PD-1 expressing islet-specific CD4 T cells promote bystander tolerance and prevent autoimmunity.

Loss of T-cell tolerance to multiple islet antigens is a key feature of autoimmune type 1 diabetes. In this study, we investigated the requirement for programmed death 1 (PD-1) expression by CD4 T cells in the maintenance of self-tolerance via bystander suppression of autoreactive CD8 T cells using nonobese diabetic mice. We used CRISPR/Cas9 to selectively knockout PD-1 in islet antigen-specific BDC2.

Aging and Aging-Related Senescence in Liver.

Aging is characterized by the progressive deterioration of cell and tissue functions. The liver, which regulates metabolic homeostasis, detoxification, and immune responses, undergoes structural and functional changes with age. These include increasing genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing and intracellular communication, mitochondrial dysfunction, cell senescence, stem cell exhaustion, chronic inflammation, disabled macroautophagy, and dysbiosis.

DHCR7 inhibition ameliorates MetALD and HCC in mice and human 3D liver spheroids.

Background & Aims: Metabolic dysfunction and alcohol-associated liver disease (MetALD) results in the development of liver steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). lipogenesis and cholesterol synthesis play an important role in the pathogenesis of MetALD. DHCR7 (7-dehydrocholesterol reductase) regulates the last stages of cholesterol production.

Polyacrylamide Hydrogels with Reversibly Photocontrolled Stiffness for 2D Mechanobiology.

We report the development of polyacrylamide hydrogels with photoswitchable stiffness using solely visible light and their application to cell culture. We have previously shown that azobenzenes can control the binding constants of dynamic covalent boronic ester bonds (. , , 5987; .

SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome.

Type 1 diabetes (T1D) is linked to an altered gut microbiota characterized by reduced short-chain fatty acid (SCFA) production. Oral delivery of a SCFA-yielding biotherapy in adults with T1D was followed by increased SCFAs, altered gut microbiota and immunoregulation, as well as delaying diabetes in preclinical models. Here, we show that SCFA-biotherapy in humans is accompanied by remodeling of the gut proteome and mucosal immune homeostasis.

Serum amyloid P (PTX2) attenuates hepatic fibrosis in mice by inhibiting the activation of fibrocytes and HSCs.

Background: Liver fibrosis is caused by chronic toxic or cholestatic liver injury. Fibrosis results from the recruitment of myeloid cells into the injured liver, the release of inflammatory and fibrogenic cytokines, and the activation of myofibroblasts, which secrete extracellular matrix, mostly collagen type I. Hepatic myofibroblasts originate from liver-resident mesenchymal cells, including HSCs and bone marrow-derived CD45+ collagen type I+ expressing fibrocytes.

Internal Catalysis in Dynamic Hydrogels with Associative Thioester Cross-Links.

Thioesters are an essential functional group in biosynthetic pathways, which has motivated their development as reactive handles in probes and peptide assembly. Thioester exchange is typically accelerated by catalysts or elevated pH. Here, we report the use of bifunctional aromatic thioesters as dynamic covalent cross-links in hydrogels, demonstrating that at physiologic pH in aqueous conditions, transthioesterification facilitates stress relaxation on the time scale of hundreds of seconds.

Caregiver reactions to babbling organize turn-taking interactions: Facilitative effects of vocal versus non-vocal responses.

Turn-taking interactions are foundational to the development of social, communicative, and cognitive skills. In infants, vocal turn-taking experience is predictive of infants' socioemotional and language development. However, different forms of turn-taking interactions may have different effects on infant vocalizing.

Developmental cascades of vocal turn-taking connect prelinguistic vocalizing with early language.

Conversational turn-taking is ubiquitously found in caregiver-infant interactions, and robustly predictive of infant communicative development. Over the first year, infants take quick adult-like vocal turns with caregivers. Many studies have documented the consistency of caregiver responsiveness and its influence on infant rapid language growth.

The distributional and embodied contexts of verbs in caregiver-infant interactions.

The process by which infants learn verbs through daily social interactions is not well-understood. This study investigated caregivers' use of verbs, which have highly abstract meanings, during unscripted toy-play. We examined how verbs co-occurred with distributional and embodied factors including pronouns, caregivers' manual actions, and infants' locomotion, gaze, and object-touching.

Definitive Treatment of Brain Metastases From a Neuroendocrine Tumor With Peptide Receptor Radionuclide Therapy With 177Lutetium DOTATATE: A Case Report.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare malignancies that arise from secretory endocrine cells of the gastroenteropancreatic system. Clinical outcomes have improved for patients with GEP-NETs due to the development and recent FDA approval of Lutetium DOTATATE. However, the response of brain metastases from GEP-NETs from Lutetium DOTATATE is unreported.

Tailoring Dynamic Hydrogels by Controlling Associative Exchange Rates.

Dithioalkylidenes are a newly-developed class of conjugate acceptors that undergo thiol exchange via an associative mechanism, enabling decoupling of key material properties for sustainability, biomedical, and sensing applications. Here, we show that the exchange rate is highly sensitive to the structure of the acceptor and tunable over four orders of magnitude in aqueous environments. Cyclic acceptors exchange rapidly, from 0.

