Preferential targeting of co-evolving Gag residues in long-term non progressors

Background: A recent analysis of mutational patterns within Gag revealed independently evolving groups of residues (termed sectors) whose mutations are collectively coordinated. Of these sectors, sector 3 is the least tolerant of multiple simultaneous mutations and therefore is proposed to be the most vulnerable to a targeted immune attack. We hypothesized that coordinated CTL targeting of sector 3 residues is associated with immune control. Methods: We completed a comprehensive evaluation of Gag-specific responses in a cohort of 9 Long-term non-progressors (LTNPs, VL 10,000 RNA copies/ml, untreated). A Gag peptide set of 11-mer peptides overlapping by 10 amino acids was generated to reflect all variants found in at least 5% of clade B sequences in the LANL HIV Sequence Database. This peptide set includes 1300 peptides and covers all 500 amino acids of Gag. All study subjects were screened for responses to all peptides by IFN-γ/IL-2 FluoroSpot. Results: We observed a trend in the preferential targeting of sector 3 residues by LTNPs (p=0.07). This trend was not observed for any other sector or in total breadth of responses. Supporting the importance of sector 3 targeting, we found a significant positive correlation in our cohort between the relative proportion of sector 3 responses and CD4 count (r=0.49, p=0.04). We found no significant differences between LTNPs and HIV-Progressors in either the targeting of conserved 11-mers or overall Gag epitope variant recognition. Interestingly, LTNPs demonstrated higher levels of variant recognition than HIV-progressors when considering only the variable regions containing sector 3 residues. Conclusion: We found that preferential targeting of sector 3 residues distinguished Gag-specific responses between LTNPs and HIV-progressors, and that coordinated targeting of sector 3 residues may require cross-reactive responses. Additional investigations are ongoing to elucidate the role of sector 3 targeting in immune control of HIV

An investigation into the minimum dimensionality required for accurate simulation of proton exchange membrane fuel cells by the comparison between 1- and 3-dimension models.

Includes abstract.Includes bibliographical references.Hydrogen has been studied intensively as a potential energy carrier as it allows for a reduced carbon footprint in the environment. Fuel cell (FC) technology has been studied in detail to implement hydrogen as well as other renewable sources as a feasible fuel. Further development in fuel cell design is hampered by the lack of fundamental models which reveal the physical and chemical interactions. While computational fluid dynamics simulations are available, the timeframe for solving these simulations renders them unfeasible in any rigorous FC design optimisation. The objective of the present investigation was to determine the minimum dimension of a mathematical model that can accurately simulate processes occurring within a proton exchange membrane fuel cell (PEMFC). To this end, 1-D (directional axis perpendicular to the membrane) and 3-D steady state isothermal mathematical models were developed and simulated in order to investigate the transport of reactant species through the various layers of the cell at the anode side

Continuous immunotypes describe human immune variation and predict diverse responses

The immune system consists of many specialized cell populations that communicate with each other to achieve systemic immune responses. Our analyses of various measured immune cell population frequencies in healthy humans and their responses to diverse stimuli show that human immune variation is continuous in nature, rather than characterized by discrete groups of similar individuals. We show that the same three key combinations of immune cell population frequencies can define an individual’s immunotype and predict a diverse set of functional responses to cytokine stimulation. We find that, even though interindividual variations in specific cell population frequencies can be large, unrelated individuals of younger age have more homogeneous immunotypes than older individuals. Across age groups, cytomegalovirus seropositive individuals displayed immunotypes characteristic of older individuals. The conceptual framework for defining immunotypes suggested by our results could guide the development of better therapies that appropriately modulate collective immunotypes, rather than individual immune components. Keywords: human immune variation; immune cell composition; systems immunology; agingNational Institutes of Health (U.S.) (Grant R01 HL120724

Comprehensive Classification of Retinal Bipolar Neurons by Single-Cell Transcriptomics

