The rockefeller university

For more than ten years, France has implemented several initiatives and programs aimed at promoting and exploiting the potential of next-generation sequencing (NGS) techniques in various fields. The country has a number of highly equipped next-generation sequencing platforms and research centers specializing in NGS. These infrastructures provide sequencing services to academic researchers, medical institutions and industrial partners. NGS is widely used in medical biology, particularly in molecular medicine and genetics, to develop personalized medicine approaches and in genomics research. Through several hearings with experts in the field of medical genetics and paleo-genomics, we obtained an overview of the contribution of NGS techniques to medicine and population genetics. We envisage several perspectives for the use of NGS in parallel with the biotechnological and bioinformatics progresses dedicated to it. (c) 2024 Published by Elsevier Masson SAS on behalf of l'Academie nationale de medecine.

Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing Cre into the globus pallidus led to similar circuit specificity and motor responses. Last, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in the subthalamic nucleus in PitX2-Cre parkinsonian mice resulted in reduced c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits noninvasively in vivo using clinically available devices.

Single-cell sequencing has characterized cell state heterogeneity across diverse healthy and malignant tissues. However, the plasticity or heritability of these cell states remains largely unknown. To address this, we introduce PATH (phylogenetic analysis of trait heritability), a framework to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. Applying PATH to a mouse model of pancreatic cancer, we observed heritability at the ends of the epithelial-to-mesenchymal transition spectrum, with higher plasticity at more intermediate states. In primary glioblastoma, we identified bidirectional transitions between stem- and mesenchymal-like cells, which use the astrocyte-like state as an intermediary. Finally, we reconstructed a phylogeny from single-cell whole-genome sequencing in B cell acute lymphoblastic leukemia and delineated the heritability of B cell differentiation states linked with genetic drivers. Altogether, PATH replaces qualitative conceptions of plasticity with quantitative measures, offering a framework to study somatic evolution.

A measurement of the production cross section of a Higgs boson with transverse momentum greater than 250 GeV is presented where the Higgs boson decays to a pair of tau leptons. It is based on proton-proton collision data collected by the CMS experiment at the CERN LHC at a center-of-mass energy of 13 TeV. The data sample corresponds to an integrated luminosity of 138 fb(-1). Because of the large transverse momentum of the Higgs boson the tau leptons from its decays are boosted and produced spatially close, with their decay products overlapping. Therefore, a dedicated algorithm was developed to reconstruct and identify them. The observed (expected) significance of the measured signal with respect to the standard model background-only hypothesis is 3.5 (2.2) standard deviations. The product of the production cross section and branching fraction is measured to be 1.64(-0.54)(+0.68) times the standard model expectation. The fiducial differential production cross section is also measured as functions of the Higgs boson and leading jet transverse momenta. This measurement extends the probed large-transverse-momentum region in the tau tau final state beyond 600 GeV.

Purpose Transcription factor 3 (TCF3) encodes 2 transcription factors generated by alternative splicing, E12 and E47, which contribute to early lymphocyte differentiation. In humans, autosomal dominant (AD) E47 transcription factor deficiency is an inborn error of immunity characterized by B-cell deficiency and agammaglobulinemia. Only the recurrent de novo p.E555K pathogenic variant has been associated with this disease and acts via a dominant-negative (DN) mechanism. In this study, we describe the first Asian patient with agammaglobulinemia caused by the TCF3 p.E555K variant and provide insights into the structure and function of this variant. Methods TCF3 variant was identified by inborn errors of immunity-related gene panel sequencing. The variant E555K was characterized by alanine scanning of the E47 basic region and comprehensive mutational analysis focused on position 555. Results The patient was a 25-year-old male with B-cell deficiency, agammaglobulinemia, and mild facial dysmorphic features. We confirmed the diagnosis of AD E47 transcription factor deficiency by identifying a heterozygous missense variant, c.1663 G>A; p.E555K, in TCF3. Alanine scanning of the E47 basic region revealed the structural importance of position 555. Comprehensive mutational analysis focused on position 555 showed that only the glutamate-to-lysine substitution had a strong DN effect. 3D modeling demonstrated that this variant not only abolished hydrogen bonds involved in protein-DNA interactions, but also inverted the charge on the surface of the E47 protein. Conclusions Our study reveals the causative mutation hotspot in the TCF3 DN variant and highlights the weak negative selection associated with the TCF3 gene.

