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Fast updating feedback from piriform cortex to the olfactory bulb relays multimodal identity and reward contingency signals during rule-reversal
Identification of hub biomarkers and immune cell infiltrations participating in the pathogenesis of endometriosis
Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing
Abstract Assembly of actin-based stereocilia is critical for cochlear hair cells to detect sound. To tune their mechanosensivity, stereocilia form bundles composed of graded rows of ascending height, necessitating the precise control of actin polymerization. Myosin 15 (MYO15A) drives hair bundle development by delivering critical proteins to growing stereocilia that regulate actin polymerization via an unknown mechanism. Here, we show that MYO15A is itself an actin nucleation-promoting factor. Moreover, a deafness-causing mutation in the MYO15A actin-binding interface inhibits nucleation activity but still preserves some movement on filaments in vitro and partial trafficking on stereocilia in vivo. Stereocilia fail to elongate correctly in this mutant mouse, providing evidence that MYO15A-driven actin nucleation contributes to hair bundle biogenesis. Our work shows that in addition to generating force and motility, the ATPase domain of MYO15A can directly regulate actin polymerization and that disrupting this activity can promote cytoskeletal disease, such as hearing loss.
Evaluation of feasibility accuracy and safety after 79 O-ARM based stereotactic brain biopsies
Mechanism of sensor kinase CitA transmembrane signaling
Abstract Membrane bound histidine kinases (HKs) are ubiquitous sensors of extracellular stimuli in bacteria. However, a uniform structural model is still missing for their transmembrane signaling mechanism. Here, we used solid-state NMR in conjunction with crystallography, solution NMR and distance measurements to investigate the transmembrane signaling mechanism of a paradigmatic citrate sensing membrane embedded HK, CitA. Citrate binding in the sensory extracytoplasmic PAS domain (PASp) causes the linker to transmembrane helix 2 (TM2) to adopt a helical conformation. This triggers a piston-like pulling of TM2 and a quaternary structure rearrangement in the cytosolic PAS domain (PASc). Crystal structures of PASc reveal both anti-parallel and parallel dimer conformations. An anti-parallel to parallel transition upon citrate binding agrees with interdimer distances measured in the lipid embedded protein using a site-specific 19 F label in PASc. These data show how Angstrom scale structural changes in the sensor domain are transmitted across the membrane to be converted and amplified into a nm scale shift in the linker to the phosphorylation subdomain of the kinase.
Association of the triglyceride glucose index with all cause and CVD mortality in the adults with diabetes aged < 65 years without cardiovascular disease
Mgl2+ cDC2s coordinate fungal allergic airway type 2, but not type 17, inflammation in mice
Abstract Fungal spores are abundant in the environment and a major cause of asthma. Originally characterised as a type 2 inflammatory disease, allergic airway inflammation that underpins asthma can also involve type 17 inflammation, which can exacerbate disease causing failure of treatments tailored to inhibit type 2 factors. However, the mechanisms that determine the host response to fungi, which can trigger both type 2 and type 17 inflammation in allergic airway disease, remain unclear. Here we find that CD11c + DCs and CD4 + T cells are essential for development of both type 2 and type 17 airway inflammation in mice repeatedly exposed to inhaled spores. Single cell RNA-sequencing with further multi-parameter cytometry shows that allergic inflammation dramatically alters the proportion of numerous DC clusters in the lung, but that only two of these (Mgl2 + cDC2s and CCR7 + DCs) migrate to the dLNs. Targeted removal of several DC subsets shows that Mgl2 + cDC2 depletion reduces type 2, but not type 17, fungal allergic airway inflammation. These data highlight distinct DC subsets as potential therapeutic targets for the treatment of pulmonary fungal disease.
Integrated analysis of genetic, proteinic, and metabolomic alterations in Behcet’s disease
Dendrites endow artificial neural networks with accurate, robust and parameter-efficient learning
Investigation of genes expression of the JAK/STAT signalling pathway and AMPs in the presence of Borrelia spirochetes in Ixodes ricinus
Abstract Multicellular animals need to control the spread of invading pathogens. This is a particular challenge for blood-feeding vectors such as ticks, which ingest large amounts of blood potentially laden with harmful microorganisms. Ticks have a basic innate immune system and protect themselves from infection through innate immune responses involving pathways such as Janus kinase (JAK) or the signalling transducer activator of transcription (STAT). Direct antimicrobial defence occurs through the rapid synthesis of numerous antimicrobial agents including antimicrobial peptides (AMPs). The tick Ixodes ricinus is one of the main vectors of the Lyme disease pathogen, the spirochete Borrelia burgdorferi sensu lato. Data suggest that the JAK/STAT signalling pathway controls the expression of AMPs and regulates the infection of the pathogen in the tick body. The innate immune system during the off-host period keeps the level of spirochete infection in check. Spirochetes may influence the innate immune response in ticks. Therefore, the aim of this study was to analyse the expression of the genes related to the JAK/STAT pathway and selected AMPs in questing ticks in which B. burgorferi s.l. was detected. In the ticks infected with spirochetes, overexpression of genes related to the JAK/STAT signalling pathway was observed in the case of STAM and SOCS genes. AMPs genes such as def1, ric, lzs were overexpressed with different expression patterns. The results obtained suggest that AMPs may be involved in infection management in ticks.
Structure and mechanism of biosynthesis of Streptococcus mutans cell wall polysaccharide
Abstract Streptococcus mutans, the causative agent of human dental caries, expresses a cell wall attached Serotype c-specific Carbohydrate (SCC) that is critical for cell viability. SCC consists of a polyrhamnose backbone of →3)α-Rha(1 → 2)α-Rha(1→ repeats with glucose (Glc) side-chains and glycerol phosphate (GroP) decorations. This study reveals that SCC has one predominant and two more minor Glc modifications. The predominant Glc modification, α-Glc, attached to position 2 of 3-rhamnose, is installed by SccN and SccM glycosyltransferases and is the site of the GroP addition. The minor Glc modifications are β-Glc linked to position 4 of 3-rhamnose installed by SccP and SccQ glycosyltransferases, and α-Glc attached to position 4 of 2-rhamnose installed by SccN working in tandem with an unknown enzyme. Both the major and the minor β-Glc modifications control bacterial morphology, but only the GroP and major Glc modifications are critical for biofilm formation.
Mechanistic insights into pachymic acid’s action on triple-negative breast Cancer through TOP2A targeting
A lightweight prosthetic hand with 19-DOF dexterity and human-level functions
Modified titanium post with polished sidewalls and prefabricated shoulders can effectively preserve the teeth with subgingival defects
Seismic versus aseismic slip for the 2023 Kahramanmaraş earthquake doublet
Understanding the influence of stratification for mine water management: a comparative study
Motif distribution and DNA methylation underlie distinct Cdx2 binding during development and homeostasis
The expanded theory of planned behavior for energy saving among academics in Romania, Bulgaria, Turkey, and Slovakia
Abstract Given the escalating global energy consumption and the concurrent economic and energy crises, energy-saving behaviour must be adopted on a large scale. Universities that are energy-intensive institutions should be one of the institutions where energy-saving behaviour is widely adopted. Academics devote a substantial portion of their time to their offices, which leads to increased energy usage. However, no study has investigated academics’ energy-saving behaviours in the literature. Most studies focus on students or employees in various organizations. Our study tries to cover the gap by examining the energy-saving behaviour of academics in four countries (Romania, Bulgaria, Turkey, and Slovakia) based on the expanded Theory of Planned Behaviour. A questionnaire was distributed to 228 academics from the four countries to gather data. The research hypotheses were tested using partial least squares structural equation modelling. The findings show that individual factors (attitude and perceived behaviour control) influence the energy-saving intention of academics but not the organisational factors due to the weak identification with their universities. The study offers valuable insights for policymakers seeking to promote energy-saving programs in academic institutions. The academics can be seen as role models for their students which emphasizes the need to study more their sustainable behaviours.
Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment
Abstract Gammaherpesviruses are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus and murine gammaherpesvirus 68, this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of gammaherpesvirus pathogenesis, we demonstrate in vivo that the tumor suppressor p53 is activated specifically in B cells latently infected by murine gammaherpesvirus 68. In the absence of p53, the early expansion of murine gammaherpesvirus 68 latency greatly increases, especially in germinal center B cells, a cell type whose proliferation is conversely restricted by p53. We identify the B cell-specific latency gene M2, a viral promoter of germinal center B cell differentiation, as a viral protein sufficient to elicit a p53-dependent anti-proliferative response caused by Src-family kinase activation. We further demonstrate that Epstein-Barr virus-encoded latent membrane protein 1 similarly triggers a p53 response in primary B cells. Our data highlight a model in which gammaherpesvirus latency gene-expression programs that promote B cell proliferation and differentiation to facilitate viral colonization of the host trigger aberrant cellular proliferation that is controlled by p53.