Patterns of gene expression can be used to characterize and classify neuronal types. It is challenging, however, to generate taxonomies that fulfill the essential criteria of being comprehensive, harmonizing with conventional classification schemes, and lacking superfluous subdivisions of genuine types. To address these challenges, we used massively parallel single-cell RNA profiling and optimized computational methods on a heterogeneous class of neurons, mouse retinal bipolar cells (BCs). From a population of ∼25,000 BCs, we derived a molecular classification that identified 15 types, including all types observed previously and two novel types, one of which has a non-canonical morphology and position. We validated the classification scheme and identified dozens of novel markers using methods that match molecular expression to cell morphology. This work provides a systematic methodology for achieving comprehensive molecular classification of neurons, identifies novel neuronal types, and uncovers transcriptional differences that distinguish types within a class

Capacitive response of biological membranes

We present a minimal model to analyze the capacitive response of a biological membrane subjected to a step voltage via blocking electrodes. Through a perturbative analysis of the underlying electrolyte transport equations, we show that the leading-order relaxation of the transmembrane potential is governed by a capacitive timescale, τC=λDLD(2+ΓδM/L4+ΓδM/λD), where λD is the Debye screening length, L is the electrolyte width, Γ is the ratio of the permittivity of the electrolyte to the membrane, δM is the membrane thickness, and D is the ionic diffusivity. This timescale is considerably shorter than the traditional RC timescale λDL/D for a bare electrolyte due to the membrane's low permittivity and finite thickness. Beyond the linear regime, however, salt diffusion in the bulk electrolyte drives a secondary, nonlinear relaxation process of the transmembrane potential over a longer timescale τL=L2/4π2D. A simple equivalent-circuit model accurately captures the linear behavior, and the perturbation expansion remains applicable across the entire range of observed physiological transmembrane potentials. Together, these findings underscore the importance of the faster capacitive timescale and nonlinear effects on the bulk diffusion timescale in determining transmembrane potential dynamics for a range of biological systems

Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys

Human immunodeficiency virus type 1 (HIV-1)-specific monoclonal antibodies with extraordinary potency and breadth have recently been described. In humanized mice, combinations of monoclonal antibodies have been shown to suppress viraemia, but the therapeutic potential of these monoclonal antibodies has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific monoclonal antibodies, as well as the single glycan-dependent monoclonal antibody PGT121, resulted in a rapid and precipitous decline of plasma viraemia to undetectable levels in rhesus monkeys chronically infected with the pathogenic simian–human immunodeficiency virus SHIV-SF162P3. A single monoclonal antibody infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa and lymph nodes without the development of viral resistance. Moreover, after monoclonal antibody administration, host Gag-specific T-lymphocyte responses showed improved functionality. Virus rebounded in most animals after a median of 56 days when serum monoclonal antibody titres had declined to undetectable levels, although, notably, a subset of animals maintained long-term virological control in the absence of further monoclonal antibody infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of monoclonal antibody therapy for HIV-1 in humans.National Institutes of Health (U.S.) (AI055332)National Institutes of Health (U.S.) (AI060354)National Institutes of Health (U.S.) (AI078526)National Institutes of Health (U.S.) (AI084794)National Institutes of Health (U.S.) (AI095985)National Institutes of Health (U.S.) (AI096040)National Institutes of Health (U.S.) (AI100148)National Institutes of Health (U.S.) (AI10063)Bill & Melinda Gates Foundation (OPP1033091)Bill & Melinda Gates Foundation (OPP1033115)Bill & Melinda Gates Foundation (OPP1040741)Bill & Melinda Gates Foundation (OPP1040753)Ragon Institute of MGH, MIT, and HarvardStavros S. Niarchos FoundationHoward Hughes Medical Institute (Investigator

Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors

Dendritic cells (DCs) and monocytes play a central role in pathogen sensing, phagocytosis, and antigen presentation and consist of multiple specialized subtypes. However, their identities and interrelationships are not fully understood. Using unbiased single-cell RNA sequencing (RNA-seq) of ~2400 cells, we identified six human DCs and four monocyte subtypes in human blood. Our study reveals a new DC subset that shares properties with plasmacytoid DCs (pDCs) but potently activates T cells, thus redefining pDCs; a new subdivision within the CD1C+ subset of DCs; the relationship between blastic plasmacytoid DC neoplasia cells and healthy DCs; and circulating progenitor of conventional DCs (cDCs). Our revised taxonomy will enable more accurate functional and developmental analyses as well as immune monitoring in health and disease

Spatial profiling of the interplay between cell type- and vision-dependent transcriptomic programs in the visual cortex

How early sensory experience during "critical periods" of postnatal life affects the organization of the mammalian neocortex at the resolution of neuronal cell types is poorly understood. We previously reported that the functional and molecular profiles of layer 2/3 (L2/3) cell types in the primary visual cortex (V1) are vision-dependent [S. Cheng et al., Cell 185, 311-327.e24 (2022)]. Here, we characterize the spatial organization of L2/3 cell types with and without visual experience. Spatial transcriptomic profiling based on 500 genes recapitulates the zonation of L2/3 cell types along the pial-ventricular axis in V1. By applying multitasking theory, we suggest that the spatial zonation of L2/3 cell types is linked to the continuous nature of their gene expression profiles, which can be represented as a 2D manifold bounded by three archetypal cell types. By comparing normally reared and dark reared L2/3 cells, we show that visual deprivation-induced transcriptomic changes comprise two independent gene programs. The first, induced specifically in the visual cortex, includes immediate-early genes and genes associated with metabolic processes. It manifests as a change in cell state that is orthogonal to cell-type-specific gene expression programs. By contrast, the second program impacts L2/3 cell-type identity, regulating a subset of cell-type-specific genes and shifting the distribution of cells within the L2/3 cell-type manifold. Through an integrated analysis of spatial transcriptomics with single-nucleus RNA-seq data, we describe how vision patterns cortical L2/3 cell types during the critical period

COVID-19 alcoholic cirrhosis and non-alcoholic steatohepatitis cirrhosis outcomes among hospitalized patients in the United States: Insight from National Inpatient Sample database

Patients with co-morbidities like cirrhosis are at risk of worse outcome from COVID-19 infection. Given limited prior studies, we evaluated outcomes associated with COVID-19 infection in alcoholic and non-alcoholic steatohepatitis cirrhotic (CC+) versus cirrhotic without COVID-19 (CC-). We performed retrospective analysis of 822,604 patients including 28,610 COVID-19 patients from the National Inpatient Sample database with alcoholic and NASH cirrhosis enrolled between 1 January 2020 to 31 December 2020, with univariate and multivariate regression analyses. Primary outcome was mortality and secondary outcomes was mechanical ventilation, vasopressor use, length of stay, hospitalization expense and predictors of mortality. In-hospital mortality was three time higher in the CC+ group compared to those in the CC- group(18.6% vs. 5.96%

Two-dimensional (2D) d-Silicates from abundant natural minerals

In the last decade, the materials community has been exploring new 2D materials (graphene, metallene, TMDs, TMCs, MXene, among others) that have unique physical and chemical properties. Recently, a new family of 2D materials, the so-called 2D silicates, have been proposed. They are predicted to exhibit exciting properties (such as high catalytic activity, piezoelectricity, and 2D magnetism). In the current work, we demonstrate a generic approach to the synthesis of large-scale 2D silicates from selected minerals, such as Diopside (d). Different experimental techniques were used to confirm the existence of the 2D structures (named 2D-d-silicates). DFT simulations were also used to gain insight into the structural features and energy harvesting mechanisms (flexoelectric response generating voltage up to 10 V). The current approach is completely general and can be utilized for large-scale synthesis of 2D silicates and their derivatives, whose large-scale syntheses have been elusive