Purpose: After September 11, 2001, nuclear threat prompted government agencies to develop medical countermeasures to mitigate two syndromes, the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS), both lethal within weeks. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS, no mitigator potentially deliverable under mass casualty conditions preserves the GI tract. We recently reported that anti-ceramide single-chain variable fragment (scFv) mitigates GI-ARS lethality, abrogating ongoing small intestinal endothelial apoptosis to rescue Lgr5+ + stem cells. Here, we examine long-term consequences of prevention of acute GI-ARS lethality. Methods and Materials: For these studies, C57BL/6J male mice were treated with 15 Gy whole body irradiation, the 90% GIARS lethal dose for this mouse strain. Results: Mice irradiated with 15 Gy alone or with 15 Gy + bone marrow transplantation (BMT) or anti-ceramide scFv, succumb to an ARS within 8 to 10 days. Autopsies reveal only mice receiving anti-ceramide scFv at 24 hours post-whole body irradiation display small intestinal rescue. No marrow reconstitution occurs in any group with attendant undetectable circulating blood elements. Mice receiving 15 Gy + BMT + scFv, however, normalize blood counts by day 12, suggesting that scFv also improves marrow reconstitution, a concept for which we provide experimental support. We show that at 14 Gy, the upper limit dose for H-ARS lethality before transition to GI-ARS lethality, anti-ceramide scFv markedly improves marrow take, reducing the quantity of marrow-conferring survival by more than 3-fold. Consistent with these fi ndings, mice receiving 15 Gy + BMT + scFv exhibit prolonged survival. At day 90, before sacrifice, fi ce, they display normal appearance, behavior, and serum biochemistries, and surprisingly, at full autopsy, near-normal physiology in all 42 tissues examined. Conclusions: Anti-ceramide scFv mitigates GI-ARS lethality and improves marrow reconstitution rendering prolonged survival with near normal autopsies. (c) 2023 Elsevier Inc. All rights reserved.

The capabilities of the human ear are remarkable. We can normally detect acoustic stimuli down to a threshold sound-pressure level of 0 dB (decibels) at the entrance to the external ear, which elicits eardrum vibrations in the picometer range. From this threshold up to the onset of pain, 120 dB, our ears can encompass sounds that differ in power by a trillionfold. The comprehension of speech and enjoyment of music result from our ability to distinguish between tones that differ in frequency by only 0.2%. All these capabilities vanish upon damage to the ear's receptors, the mechanoreceptive sensory hair cells. Each cochlea, the auditory organ of the inner ear, contains some 16,000 such cells that are frequency-tuned between similar to 20 Hz (cycles per second) and 20,000 Hz. Remarkably enough, hair cells do not simply capture sound energy: they can also exhibit an active process whereby sound signals are amplified, tuned, and scaled. This article describes the active process in detail and offers evidence that its striking features emerge from the operation of hair cells on the brink of an oscillatory instability-one example of the critical phenomena that are widespread in physics.

Hidradenitis suppurativa (HS) is a chronic skin disease characterized by painful, recurrent abscesses, nodules, and scarring, primarily in skin folds. The exact causes of HS are multifactorial, involving genetic, hormonal, and environmental factors. It is associated with systemic diseases such as metabolic syndrome and inflammatory bowel disease. Genetic studies have identified mutations in the gamma-secretase complex that affect Notch signaling pathways critical for skin cell regulation. Despite its high heritability, most reported HS cases do not follow a simple genetic pattern. In this article, we performed whole-exome sequencing (WES) on a cohort of 100 individuals with HS, and we provide a comprehensive review of the variants known to be described or associated with HS. 91 variants were associated with the gamma-secretase complex, and 78 variants were associated with other genes involved in the Notch pathway, keratinization, or immune response. Through this new genetic analysis, we have added ten new variants to the existing catalogs. All variants are available in a .vcf file and are provided as a resource for future studies.

RNA's ability to form and interconvert between multiple secondary and tertiary structures is critical to its functional versatility and the traditional view of RNA structures as static entities has shifted towards understanding them as dynamic conformational ensembles. In this review we discuss RNA structural ensembles and their dynamics, highlighting the concept of conformational energy landscapes as a unifying framework for understanding RNA processes such as folding, misfolding, conformational changes, and complex formation. Ongoing advancements in cryo-electron microscopy and chemical probing techniques are significantly enhancing our ability to investigate multiple structures adopted by conformationally dynamic RNAs, while traditional methods such as nuclear magnetic resonance spectroscopy continue to play a crucial role in providing high-resolution, quantitative spatial and temporal information. We discuss how these methods, when used synergistically, can provide a comprehensive understanding of RNA conformational ensembles, offering new insights into their regulatory functions.