Systematic Review of Radiology Residency Artificial Intelligence Curricula: Preparing Future Radiologists for the Artificial Intelligence Era.

Objective: Although educating radiology trainees about artificial intelligence (AI) has become increasingly emphasized, the types of AI educational curricula are not well understood. We performed a systematic review of original studies describing curricula used to teach AI concepts and practical applications for radiology residents and fellows.

Materials And Methods: We performed a PubMed search for original studies published as of July 22, 2022, describing AI curricula geared toward radiology residents or fellows.

Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease.

Alcohol-associated liver disease is accompanied by intestinal mycobiome dysbiosis, yet the impacts on liver disease are unclear. We demonstrate that Candida albicans-specific T helper 17 (Th17) cells are increased in circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration in mice causes migration of Candida albicans (C.

Structure-Reactivity-Property Relationships in Covalent Adaptable Networks.

Polymer networks built out of dynamic covalent bonds offer the potential to translate the control and tunability of chemical reactions to macroscopic physical properties. Under conditions at which these reactions occur, the topology of covalent adaptable networks (CANs) can rearrange, meaning that they can flow, self-heal, be remolded, and respond to stimuli. Materials with these properties are necessary to fields ranging from sustainability to tissue engineering; thus the conditions and time scale of network rearrangement must be compatible with the intended use.

Islet-specific CD8 T cells gain effector function in the gut lymphoid tissues via bystander activation not molecular mimicry.

Type 1 diabetes (T1D) is caused by aberrant activation of autoreactive T cells specific for the islet beta cells. How islet-specific T cells evade tolerance to become effector T cells is unknown, but it is believed that an altered gut microbiota plays a role. Possible mechanisms include bystander activation of autoreactive T cells in the gut or "molecular mimicry" from cross-reactivity between gut microbiota-derived peptides and islet-derived epitopes.

Metabolic Injury of Hepatocytes Promotes Progression of NAFLD and AALD.

Nonalcoholic liver disease is a component of metabolic syndrome associated with obesity, insulin resistance, and hyperlipidemia. Excessive alcohol consumption may accelerate the progression of steatosis, steatohepatitis, and fibrosis. While simple steatosis is considered a benign condition, nonalcoholic steatohepatitis with inflammation and fibrosis may progress to cirrhosis, liver failure, and hepatocellular cancer.

The Field of Cell Competition Comes of Age: Semantics and Technological Synergy.

Stem cells experience many selective pressures which shape their cellular populations, potentially pushing them to skew towards dominance of a few break-through clones. An evolutionarily conserved answer to curb these aberrant selective pressures is cell competition, the elimination of a subset of cells by their neighbours in a seemingly homogenous population. Cell competition in mammalian systems is a relatively recent discovery that has now been observed across many tissue systems, such as embryonic, haematopoietic, intestinal, and epithelial compartments.

Epigenetic maintenance strategies after allogeneic stem cell transplantation in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an aggressive blood malignancy characterized by the accumulation of immature blood cells that can severely impede the normal functions of the hematopoietic system. AML still has a poor 5-year survival rate of around 30%, and efforts to develop novel targeted therapies have been met with challenges. Allogeneic hematopoietic stem cell transplantation represents a potentially curative treatment for many AML patients.

The role of Mesothelin signaling in Portal Fibroblasts in the pathogenesis of cholestatic liver fibrosis.

Liver fibrosis develops in response to chronic toxic or cholestatic injury, and is characterized by apoptosis of damaged hepatocytes, development of inflammatory responses, and activation of Collagen Type I producing myofibroblasts that make liver fibrotic. Two major cell types, Hepatic Stellate Cells (HSCs) and Portal Fibroblasts (PFs) are the major source of hepatic myofibroblasts. Hepatotoxic liver injury activates Hepatic Stellate Cells (aHSCs) to become myofibroblasts, while cholestatic liver injury activates both aHSCs and Portal Fibroblasts (aPFs).

Tolerance induction by liposomes targeting a single CD8 epitope IGRP in a model of type 1 diabetes is impeded by co-targeting a CD4 islet epitope.

The autoimmune disease type 1 diabetes is predominantly mediated by CD8 cytotoxic T-cell destruction of islet beta cells, of which islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is a dominant target antigen specificity. Previously, we found that a liposome-based antigen-specific immunotherapy encapsulating the CD4 T-cell islet epitope 2.5 together with the nuclear factor-κB inhibitor calcitriol induced regulatory T cells and protected from diabetes in NOD mice.

HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling.

Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses cause aberrant tissue remodelling, as observed in asthma. Severe respiratory viral infections in infancy predispose to later asthma, however, the processes that mediate tissue damage-induced type-2 inflammation and the origins of airway remodelling remain ill-defined. Here, using a preclinical mouse model of viral bronchiolitis, we find that increased epithelial and mesenchymal high-mobility group box 1 (HMGB1) expression is associated with increased numbers of IL-13-producing type-2 innate lymphoid cell (ILC2s) and the expansion of the airway smooth muscle (ASM) layer.

Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK.