Darkness descends with two Rabs

Over 60 distinct Rab GTPases regulate specific vesicular transport steps in the mammalian central vacuolar system. Wasmeier et al. (this issue, p. 271) reveal a redundant role for two tissue-specific Rab proteins in regulating transport to a tissue-specific lysosome-related organelle, the melanosome

Nicotinic acetylcholine receptors (nACh) in GtoPdb v.2021.3

Nicotinic acetylcholine (ACh) receptors are members of the Cys-loop family of transmitter-gated ion channels that includes the GABAA, strychnine-sensitive glycine and 5-HT3 receptors [215, 3, 159, 225, 259]. All nicotinic receptors are pentamers in which each of the five subunits contains 4 TM domains. Genes encoding a total of 17 subunits (α1-10, β1-4, γ, δ and ε) have been identified [120]. All subunits with the exception of α8 (present in avian species) have been identified in mammals. All α subunits possess two tandem cysteine residues near to the site involved in acetylcholine binding, and subunits not named α lack these residues [159]. The orthosteric ligand binding site is formed by residues within at least three peptide domains on the α subunit (principal component), and three on the adjacent subunit (complementary component). Nicotinic ACh receptors contain several allosteric modulatory sites. One such site, for positive allosteric modulators (PAMs) and allosteric agonists, has been proposed to reside within an intrasubunit cavity between the 4 TM domains [264, 87]; see also [106]). The high resolution crystal structure of the molluscan ACh binding protein, a structural homologue of the extracellular binding domain of a nicotinic receptor pentamer, in complex with several nicotinic receptor ligands (e.g.[35]) and the crystal structure of the extracellular domain of the α1 subunit bound to α-bungarotoxin at 1.94Â resolution [55], has revealed the orthosteric binding site in detail (reviewed in [215, 120, 39, 198]). Nicotinic receptors at the somatic neuromuscular junction of adult animals have the stoichiometry (α1)2β1δε, whereas an extrajunctional (α1)2β1γδ receptor predominates in embryonic and denervated skeletal muscle and other pathological states. Other nicotinic receptors are assembled as combinations of α(2-6) and β(2-4) subunits. For α2, α3, α4 and β2 and β4 subunits, pairwise combinations of α and β (e.g. α3β4 and α4β2) are sufficient to form a functional receptor in vitro, but far more complex isoforms may exist in vivo (reviewed in [96, 93, 159]). There is strong evidence that the pairwise assembly of some α and β subunits can occur with variable stoichiometry [e.g. (α4)2(β2)2 or (α4)3(β2)2] which influences the biophysical and pharmacological properties of the receptor [159]. α5 and β3 subunits lack function when expressed alone, or pairwise, but participate in the formation of functional hetero-oligomeric receptors when expressed as a third subunit with another α and β pair [e.g. α4α5αβ2, α4αβ2β3, α5α6β2, see [159] for further examples]. The α6 subunit can form a functional receptor when co-expressed with β4 in vitro, but more efficient expression ensues from incorporation of a third partner, such as β3 [263]. The α7, α8, and α9 subunits form functional homo-oligomers, but can also combine with a second subunit to constitute a hetero-oligomeric assembly (e.g. α7β2 and α9α10). For functional expression of the α10 subunit, co-assembly with α9 is necessary. The latter, along with the α10 subunit, appears to be largely confined to cochlear and vestibular hair cells. Comprehensive listings of nicotinic receptor subunit combinations identified from recombinant expression systems, or in vivo, are given in [159]. In addition, numerous proteins interact with nicotinic ACh receptors modifying their assembly, trafficking to and from the cell surface, and activation by ACh (reviewed by [158, 9, 118]).The nicotinic receptor Subcommittee of NC-IUPHAR has recommended a nomenclature and classification scheme for nicotinic acetylcholine (nACh) receptors based on the subunit composition of known, naturally- and/or heterologously-expressed nACh receptor subtypes [143]. Headings for this table reflect abbreviations designating nACh receptor subtypes based on the predominant α subunit contained in that receptor subtype. An asterisk following the indicated α subunit denotes that other subunits are known to, or may, assemble with the indicated α subunit to form the designated nACh receptor subtype(s). Where subunit stoichiometries within a specific nACh receptor subtype are known, numbers of a particular subunit larger than 1 are indicated by a subscript following the subunit (enclosed in parentheses- see also [46])

Neutron Correlations in the Decay of the First Excited State of 11Li

The decay of unbound excited 11Li was measured after being populated by a two-proton removal from a 13B beam at 71 MeV/nucleon. Decay energy spectra and Jacobi plots were obtained from measurements of the momentum vectors of the 9Li fragment and neutrons. A resonance at an excitation energy of ∼1.2 MeV was observed. The kinematics of the decay are equally well fit by a simple dineutron-like model or a phase-space model that includes final state interactions. A sequential decay model can be excluded

Use of ICD-10 codes for identification of injection drug use-associated infective endocarditis is nonspecific and obscures critical findings on impact of medications for opioid use disorder

