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Tuberculosis (TB) is a major global health threat, resulting in an urgent unmet need for a rapid, non-sputum-based quantitative test to detect active Mycobacterium tuberculosis (Mtb) infections in clinically diverse populations and quickly assess Mtb treatment responses for emerging drug-resistant strains. We have identified Mtb-specific peptide fragments and developed a method to rapidly quantify their serum concentrations, using antibody-labeled and energy-focusing porous discoidal silicon nanoparticles (nanodisks) and high-throughput mass spectrometry (MS) to enhance sensitivity and specificity. NanoDisk-MS diagnosed active Mtb cases with high sensitivity and specificity in a case-control study with cohorts reflecting the complexity of clinical practice. Similar robust sensitivities were obtained for cases of culture-positive pulmonary TB (PTB; 91.3%) and extrapulmonary TB (EPTB; 92.3%), and the sensitivities obtained for culture-negative PTB (82.4%) and EPTB (75.0%) in HIV-positive patients significantly outperformed those reported for other available assays. NanoDisk-MS also exhibited high specificity (87.1-100%) in both healthy and high-risk groups. Absolute quantification of serum Mtb antigen concentration was informative in assessing responses to antimycobacterial treatment. Thus, a NanoDisk-MS assay approach could significantly improve the diagnosis and management of active TB cases, and perhaps other infectious diseases as well. [ABSTRACT FROM AUTHOR]

Natriuretic peptides (NPs) are a family of cardiacand vascular-derived hormones that are well known for regulating blood pressure, but their expression in the brain poses an intriguing yet unanswered question concerning their roles in the nervous system. Here, we report several unique activities of these hormones in regulating axonal development of dorsal root ganglion (DRG) neurons in the spinal cord. First, the C-type NP ((NP) is expressed in a restricted area of the dorsal spinal cord and provides a cue that is necessary for bifurcation of central sensory afferents. Second, in the culture of embryonic DRG neurons, CNP stimulates branch formation, induces axon outgrowth, and attracts growth cones. Furthermore, these activities are mediated by cyclic guanosine3',5'-monophosphate (cGMP) signaling and can be elicited by other members of NP hormones. Thus, NPs represent a new class of extracellular factors that regulate key axonal processes during development. Because their receptors are present in many regions of the embryonic and adult brain, we propose that these hormones have wide influence on the development and function of the nervous system. [ABSTRACT FROM AUTHOR]

Nonclassical estrogen receptor a (ERα) signaling can mediate E[sub2] negative feedback actions in the reproductive axis; however. downstream pathways conveying these effects remain unclear. These studies tested the hypothesis that p21-activated kinase 1 (PAK1), a serine/threonine kinase rapidly activated by E[sub2] in nonneural cells, functions as a downstream node for E[sub2] signaling pathways in cells of the preoptic area, and it may thereby mediate E[sub2] negative feedback effects. Treatment of ovariectomized (OVX) rats with estradiol benzoate (EB) caused rapid and transient induction of phosphorylated PAK1 immunoreactivity in the medial preoptic nucleus (MPN) but not the arcuate nucleus. To determine whether rapid induction of PAK phosphorylation by E[sub2] is mediated by nonclassical [estrogen response element (ERE)-independent] ERα signaling, we used female ERα null (ERα[sup-/-]) mice possessing an ER knock-in mutation (E207A/G208A; AA). in which the mutant ERa is incapable of binding DNA and can signal only through membrane-initiated or EKE-independent genotropic pathways (ERα[sup-/AA] mice). After 1-h EB treatment, the number of pPAK1-immunoreactive cells in the MPN was increased in both wild-type (ERα[sup+/+]) and ERα[sup-/AA] mice but was unchanged in ERα[sup-/-] mice. Serum luteinizing hormone (LH) was likewise suppressed within 1 h after EB treatment in ERα[sup+/+] and ERα[sup-/AA] but not ERα[sup-/-] mice. In OVX rats. 5-mm intracerebroventricular infusion of a PAK inhibitor peptide but not control peptide blocked rapid EB suppression of LH secretion. Taken together, our findings implicate PAK1 activation subsequent to nondassical ERa signaling as an important component of the negative feedback actions of E[sub2] in the brain. [ABSTRACT FROM AUTHOR]

Selective oxidation of methane to organic oxygenates over metal–organic frameworks (MOFs) catalysts at low temperature is a challenging topic in the field of C1 chemistry because of the inferior stability of MOFs. Modifying the surface of Cu-BTC via hydrophobic polydimethylsiloxane (PDMS) at 235 °C under vacuum not only can dramatically improve its catalytic cycle stability in a liquid phase but also generate coordinatively unsaturated Cu(I) sites, which significantly enhances the catalytic activity of Cu-BTC catalyst. The results of spectroscopy characterizations and theoretical calculation proved that the coordinatively unsaturated Cu(I) sites made H2O2 dissociative into •OH, which formed Cu(II)-O active species by combining with coordinatively unsaturated Cu(I) sites for activating the C−H bond of methane. The high productivity of C1 oxygenates (CH3OH and CH3OOH) of 10.67 mmol gcat. −1h−1 with super high selectivity of 99.6% to C1 oxygenates was achieved over Cu-BTC-P-235 catalyst, and the catalyst possessed excellent reusability. [ABSTRACT FROM AUTHOR]

Enveloped viruses exploit the endomembrane system to enter host cells. Through a cascade of membrane-trafficking events, virus-bearing vesicles fuse with acidic endosomes and/or lysosomes mediated by SNAREs triggering viral fusion. However, the molecular mechanisms underlying this process remain elusive. Here, we found that UV-radiation resistance-associated gene (UVRAG), an autophagic tumor suppressor, is required for the entry of the prototypic negative-strand RNA virus, including influenza A virus and vesicular stomatitis virus, by a mechanism independent of IFN and autophagy. UVRAG mediates viral endocytic transport and membrane penetration through interactions with the class C vacuolar protein sorting (C-Vps) tethering complex and endosomal glutamine-containing SNAREs [syntaxin 7 (STX7), STX8, and vesicle transport through t-SNARE homolog 1B (Vti1b)], leading to the assembly of a fusogenic frans-SNARE complex involving vesicle-associated membrane protein (VAMP8), but not VAMP7. Indeed, UVRAG stimulates VAMP8 translocation to virus-bearing endosomes. Inhibition of VAMP8, but not VAMP7, significantly reduces viral entry. Our data indicate that UVRAG, in concert with C-Vps, regulates viral entry by assembling a specific fusogenic SNARE complex. Thus, UVRAG governs downstream viral entry, highlighting an important pathway capable of potential antiviral therapeutics. [ABSTRACT FROM AUTHOR]