Enforced E-selectin ligand installation enhances homing and efficacy of adoptively transferred T cells.

Adoptive T-cell transfer has revolutionized the treatment of hematological malignancies. However, this approach has had very limited success in treating solid tumors, largely due to inadequate infiltration of vascularly administered T cells at tumor sites. The shear-resistant interaction between endothelial E-selectin and its cognate ligand expressed on leukocytes, sialyl Lewis X (sLe), is an essential prerequisite for extravasation of circulating leukocytes.

Novel isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis.

Screening of the ChemDiv molecular library in cholesterol media against Mycobacterium tuberculosis (Mtb) H37Rv strain identified a novel isoxazole thiophene hit as a putative Rv1625c/Cya activator with a promising in vitro activity and good pharmacokinetic properties. Twenty-nine analogs were synthesized to assess the structure-activity relationships (SAR) to further improve potency. The most notable analog was P15, which showed an intramacrophage EC = 1.

Flunarizine as a Candidate for Drug Repurposing Against Human Pathogenic Mammarenaviruses.

Lassa fever (LF), a viral hemorrhagic fever disease with a case fatality rate that can be over 20% among hospitalized LF patients, is endemic to many West African countries. Currently, no vaccines or therapies are specifically licensed to prevent or treat LF, hence the significance of developing therapeutics against the mammarenavirus Lassa virus (LASV), the causative agent of LF. We used in silico docking approaches to investigate the binding affinities of 2015 existing drugs to LASV proteins known to play critical roles in the formation and activity of the virus ribonucleoprotein complex (vRNP) responsible for directing replication and transcription of the viral genome.

Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance.

The ongoing monkeypox (mpox) disease outbreak has spread to multiple countries in Central Africa and evidence indicates it is driven by a more virulent clade I monkeypox virus (MPXV) strain than the clade II strain associated with the 2022 global mpox outbreak, which led the WHO to declare this mpox outbreak a public health emergency of international concern. The FDA-approved small molecule antiviral tecovirimat (TPOXX) is recommended to treat mpox cases with severe symptoms, but the limited efficacy of TPOXX and the emergence of TPOXX resistant MPXV variants has challenged this medical practice of care and highlighted the urgent need for alternative therapeutic strategies. In this study we have used vaccinia virus (VACV) as a surrogate of MPXV to assess the antiviral efficacy of combination therapy of TPOXX together with mycophenolate mofetil (MMF), an FDA-approved immunosuppressive agent that we have shown to inhibit VACV and MPXV, or the N-myristoyltransferase (NMT) inhibitor IMP-1088.

Free radicals and their impact on health and antioxidant defenses: a review.

Free radicals, characterized by the presence of unpaired electrons, are highly reactive species that play a significant role in human health. These molecules can be generated through various endogenous processes, such as mitochondrial respiration and immune cell activation, as well as exogenous sources, including radiation, pollution, and smoking. While free radicals are essential for certain physiological processes, such as cell signaling and immune defense, their overproduction can disrupt the delicate balance between oxidants and antioxidants, leading to oxidative stress.

Consensus statement on the treatment of proximal humerus fractures: a Delphi approach by the Neer Circle of the American Shoulder and Elbow Surgeons.

Background: The treatment of patients who suffer a proximal humeral fracture (PHF) remains controversial. The purpose of this study was to find consensus among experts using a validated iterative process in the treatment of patients after a PHF.

Methods: The Neer Circle is an organization of shoulder experts recognized for their service to the American Shoulder and Elbow Surgeons.

The Songdo consensus: Development of minimum reporting standards for studies of intervention in idiopathic anal fistula using a modified nominal group technique.

Aim: Cryptoglandular anal fistulas carry a substantial burden to quality of life. Surgery is the only effective curative treatment but requires balancing fistula healing against pain, wounds and continence impairment. Sphincter-preserving procedures do exist but demonstrate variable rates of success.

RNase T2 deficiency promotes TLR13-dependent replenishment of tissue-protective Kupffer cells.