Background: No International Classification of Diseases, 10th revision (ICD-10), diagnosis code exists for injection drug use-associated infective endocarditis (IDU-IE). Instead, public health researchers regularly use combinations of nonspecific ICD-10 codes to identify IDU-IE; however, the accuracy of these codes has not been evaluated. Methods: We compared commonly used ICD-10 diagnosis codes for IDU-IE with a prospectively collected patient cohort diagnosed with IDU-IE at Barnes-Jewish Hospital to determine the accuracy of ICD-10 diagnosis codes used in IDU-IE research. Results: ICD-10 diagnosis codes historically used to identify IDU-IE were inaccurate, missing 36.0% and misclassifying 56.4% of patients prospectively identified in this cohort. Use of these nonspecific ICD-10 diagnosis codes resulted in substantial biases against the benefit of medications for opioid use disorder (MOUD) with relation to both AMA discharge and all-cause mortality. Specifically, when data from all patients with ICD-10 code combinations suggestive of IDU-IE were used, MOUD was associated with an increased risk of AMA discharge (relative risk [RR], 1.12; 95% CI, 0.48-2.64). In contrast, when only patients confirmed by chart review as having IDU-IE were analyzed, MOUD was protective (RR, 0.49; 95% CI, 0.19-1.22). Use of MOUD was associated with a protective effect in time to all-cause mortality in Kaplan-Meier analysis only when confirmed IDU-IE cases were analyzed ( Conclusions: Studies using nonspecific ICD-10 diagnosis codes for IDU-IE should be interpreted with caution. In the setting of an ongoing overdose crisis and a syndemic of infectious complications, a specific ICD-10 diagnosis code for IDU-IE is urgently needed

Low knowledge of HIV PrEP within a midwestern US cohort of persons who inject drugs

We interviewed persons who inject drugs (PWID) to understand perceptions of pre-exposure prophylaxis (PrEP) to prevent HIV infection. Knowledge of PrEP was poor. Patients felt that PrEP was for sexual intercourse rather than injection drug use, and PWID managed on medications for opioid use disorder felt that they had no need for PrEP

A novel Streptococcus pneumoniae human challenge model demonstrates Treg lymphocyte recruitment to the infection site

To investigate local tissue responses to infection we have developed a human model of killed Streptococcus pneumoniae challenge by intradermal injection into the forearm. S. pneumoniae intradermal challenge caused an initial local influx of granulocytes and increases in TNF, IL6 and CXCL8. However, by 48 h lymphocytes were the dominant cell population, mainly consisting of CD4 and CD8 T cells. Increases in local levels of IL17 and IL22 and the high proportion of CD4 cells that were CCR6+ suggested a significant Th17 response. Furthermore, at 48 h the CD4 population contained a surprisingly high proportion of likely memory Treg cells (CCR6 positive and CD45RA negative CD4+CD25highCD127low cells) at 39%. These results demonstrate that the intradermal challenge model can provide novel insights into the human response to S. pneumoniae and that Tregs form a substantial contribution of the normal human lymphocyte response to infection with this important pathogen

Experiences using a multidisciplinary model for treating injection drug use associated infections: A qualitative study

Background: Over the past two decades, the United States has experienced a dramatic increase in the rate of injection drug use, injection associated infections, and overdose mortality. A hospital-based program for treating opioid use disorder in people who inject drugs presenting with invasive infections was initiated at an academic tertiary care center in 2020. The goal of this program was to improve care outcomes, enhance patient experiences, and facilitate transition from the hospital to longer term addiction care. The purpose of this study was to interview two cohorts of patients, those admitted before vs. after initiation of this program, to understand the program\u27s impact on care from the patient\u27s perspective and explore ways in which the program could be improved. Methods: Thirty patients admitted to the hospital with infectious complications of injection drug use were interviewed using a semi-structured format. Interviews were transcribed and coded. Emergent themes were reported. Limited descriptive statistics were reported based on chart review. Results: Thirty interviews were completed; 16 participants were part of the program (admitted after program implementation) while 14 were not participants (admitted prior to implementation). Common themes associated with hospitalization included inadequate pain control, access to medications for opioid use disorder (MOUD), loss of freedom, stigma from healthcare personnel, and benefits of having an interprofessional team. Participants in the program were more likely to report adequate pain control and access to MOUD and many cited benefits from receiving care from an interprofessional team. Conclusions: Patients with opioid use disorder admitted with injection related infections reported improved experiences when receiving care from an interprofessional team focused on their addiction. However, perceived stigma from healthcare personnel and loss of freedom related to hospitalization were continued barriers to care before and after implementation of this program

Syngeneic B16-F1 cells are more efficient than allogeneic Cloudman cells as antigen source in DC-based vaccination in the B16-F1 murine melanoma model

A major obstacle to obtaining relevant results in cancer vaccination has been the lack of identification of immunogenic antigens. Dendritic cell (DC)-based cancer vaccines used preventively may afford protection against tumor inoculation, but the effect of antigen choice on anti-tumor protection is not clear. When using irradiated syngeneic tumor cells to load DCs, tumor self-antigens are provided, including tumor-associated antigens (TAAs) and neoantigens generated by tumor mutations. On the other hand, allogeneic tumor cells could only supply shared TAAs. To assess the advantages of each source in protective vaccination, we analyzed in C57BL/6 mice the effect of loading DCs with irradiated syngeneic B16-F1 or allogeneic Cloudman melanoma cells; both cell lines were characterized by whole exome sequencing and RNAseq. Tumor cell components from the two irradiated cell lines were efficiently internalized by DCs, and transported to MHC-class II positive tubulovesicular compartments (MIICs). DCs loaded with allogeneic irradiated Cloudman cells (DC-ApoNecALLO) induced a partially effective anti-melanoma protection, although Cloudman and B16-F1 cells share the expression of melanocyte differentiation antigens (MDAs), cancer-testis antigens (CTAs) and other TAAs. DCs loaded with syngeneic B16-F1 cells (DC-ApoNecSYN) established a more potent and long-lasting protection and induced a humoral anti-B16F1 response, thus suggesting that neoepitopes are needed for inducing long-lasting protection.Fil: Mac Keon, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Bentivegna, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; ArgentinaFil: Marks, Michael S.. The Children's Hospital Of Philadelphia; Estados UnidosFil: Mantegazza, Adriana Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Wainstok, Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Mordoh, Jose. Instituto Alexander Fleming; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentin