A
bstract
We describe a proposal to add a set of very forward detectors to the CMS experiment for the high-luminosity era of the Large Hadron Collider to search for beyond the standard model ...long-lived particles, such as dark photons, heavy neutral leptons, axion-like particles, and dark Higgs bosons. The proposed subsystem is called
FACET
for
F
orward-
A
perture
C
MS
E
x
T
ension, and will be sensitive to any particles that can penetrate at least 50 m of magnetized iron and decay in an 18 m long, 1 m diameter vacuum pipe. The decay products will be measured in detectors using identical technology to the planned CMS Phase-2 upgrade.
Beyond neutralization, antibodies binding to their Fc receptors elicit several innate immune functions including antibody-dependent complement deposition (ADCD), antibody-dependent cell-mediated ...phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). These functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation. We tested the possibility that qualitative differences in SARS-CoV-2-specific antibody-mediated innate immune functions contribute to coronavirus disease 2019 (COVID-19) severity. We found that anti-S1 and anti-RBD antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from nonhospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation, whereas higher ADCP was associated with lower systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 specific antibodies as potential contributors to COVID-19 severity. Understanding these qualitative features of natural and vaccine-induced antibodies will be important in achieving optimal efficacy and safety of SARS-CoV-2 vaccines and/or COVID-19 therapeutics.
A state of hyperinflammation and increased complement activation has been associated with coronavirus disease 2019 (COVID-19) severity. However, the pathophysiological mechanisms that contribute to this phenomenon remain mostly unknown. Our data point to a qualitative, rather than quantitative, difference in SARS-CoV-2-specific antibodies' ability to elicit Fc-mediated innate immune functions as a potential contributor to COVID-19 severity and associated inflammation. These data highlight the need for further studies to understand these qualitative features and their potential contribution to COVID-19 severity. This understanding could be essential to develop antibody-based COVID-19 therapeutics and SARS-CoV-2 vaccines with an optimal balance between efficacy and safety.
AKI involves early Toll-like receptor (TLR)-driven immunopathology, and resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, activation of TLRs also has been ...implicated in epithelial repair. We hypothesized that TLR signaling drives tubule regeneration after acute injury through the induction of certain ILs. Systematic screening in vitro identified IL-22 as a candidate proregeneratory factor in primary tubular cell recovery, and IL-22 deficiency or IL-22 blockade impaired post-ischemic tubular recovery after AKI in mice. Interstitial mononuclear cells, such as dendritic cells and macrophages, were the predominant source of IL-22 secretion, whereas IL-22 receptor was expressed by tubular epithelial cells exclusively. Depleting IL-22-producing cells during the healing phase impaired epithelial recovery, which could be rescued entirely by reconstituting mice with IL-22. In vitro, necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4. Although TLR4 blockade during the early injury phase prevented tubular necrosis and AKI, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration. Taken together, these results suggest that necrotic cell-derived TLR4 agonists activate intrarenal mononuclear cells to secrete IL-22, which accelerates tubular regeneration and recovery in AKI.
Monogenic diabetes includes several clinical conditions generally characterized by early-onset diabetes, such as neonatal diabetes, maturity-onset diabetes of the young (MODY) and various ...diabetes-associated syndromes. However, patients with apparent type 2 diabetes mellitus may actually have monogenic diabetes. Indeed, the same monogenic diabetes gene can contribute to different forms of diabetes with early or late onset, depending on the functional impact of the variant, and the same pathogenic variant can produce variable diabetes phenotypes, even in the same family. Monogenic diabetes is mostly caused by impaired function or development of pancreatic islets, with defective insulin secretion in the absence of obesity. The most prevalent form of monogenic diabetes is MODY, which may account for 0.5-5% of patients diagnosed with non-autoimmune diabetes but is probably underdiagnosed owing to insufficient genetic testing. Most patients with neonatal diabetes or MODY have autosomal dominant diabetes. More than 40 subtypes of monogenic diabetes have been identified to date, the most prevalent being deficiencies of GCK and HNF1A. Precision medicine approaches (including specific treatments for hyperglycaemia, monitoring associated extra-pancreatic phenotypes and/or following up clinical trajectories, especially during pregnancy) are available for some forms of monogenic diabetes (including GCK- and HNF1A-diabetes) and increase patients' quality of life. Next-generation sequencing has made genetic diagnosis affordable, enabling effective genomic medicine in monogenic diabetes.
Abstract
Purpose
Regular participation in physical activity is critical for nurturing optimum health and well-being. It also prevents the onset of obesity and associated non-communicable diseases. ...Indeed, urban Indian men are more prone to these chronic illnesses as most of them lead a very sedentary lifestyle. Thus, a public health priority is to increase physical activity levels among sedentary urban Indian men. With this objective in mind, an exploratory study was designed to understand men's perspective of physical activity and the factors influencing physical activity participation.
Methods
Five focus group discussions (FGDs) were conducted with adult men (n = 26; age: 20-60 years) between August and November 2019. The participants were recruited from Mumbai Metropolitan Area through snowballing. All the FGDs were audio-recorded and conducted in both Hindi and English. The audio recordings were transcribed and translated. Content analysis was used to obtain frequencies of different barriers and facilitators. Thematic analysis was applied to cluster responses, identify themes in the data, and build an explanation from the FGDs.
Results
All the participants perceived the need to participate in physical activity as it was associated with a better quality of life. Commonly identified facilitators were health benefits, physical appearance, and adequate facilities in the neighbourhood to engage in physical activity. Self-reported barriers included lack of time because of hectic work schedules and commuting, laziness, physical activity not viewed as a priority, and engagement with mobile phones.
Conclusions
The emerging findings can inform the development of a physical activity intervention to support behaviour change as well as ensure its sustainability among inactive urban Indian men. This qualitative inquiry contributes to the body of knowledge on physical activity in a culture that is relatively underrepresented in the current literature.
Key messages
Physical activity was influenced by multiple factors at multiple levels i.e. intrapersonal level, interpersonal level, and community level. There is a need to design effective public health interventions to increase physical activity and thereby control the prevailing disease burden.
Wide-field surveys are discovering a growing number of rare transients whose physical origin is not yet well understood. Here we present optical and UV data and analysis of intermediate Palomar ...Transient Factory (iPTF) 16asu, a luminous, rapidly evolving, high-velocity, stripped-envelope supernova (SN). With a rest-frame rise time of just four days and a peak absolute magnitude of mag, the light curve of iPTF 16asu is faster and more luminous than that of previous rapid transients. The spectra of iPTF 16asu show a featureless blue continuum near peak that develops into an SN Ic-BL spectrum on the decline. We show that while the late-time light curve could plausibly be powered by 56Ni decay, the early emission requires a different energy source. Nondetections in the X-ray and radio strongly constrain the energy coupled to relativistic ejecta to be at most comparable to the class of low-luminosity gamma-ray bursts (GRBs). We suggest that the early emission may have been powered by either a rapidly spinning-down magnetar or by shock breakout in an extended envelope of a very energetic explosion. In either scenario a central engine is required, making iPTF 16asu an intriguing transition object between superluminous SNe, SNe Ic-BL, and low-luminosity GRBs.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during ...severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity ADCC assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9
NK cells. Consistently, Siglec-9
NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9
CD56
NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9
CD56
NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells.
One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9
NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance.
A once every eight-week cabotegravir (CAB) long-acting parenteral is more effective than daily oral emtricitabine and tenofovir disoproxil fumarate in preventing human immunodeficiency virus type one ...(HIV-1) transmission. Extending CAB dosing to a yearly injectable advances efforts for the elimination of viral transmission. Here we report rigor, reproducibility and mechanistic insights for a year-long CAB injectable. Pharmacokinetic (PK) profiles of this nanoformulated CAB prodrug (NM2CAB) are affirmed at three independent research laboratories. PK profiles in mice and rats show plasma CAB levels at or above the protein-adjusted 90% inhibitory concentration for a year after a single dose. Sustained native and prodrug concentrations are at the muscle injection site and in lymphoid tissues. The results parallel NM2CAB uptake and retention in human macrophages. NM2CAB nanocrystals are stable in blood and tissue homogenates. The long apparent drug half-life follows pH-dependent prodrug hydrolysis upon slow prodrug nanocrystal dissolution and absorption. In contrast, solubilized prodrug is hydrolyzed in hours in plasma and tissues from multiple mammalian species. No toxicities are observed in animals. These results affirm the pharmacological properties and extended apparent half-life for a nanoformulated CAB prodrug. The report serves to support the mechanistic design for drug formulation safety, rigor and reproducibility.
We consider an
spin chain within the framework of the generalized algebraic Bethe ansatz. We study scalar products of the transfer matrix eigenvectors and arbitrary Bethe vectors. In the particular ...case of free fermions, we obtain explicit expressions for the scalar products with different number of parameters in two Bethe vectors.
During meiosis, crossover recombination connects homologous chromosomes to direct their accurate segregation
. Defective crossing over causes infertility, miscarriage and congenital disease. Each ...pair of chromosomes attains at least one crossover via the formation and biased resolution of recombination intermediates known as double Holliday junctions
. A central principle of crossover resolution is that the two Holliday junctions are resolved in opposite planes by targeting nuclease incisions to specific DNA strands
. The endonuclease activity of the MutLγ complex has been implicated in the resolution of crossovers
, but the mechanisms that activate and direct strand-specific cleavage remain unknown. Here we show that the sliding clamp PCNA is important for crossover-biased resolution. In vitro assays with human enzymes show that PCNA and its loader RFC are sufficient to activate the MutLγ endonuclease. MutLγ is further stimulated by a co-dependent activity of the pro-crossover factors EXO1 and MutSγ, the latter of which binds Holliday junctions
. MutLγ also binds various branched DNAs, including Holliday junctions, but does not show canonical resolvase activity, implying that the endonuclease incises adjacent to junction branch points to achieve resolution. In vivo, RFC facilitates MutLγ-dependent crossing over in budding yeast. Furthermore, PCNA localizes to prospective crossover sites along synapsed chromosomes. These data highlight similarities between crossover resolution and the initiation steps of DNA mismatch repair
and evoke a novel model for crossover-specific resolution of double Holliday junctions during meiosis.
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