular,cytotoxic T lymphocytes.Currently,no established methodologies are available that can unequivocally distinguish immunosuppressive TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells(G/PMN-MDSC).In view of the critical role of PMN-MDSCs in immune evasion and resistance to cancer immunotherapy,as established from data obtained with diverse cancer models,therapeutic strategies targeting these cells have been actively developed to enhance the efficacy of immunotherapy.Here,we have reviewed the available literature on strategies targeting PMN-MDSCs and summarized the findings into four categories:(1)depletion of existing PMN-MDSCs,(2)blockade of the development of PMNMDSCs,(3)blockade of PMN-MDSC recruitment,(4)inhibition of immunosuppressive function.Owing to their high mobility to inflamed organs and ability to trespass the blood-brain barrier,neutrophils are outstanding candidate carriers in nanoparticle-based therapies.Another attractive application of neutrophils in cancer therapy is the use of neutrophil membrane-derived nanovesicles as a surrogate of extracellular vesicles for more efficient and scalable drug delivery.In the second part of the review,we have highlighted recent advances in the field of neutrophil-based cancer drug delivery.Overall,we believe that neutrophil-based therapeutics are a rapidly growing area of cancer therapy with significant potential benefits.

Interactions of primary insult biomechanics and secondary cascades in spinal cord injury： implications for therapy

The complex and variable nature of traumatic spinal cord inju- ry （SCI） presents a unique challenge for translational research. SCI is not bound by any demographic nor is it limited to specific injury biomechanics.

Cancer-cell-intrinsic mechanisms shaping the immunosuppressive landscape of prostate cancer

Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy.This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer.Therefore,it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment.Here,we review recent findings that reveal the roles of the genetic alterations,androgen receptor signaling,cancer cell plasticity,and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance.Based on preclinical and clinical observations,a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.

McSNAC:A software to approximate first-order signaling networks from mass cytometry data

Background:Mass cytometry(CyTOF)gives unprecedented opportunity to simultaneously measure up to 40 proteins in single cells,with a theoretical potential to reach 100 proteins.This high-dimensional single-cell information can be very useful in dissecting mechanisms of cellular activity.In particular,measuring abundances of signaling proteins like phospho-proteins can provide detailed information on the dynamics of single-cell signaling processes.However,computational analysis is required to reconstruct such networks with a mechanistic model.Methods:We propose our Mass cytometry Signaling Network Analysis Code(McSNAC),a new software capable of reconstructing signaling networks and estimating their kinetic parameters from CyTOF data.McSNAC approximates signaling networks as a network of first-order reactions between proteins.This assumption often breaks down as signaling reactions can involve binding and unbinding,enzymatic reactions,and other nonlinear constructions.Furthermore,McSNAC may be limited to approximating indirect interactions between protein species,as cytometry experiments are only able to assay a small fraction of protein species involved in signaling.Results:We carry out a series of in silico experiments here to show(1)McSNAC is capable of accurately estimating the ground-truth model in a scalable manner when given data originating from a first-order system;(2)McSNAC is capable of qualitatively predicting outcomes to perturbations of species abundances in simple second-order reaction models and in a complex in silico nonlinear signaling network in which some proteins are unmeasured.Conclusions:These findings demonstrate that McSNAC can be a valuable screening tool for generating models of signaling networks from time-stamped CyTOF data.

Targeted PERK inhibition with biomimetic nanoclusters confers preventative and interventional benefits to elastase-induced abdominal aortic aneurysms

Abdominal aortic aneurysm(AAA)is a progressive aortic dilatation,causing~80%mortality upon rupture.Currently,there is no approved drug therapy for AAA.Surgical repairs are invasive and risky and thus not recommended to patients with small AAAs which,however,account for~90%of the newly diagnosed cases.It is therefore a compelling unmet clinical need to discover effective non-invasive strategies to prevent or slow down AAA progression.We contend that the first AAA drug therapy will only arise through discoveries of both effective drug targets and innovative delivery methods.There is substantial evidence that degenerative smooth muscle cells(SMCs)orchestrate AAA pathogenesis and progression.In this study,we made an exciting finding that PERK,the endoplasmic reticulum(ER)stress Protein Kinase R-like ER Kinase,is a potent driver of SMC degeneration and hence a potential therapeutic target.Indeed,local knockdown of PERK in elastase-challenged aorta significantly attenuated AAA lesions in vivo.In parallel,we also conceived a biomimetic nanocluster(NC)design uniquely tailored to AAA-targeting drug delivery.This NC demonstrated excellent AAA homing via a platelet-derived biomembrane coating;and when loaded with a selective PERK inhibitor(PERKi,GSK2656157),the NC therapy conferred remarkable benefits in both preventing aneurysm development and halting the progression of pre-existing aneurysmal lesions in two distinct rodent models of AAA.In summary,our current study not only establishes a new intervention target for mitigating SMC degeneration and aneurysmal pathogenesis,but also provides a powerful tool to facilitate the development of effective drug therapy of AAA.

Advances on the biosynthesis of pyridine rings

Numerous studies have investigated the biosynthesis of pyridine heterocycles derived from nicotinic acid.How-ever,metabolic pathways generating pyridine heterocycles in nature remain uninvestigated.Here,we summarize recent contributions conducted in the last decade on the biosynthetic pathways of non-derivate from nicotinic acid pyridine rings and discuss their implication on the study of natural products with pyridine structures.

Nano functional neural interfaces

Engineered functional neural interfaces （fNIs） serve as essential abiotic-biotic transducers between an engineered system and the nervous system. They convert external physical stimuli to cellular signals in stimulation mode or read out biological processes in recording mode. Information can be exchanged using electricity, light, magnetic fields, mechanical forces, heat, or chemical signals. fNIs have found applications for studying processes in neural circuits from cell cultures to organs to whole organisms, fNI-facilitated signal transduction schemes, coupled with easily manipulable and observable external physical signals, have attracted considerable attention in recent years. This enticing field is rapidly evolving toward miniaturization and biomimicry to achieve long-term interface stability with great signal transduction efficiency. Not only has a new generation of neuroelectrodes been invented, but the use of advanced fNIs that explore other physical modalities of neuromodulation and recording has begun to increase. This review covers these exciting developments and applications of fNIs that rely on nanoelectrodes, nanotransducers, or bionanotransducers to establish an interface with the nervous system. These nano fNIs are promising in offering a high spatial resolution, high target specificity, and high communication bandwidth by allowing for a high density and count of signal channels with minimum material volume and area to dramatically improve the chronic integration of the fNI to the target neural tissue. Such demanding advances in nano fNIs will greatly facilitate new opportunities not only for studying basic neuroscience but also for diagnosing and treating various neurological diseases.