The rockefeller university

We examine the role of higher- order transient structures (HOTS) in M2R regulation of GIRK channels. Electron microscopic membrane protein location maps show that both proteins form HOTS that exhibit a statistical bias to be near each other. Theoretical calculations and electrophysiological measurements suggest that channel activity is isolated near larger M2R HOTS. By invoking weak interactions that permit transient binding of M2R to M2R and GIRK to GIRK ( i-i interactions) and M2R to GIRK ( i-j interactions), the distribution patterns and electrophysiological properties of HL- 1 cells are replicated in a reaction- diffusion simulation. We propose the principle of dynamic connectivity to explain communication between protein components of a membrane signaling pathway. Dynamic connectivity is mediated by weak, transient interactions between proteins. HOTS created by weak i-i interactions, and statistical biases created by weak i-j interactions promoted by the multivalence of HOTS, are the key elements of dynamic connectivity.

JMJD1C (Jumonji Domain Containing 1C), a member of the lysine demethylase 3 (KDM3) family, is universally required for the survival of several types of acute myeloid leukemia (AML) cells with different genetic mutations, representing a therapeutic opportunity with broad application. Yet how JMJD1C regulates the leukemic programs of various AML cells is largely unexplored. Here we show that JMJD1C interacts with the master hematopoietic transcription factor RUNX1, which thereby recruits JMJD1C to the genome to facilitate a RUNX1-driven transcriptional program that supports leukemic cell survival. The underlying mechanism hinges on the long N-terminal disordered region of JMJD1C, which harbors two inseparable abilities: condensate formation and direct interaction with RUNX1. This dual capability of JMJD1C may influence enhancer-promoter contacts crucial for the expression of key leukemic genes regulated by RUNX1. Our findings demonstrate a previously unappreciated role for the non-catalytic function of JMJD1C in transcriptional regulation, underlying a mechanism shared by different types of leukemias.

Ticks are obligate hematophagous arthropods that can transmit pathogens and are important vectors of diseases affecting wild and domestic animals, as well as humans, thus representing a serious risk to public health. Despite the growing concern about arboviruses, our understanding of tick-borne viruses remains limited compared to those transmitted by mosquitoes. We performed metagenomic analysis, focusing on the virome of ticks collected from wild animals in the countryside of the state of S & atilde;o Paulo, Brazil. The experimental analysis highlighted important molecular evidence of a potential new virus from the Jingmenvirus group in ticks collected from wild animals. The four pools that were positive included Amblyomma sculptum and A. nodosum ticks, collected from Myrmecophaga tridactyla, Callithrix penicillata, and Cerdocyon thous. These data suggest that it is a new member of the Jingmenvirus group, which we propose to be named Rio Preto tick virus (RPTV). In addition, the RPTV genome was analysed in silico, and proteins with high homology to those of the Jingmenvirus group were identified. Here, we report the identification of a potentially novel virus found in ticks from wild animals in southeastern Brazil. This study contributes to the epidemiological surveillance of the region and helps to understand the potential risks of the emergence of zoonoses, which can impact human health, in addition to the potential impacts on the fauna.

The diversity of germ cell developmental strategies has been well documented across many vertebrate clades. However, much of our understanding of avian primordial germ cell (PGC) specification and differentiation has derived from only one species, the chicken ( Gallus gallus). ). Of the three major classes of birds, chickens belong to Galloanserae, representing less than 4% of species, while nearly 95% of extant bird species belong to Neoaves. This represents a significant gap in our knowledge of germ cell development across avian species, hampering efforts to adapt genome editing and reproductive technologies developed in chicken to other birds. We therefore applied single-cell RNA sequencing to investigate inter-species differences in germ cell development between chicken and zebra finch ( Tae- niopygia castanotis), ), a Neoaves songbird species and a common model of vocal learning. Analysis of early embryonic male and female gonads revealed the presence of two distinct early germ cell types in zebra finch and only one in chicken. Both germ cell types expressed zebra finch Germline Restricted Chromosome (GRC) genes, present only in songbirds among birds. One of the zebra finch germ cell types expressed the canonical PGC markers, as did chicken, but with expression differences in several signaling pathways and biological processes. The second zebra finch germ cell cluster was marked by proliferation and fate determination markers, indicating beginning of differentiation. Notably, these two zebra finch germ cell populations were present in both male and female zebra finch gonads as early as HH25. Using additional chicken developmental stages, similar germ cell heterogeneity was identified in the more developed gonads of females, but not males. Overall, our study demonstrates a substantial heterochrony in zebra finch germ cell development compared to chicken, indicating a richer diversity of avian germ cell developmental strategies than previously known.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. The rapid development of highly effective vaccines2,3 against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics4 have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity5. Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant (Kd) of 61 pM and a half-maximal effective concentration (EC50) of 11 nM, inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in primary small airway epithelial cells and in a transgenic mouse model of SARS CoV-2 infection with an efficacy comparable with the FDA-approved reversible covalent protease inhibitor nirmatrelvir6. The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.

Histone H3 monoaminylations at Gln5 represent an important family of epigenetic marks in brain that have critical roles in permissive gene expression1, 2-3. We previously demonstrated that serotonylation4, 5, 6, 7, 8, 9-10 and dopaminylation9,11, 12-13 of Gln5 of histone H3 (H3Q5ser and H3Q5dop, respectively) are catalysed by transglutaminase 2 (TG2), and alter both local and global chromatin states. Here we found that TG2 additionally functions as an eraser and exchanger of H3 monoaminylations, including H3Q5 histaminylation (H3Q5his), which displays diurnally rhythmic expression in brain and contributes to circadian gene expression and behaviour. We found that H3Q5his, in contrast to H3Q5ser, inhibits the binding of WDR5, a core member of histone H3 Lys4 (H3K4) methyltransferase complexes, thereby antagonizing methyltransferase activities on H3K4. Taken together, these data elucidate a mechanism through which a single chromatin regulatory enzyme has the ability to sense chemical microenvironments to affect the epigenetic states of cells, the dynamics of which have critical roles in the regulation of neural rhythmicity.

IntroductionPatient demographics, disease characteristics, and treatment history can impact the efficacy of biologic treatments in patients with psoriasis. Understanding the efficacy of biologics, such as bimekizumab, across diverse patient subgroups is important for optimising treatment outcomes. Here, we assess whether high overall clinical responses observed in bimekizumab-treated patients with moderate to severe plaque psoriasis are consistent across subgroups, both versus comparators and with long-term treatment. MethodsData were analysed post hoc from the BE SURE, BE VIVID, and BE READY phase 3 trials, their open-label extension (OLE) BE BRIGHT, and the BE RADIANT phase 3b trial. Patients received either bimekizumab or adalimumab to week 24 (BE SURE), bimekizumab or ustekinumab to week 52 (BE VIVID), and bimekizumab or secukinumab to week 48 (BE RADIANT). In the 3-year pooled analysis (all trials), included patients received bimekizumab continuously from baseline into the OLE. Subgroups of patients with moderate to severe plaque psoriasis were defined by age, sex, weight, disease duration, disease severity, nail involvement (modified Nail Psoriasis Severity Index > 0), and prior biologic exposure, at baseline. The proportions of patients achieving complete skin clearance (PASI 100; 100% improvement from baseline in Psoriasis Area and Severity Index) in each subgroup are reported alongside 95% confidence intervals (CI). Modified non-responder imputation (mNRI) was used for missing data. ResultsFollowing comparator-controlled periods, the proportion of bimekizumab-treated patients who achieved PASI 100 was consistent across subgroups and numerically greater versus patients who received adalimumab (to week 24), ustekinumab (to week 52), and secukinumab (to week 48) in all subgroups. Among patients who received bimekizumab continuously for 3 years (N = 1107), PASI 100 response rates remained consistent across age (68.6% [40 to < 65 years]-73.7% [>= 65 years]), sex (69.6% [male]-71.4% [female]), weight (63.4% [>= 103.9 kg]-75.5% [< 74.3 kg]), disease duration (65.5% [<= 5 years]-71.1% [> 20 years]), disease severity (67.7% [PASI 12 to < 15]-71.1% [PASI >= 20]), nail involvement (69.1% [yes]/71.3% [no]), and prior biologic exposure (71.7% [yes]/69.1% [no]; prior anti-TNF exposure 67.6% [yes]/70.6% [no]) subgroups; 95% CIs overlapped in all instances, indicating no meaningful differences between subgroups. ConclusionBimekizumab demonstrated consistently high long-term efficacy in patients with psoriasis across diverse subgroups. Higher rates of PASI 100 were achieved with bimekizumab versus adalimumab, ustekinumab, and secukinumab, across all subgroups. These results highlight bimekizumab as an effective treatment for a broad range of people living with psoriasis. Trial RegistrationNCT03412747, NCT03370133, NCT03410992, NCT03598790, NCT03536884. PLAIN LANGUAGE SUMMARY Psoriasis is a long-lasting skin condition affect-ing around 1 in every 50 people. Since psoriasis is common, people with the condition differ in terms of who they are, how psoriasis affects them, other health conditions they may have, and past treatments. These differences can affect how a drug works and choosing the correct treatment for individual patients is important. Finding treat-ments that work equally well across diverse groups of people would help make treatment decisions easier. Previous studies have shown that bimeki-zumab, a treatment for psoriasis, works better than other treatments (adalimumab, ustekinumab, and secukinumab) to completely clear the skin and keep it clear for a long time. To see if these results were consistent across diverse groups of people, we categorised patients into subgroups based on age, sex, body weight, health conditions, psoria-sis duration and severity, and prior treatments. We analysed results from people taking bimeki-zumab and other similar treatments for periods of up to 1 year, as well as those receiving bime-kizumab continuously for 3 years. Bimekizumab consistently helped a high number of patients achieve completely clear skin, regardless of their background. In all subgroups, approximately 7 out of 10 patients had completely clear skin after 3 years of continuous bimekizumab treatment. Over periods of up to 1 year, more patients treated with bimekizumab had completely clear skin com-pared with adalimumab, ustekinumab, and secuki-numab, in all analysed subgroups. These results indicate that bimekizumab is an effective treat-ment for a wide range of people with moderate to severe psoriasis.

Despite significant interest in therapeutic targeting of splicing, few chemical probes are available for the proteins involved in splicing. Here, we show that elaborated stereoisomeric acrylamide EV96 and its analogues lead to a selective T cell state-dependent loss of interleukin 2-inducible T cell kinase (ITK) by targeting one of the core splicing factors SF3B1. Mechanistic investigations suggest that the state-dependency stems from a combination of differential protein turnover rates and extensive ITK mRNA alternative splicing. We further introduce the most comprehensive list to date of proteins involved in splicing and leverage cysteine- and protein-directed activity-based protein profiling with electrophilic scout fragments to demonstrate covalent ligandability for many classes of splicing factors and splicing regulators in T cells. Taken together, our findings show how chemical perturbation of splicing can lead to immune state-dependent changes in protein expression and provide evidence for the broad potential to target splicing factors with covalent chemistry.

Background Reference genomes for the entire sea turtle clade have the potential to reveal the genetic basis of traits driving the ecological and phenotypic diversity in these ancient and iconic marine species. Furthermore, these genomic resources can support conservation efforts and deepen our understanding of their unique evolution.Results We present haplotype-resolved, chromosome-level reference genomes and high-quality gene annotations for 5 sea turtle species. This completes the catalog of reference genomes of the entire sea turtle clade when combined with our previously published reference genomes. Our analysis reveals remarkable genome synteny and collinearity across all species, despite the clade's origin dating back more than 60 million years. Regions of high interspecific genetic distance and intraspecific genetic diversity are consistently clustered in genomic hotspots, which are enriched with genes coding for immune response proteins, olfactory receptors, zinc fingers, and G-protein-coupled receptors. These hotspot regions may offer insights into the genetic mechanisms driving phenotypic divergence among species and represent areas of significant adaptive potential. Ancient demographic analysis revealed a synchronous population expansion among sea turtle species during the Pleistocene, with varying magnitudes of demographic change, likely shaped by their diverse ecological adaptations and biogeographic contexts.Conclusions Our work provides genomic resources for exploring genetic diversity, evolutionary adaptations, and demographic histories of sea turtles. We outline genomic regions with increased diversity, linked to immune response, sensory evolution, and adaptation to varying environments that have historically been subject to strong diversifying selection and likely will underpin sea turtles' responses to future environmental change. These reference genomes can assist conservation by providing insights into the demographic and evolutionary processes that sustain and threaten these iconic species.