Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.

Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs).

Empyema Necessitatis: A Rare Complication of Empyema.

Empyema necessitatis (EN) is an exceedingly rare complication of empyema. EN refers to the expansion and progression of an empyema beyond the thoracic cavity toward the skin wall. Herein, we present the case of a man with EN and detail his clinical course.

C-Terminal Arginine-Selective Cleavage of Peptides as a Method for Mimicking Carboxypeptidase B.

C-Terminal residues play a pivotal role in dictating the structure and functions of proteins. Herein, we report a mild, efficient, chemoselective, and site-selective chemical method that allows for precise chemical proteolysis at C-terminal arginine dictated by 9,10-phenanthrenequinone independent of the remaining sequence. This biomimetic approach also exhibits the potential to synthesize C-terminal methyl ester (-COMe) peptides.

Fibroblast-derived PI16 sustains inflammatory pain via regulation of CD206 myeloid cells.

Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve barrier permeability and leukocyte infiltration, though its impact on inflammatory pain has not been established. Using the complete Freund's Adjuvant inflammatory pain model, we show that Pi16 mice are protected against sustained inflammatory pain. Accordingly, intrathecal delivery of a PI16 neutralizing antibody in wild-type mice prevented sustained CFA pain.

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.

Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole body energy expenditure, counteracts obesity, and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs).

Mitochondrial uncouplers induce proton leak by activating AAC and UCP1.

Mitochondria generate heat due to H leak (I) across their inner membrane. I results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat and ADP/ATP carrier (AAC) in other tissues, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of I through UCP1 and AAC is lacking, I is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP).

In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates.

Gene-editing technologies, which include the CRISPR-Cas nucleases and CRISPR base editors, have the potential to permanently modify disease-causing genes in patients. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis).

pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise.

In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation.

A Quantitative Tissue-Specific Landscape of Protein Redox Regulation during Aging.

Mammalian tissues engage in specialized physiology that is regulated through reversible modification of protein cysteine residues by reactive oxygen species (ROS). ROS regulate a myriad of biological processes, but the protein targets of ROS modification that drive tissue-specific physiology in vivo are largely unknown. Here, we develop Oximouse, a comprehensive and quantitative mapping of the mouse cysteine redox proteome in vivo.

H transport is an integral function of the mitochondrial ADP/ATP carrier.

The mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms.

Accumulation of succinate controls activation of adipose tissue thermogenesis.

Thermogenesis by brown and beige adipose tissue, which requires activation by external stimuli, can counter metabolic disease. Thermogenic respiration is initiated by adipocyte lipolysis through cyclic AMP-protein kinase A signalling; this pathway has been subject to longstanding clinical investigation. Here we apply a comparative metabolomics approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo.

Glycosylation affects both the three-dimensional structure and antibody binding properties of the HIV-1IIIB GP120 peptide RP135.

We have prepared glycosylated analogues of the principal neutralizing determinant of gp120 and studied their conformations by NMR and circular dichroism spectroscopies. The 24-residue peptide from the HIV-1IIIB isolate (residues 308-331) designated RP135, which contains the immunodominant tip of the V3 loop, was glycosylated with both N- and O-linked sugars. The structures of two glycopeptides, one with an N-linked beta-glucosamine (RP135NG) and the other with two O-linked alpha-galactosamine units (RP135digal), were studied by NMR and circular dichroism spectroscopies.

Preliminary findings of an in vitro human spleen mononuclear cell culture system for primary isolates of HIV type 1.

Acute HIV-1 infection is often manifested with a high level of viremia. The cell types and tissues/organs that contribute to the virus load are thought to be of central and peripheral lymphoreticular origin. The establishment and permissiveness of organ-based cell culture systems from spleen with laboratory strains or primary isolates of HIV-1 have not been reported.

Refocusing neutralizing antibody response by targeted dampening of an immunodominant epitope.

Immunodominant epitopes are known to suppress a primary immune response to other antigenic determinants by a number of mechanisms. Many pathogens have used this strategy to subvert the immune response and may be a mechanism responsible for limited vaccine efficacies. HIV-1 vaccine efficacy appears to be complicated similarly by a limited, immunodominant, isolate-restricted immune response generally directed toward determinants in the third variable domain (V3) of the major envelope glycoprotein, gp120.

Preliminary in vitro growth cycle and transmission studies of HIV-1 in an autologous primary cell assay of blood-derived macrophages and peripheral blood mononuclear cells.

Recent interest focused on the dynamics of HIV-1 replication in primary monocytes/macrophages and T-lymphocytes of the immune system, as well as the standardization of virological and immunological in vitro assays with primary isolates, provided the impetus for these studies. These types of studies have never been performed as they would occur in vivo, i.e.

Neutralization of HIV-1: a paradox of humoral proportions.

The production of immunoglobulin capable of neutralizing the infectivity of a virus represents one of the most remarkable molecular accomplishments of the host's available immune defenses. It should be no surprise that a virus that has existed in the parenchyma of the immune system has evolved as an equally dynamic molecule (i.e.