Lysosomal stress due to the accumulation of nucleic acids (NAs) activates endosomal TLRs in macrophages. Here, we show that lysosomal RNA stress, caused by the lack of RNase T2, induces macrophage accumulation in multiple organs such as the spleen and liver through TLR13 activation by microbiota-derived ribosomal RNAs. TLR13 triggered emergency myelopoiesis, increasing the number of myeloid progenitors in the bone marrow and spleen.

Comparisons of neurodegenerative disease biomarkers across different biological fluids from patients with Huntington's disease.

Fluid biomarkers play important roles in many aspects of neurodegenerative diseases, such as Huntington's disease (HD). However, a main question relates to how well levels of biomarkers measured in CSF are correlated with those measured in peripheral fluids, such as blood or saliva. In this study, we quantified levels of four neurodegenerative disease-related proteins, neurofilament light (NfL), total tau (t-tau), glial fibrillary acidic protein (GFAP) and YKL-40 in matched CSF, plasma and saliva samples from Huntingtin (HTT) gene-positive individuals (n = 21) using electrochemiluminescence assays.

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques.

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (β-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other β-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather than the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines.

Itaconate mechanism of action and dissimilation in .

Itaconate, an abundant metabolite produced by macrophages upon interferon-γ stimulation, possesses both antibacterial and immunomodulatory properties. Despite its crucial role in immunity and antimicrobial control, its mechanism of action and dissimilation are poorly understood. Here, we demonstrate that infection of mice with increases itaconate levels in lung tissues.

Burnt Plastic (Pyroplastic) from the M/V Ship Fire and Plastic Spill Contain Compounds That Activate Endocrine and Metabolism-Related Human and Fish Transcription Factors.

In May 2021, the M/V ship fire disaster led to the largest maritime spill of resin pellets (nurdles) and burnt plastic (pyroplastic). Field samples collected from beaches in Sri Lanka nearest to the ship comprised nurdles and pieces of pyroplastic. Three years later, the toxicity of the spilled material remains unresolved.

Understanding the Glycosylation Pathways Involved in the Biosynthesis of the Sulfated Glycan Ligands for Siglecs.

Carbohydrate sulfation plays a pivotal role in modulating the strength of Siglec-glycan interactions. Recently, new aspects of Siglec binding to sulfated cell surface carbohydrates have been discovered, but the class of glycan presenting these sulfated Siglec ligands has not been fully elucidated. In this study, the contribution of different classes of glycans to and Siglec ligands was investigated within cells expressing the carbohydrate sulfotransferase 1 (CHST1) or CHST2.

Proximity based proteomics reveals Git1 as a regulator of Smoothened signaling.

The GPCR-like protein Smoothened (Smo) plays a pivotal role in the Hedgehog (Hh) pathway. To initiate Hh signaling, active Smo binds to and inhibits the catalytic subunit of PKA in the primary cilium, a process facilitated by G protein-coupled receptor kinase 2 (Grk2). However, the precise regulatory mechanisms underlying this process, as well as the events preceding and following Smo activation, remain poorly understood.

The Q226L mutation can convert a highly pathogenic H5 2.3.4.4e virus to bind human-type receptors.

H5Nx viruses continue to wreak havoc in avian and mammalian species worldwide. The virus distinguishes itself by the ability to replicate to high titers and transmit efficiently in a wide variety of hosts in diverse climatic environments. Fortunately, transmission to and between humans is scarce.

Tissue-specific modulation of NADH consumption as an anti-aging intervention in Drosophila.

Aging is characterized by extensive metabolic dysregulation. Redox coenzyme nicotinamide adenine dinucleotide (NAD) can exist in oxidized (NAD) or reduced (NADH) states, which together form a key NADH/NAD redox pair. Total levels of NAD decline with age in a tissue-specific manner, thereby playing a significant role in the aging process.

Syngap1 promotes cognitive function through regulation of cortical sensorimotor dynamics.

Perception, a cognitive construct, emerges through sensorimotor integration (SMI). The genetic mechanisms that shape SMI required for perception are unknown. Here, we demonstrate in mice that expression of the autism/intellectual disability gene, Syngap1, in cortical excitatory neurons is required for the formation of somatomotor networks that promote SMI-mediated perception.

Anti-immune complex antibodies are elicited during repeated immunization with HIV Env immunogens.

Vaccination strategies against HIV-1 aim to elicit broadly neutralizing antibodies (bnAbs) using prime-boost regimens with HIV envelope (Env) immunogens. Epitope mapping has shown that early antibody responses are directed to easily accessible nonneutralizing epitopes on Env instead of bnAb epitopes. Autologously neutralizing antibody responses appear upon boosting, once immunodominant epitopes are saturated.

Targeting CD45 by gene-edited CAR T cells for leukemia eradication and hematopoietic stem cell transplantation preconditioning.

Hematopoietic stem cell transplantation (HSCT) is widely used to treat patients with life-threatening hematologic and immune system disorders. Current nontargeted chemo-/radiotherapy conditioning regimens cause tissue injury and induce an array of immediate and delayed adverse effects, limiting the application of this life-saving treatment. The growing demand to replace canonical conditioning regimens has led to the development of alternative approaches, such as antibody-drug conjugates, naked antibodies, and CAR T cells.

Harnessing Multi-Center-2-Electron Bonds for Carbene Metal-Hydride Nanocluster Catalysis.

N-Heterocyclic carbene (NHC) ligands possess the ability to stabilize metal-based nanomaterials for a broad range of applications. With respect to metal-hydride nanomaterials, however, carbenes are rare, which is surprising if one considers the importance of metal-hydride bonds across the chemical sciences. In this study, we introduce a bottom-up approach leveraging preexisting metal-metal m-center-n-electron (mc-ne) bonds to access a highly stable cyclic(alkyl)amino carbene (CAAC) copper-hydride nanocluster, [(CAAC)6Cu14H12][OTf]2 with superior stability compared to Stryker's reagent, a popular commercial phosphine-based copper hydride catalyst.

Synthesis of Chiral Saturated Heterocycles Bearing Quaternary Centers via Enantioselective β-C(sp)-H Activation of Lactams.

The development of catalytic methods for the synthesis of enantiopure saturated heterocycles has been a long-standing challenge in asymmetric catalysis. We describe the first highly enantioselective palladium-catalyzed βC(sp)-H arylation and olefination of lactams for the preparation of various chiral N-heterocycles bearing quaternary carbon centers. The presence of strongly electron-withdrawing groups on the chiral bifunctional MPAThio ligand is crucial to the reactivity of weakly coordinating lactams.

Daily sleep and physical activity from accelerometry in adults: Temporal associations and lag effects.

Objectives: Insufficient sleep is linked to various health issues, while physical activity is a protective measure against chronic diseases. Despite the importance of sleep and physical activity for supporting public health, there remains scant research investigating daily and cumulative associations between objectively measured physical activity and sleep. Understanding the associations of physical activity and sleep behaviors over multiple days may inform the efficacy of interventions to synergistically support both behaviors.

Spatial covariance reveals isothiocyanate natural products adjust redox stress to restore function in alpha-1-antitrypsin deficiency.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is a monogenic disease caused by misfolding of AAT variants resulting in gain-of-toxic aggregation in the liver and loss of monomer activity in the lung leading to chronic obstructive pulmonary disease (COPD). Using high-throughput screening, we discovered a bioactive natural product, phenethyl isothiocyanate (PEITC), highly enriched in cruciferous vegetables, including watercress and broccoli, which improves the level of monomer secretion and neutrophil elastase (NE) inhibitory activity of AAT-Z through the endoplasmic reticulum (ER) redox sensor protein disulfide isomerase (PDI) A4 (PDIA4). The intracellular polymer burden of AAT-Z can be managed by combination treatment of PEITC and an autophagy activator.