Thermodynamics of nucleosome breathing and positioning.

Nucleosomes are fundamental units of chromatin in which a length of genomic DNA is wrapped around a histone octamer spool in a left-handed superhelix. Large-scale nucleosome maps show a wide distribution of DNA wrapping lengths, which in some cases are tens of base pairs (bp) shorter than the 147 bp canonical wrapping length observed in nucleosome crystal structures. Here, we develop a thermodynamic model that assumes a constant free energy cost of unwrapping a nucleosomal bp.

Nighttime safety of daridorexant: Evaluation of responsiveness to an external noise stimulus, postural stability, walking, and cognitive function.

Background: Daridorexant is a dual orexin receptor antagonist approved for the treatment of chronic insomnia disorder.

Aims: Investigate the auditory awakening threshold (AAT), postural stability, and cognitive function during the night following evening administration of daridorexant 25 and 50 mg.

Methods: Double-blind, placebo-controlled, randomized, 3-way (placebo, 25, 50 mg) crossover study in 36 healthy male and female nonelderly adult and elderly subjects (1:1 sex/age ratio).

Discovery, synthesis and SAR of 2-acyl-1-biarylmethyl pyrazolidines, dual orexin receptor antagonists designed as fast and short-acting sleeping drugs.

Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (<4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and in vivo experiments to identify DORAs eliciting this specific hypnotic profile.

Prenatal Diagnosis of Myhre Syndrome in Two Cases: Further Delineation of the Cardiac and External Phenotype.

Myhre syndrome is a rare genetic disease caused by recurrent gain-of-function variants in SMAD4 (Ile500Thr, Ile500Val, Arg496Cys, and Ile500Met) characterized by postnatal short stature with pseudo-muscular build, joint stiffness, variable intellectual disability, hearing loss, and a distinctive pattern of dysmorphic facial features. The course can be severe in some cases, with life-threatening cardiac and pulmonary complications caused by connective tissue involvement. These progressive features over time make early clinical diagnosis difficult but possible by astute clinicians who evaluate young children with autism or short stature and unusual appearance.

Daridorexant for patients with chronic insomnia disorder: number needed to treat, number needed to harm, and likelihood to be helped or harmed.

Objectives: Appraise the evidence for daridorexant 50 mg and 25 mg versus placebo when treating chronic insomnia disorder in terms of number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).

Methods: NNT, NNH, and LHH were calculated from a 3-month pivotal Phase 3 study ( = 930; randomized 1:1:1 to daridorexant 50 mg, daridorexant 25 mg, or placebo once nightly). Wakefulness after sleep onset, latency to persistent sleep, self-reported total sleep time, Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), and Insomnia Severity Index were used for the NNT efficacy analysis.

Evaluating the efficacy of the selective orexin 1 receptor antagonist nivasorexant in an animal model of binge-eating disorder.

Objective: Test the efficacy of the selective orexin 1 receptor (OX1R) antagonist (SO1RA) nivasorexant in an animal model of binge-eating disorder (BED) and study its dose-response relationship considering free brain concentrations and calculated OX1R occupancy. Compare nivasorexant's profile to that of other, structurally diverse SO1RAs. Gain understanding of potential changes in orexin-A (OXA) neuropeptide and deltaFosB (ΔFosB) protein expression possibly underlying the development of the binge-eating phenotype in the rat model used.

Nonsurgical Treatment of Postburn Hypopigmentation: A Literature Review.

The treatment of postburn hypopigmentation was primarily surgical before the advent of new technologies. Medical devices and therapies are emerging to manage scar sequelae that can be disfiguring and associated with severe psychosocial impact. These innovations have been poorly investigated for hypopigmentation, but they represent a real hope.

Analysis of the rate of force development reveals high neuromuscular fatigability in elderly patients with chronic kidney disease.

Background: Chronic kidney disease (CKD) induces muscle wasting and a reduction in the maximum voluntary force (MVF). Little is known about the neuromuscular fatigability in CKD patients, defined as the reduction of muscle force capacities during exercise. Neuromuscular fatigability is a crucial physical parameter of the daily living.

NOTCH2 related disorders: Description and review of the fetal presentation.

Signs of skeletal dysplasias are relatively common in fetuses with abnormal ultrasound (US) findings. The diversity of congenital skeletal disorders, the possibility of late-onset severe phenotypes and overlapping syndromes can be a challenge in the way of diagnosis, even if prenatal high-throuput sequencing allows for a better diagnosis, prognosis and genetic counseling. Hajdu-Cheney spectrum pathologies are rarely described in prenatal, and the signs associated remain poorly known, and do not include specific postnatal signs as acro-osteolysis and premature osteoporosis.

The orexin story and orexin receptor antagonists for the treatment of insomnia.

Insomnia is present in up to one third of the adult population worldwide, and it can present independently or with other medical conditions such as mental, metabolic, or cardiovascular diseases, which highlights the importance of treating this multifaceted disorder. Insomnia is associated with an abnormal state of hyperarousal (increased somatic, cognitive, and cortical activation) and orexin has been identified as a key promotor of arousal and vigilance. The current standards of care for the treatment of insomnia recommend non-pharmacological interventions (cognitive behavioural therapy) as first-line treatment and, if behavioural interventions are not effective or available, pharmacotherapy.

4D epigenomics: deciphering the coupling between genome folding and epigenomic regulation with biophysical modeling.

Recent experimental observations suggest a strong coupling between the 3D nuclear chromosome organization and epigenomics. However, the mechanistic and functional bases of such interplay remain elusive. In this review, we describe how biophysical modeling has been instrumental in characterizing how genome folding may impact the formation of epigenomic domains and, conversely, how epigenomic marks may affect chromosome conformation.

Can a Predetermined Grid and Multidisciplinary Consultation Improve the Description of Cleft lip with or Without Cleft Palate?

Objective: Evaluate the two-dimensional (2D) ultrasound (US) grid and multidisciplinary consultation (maxillofacial surgeon-sonographer) during prenatal US imaging to improve the sensitivity of prenatal description for cleft lip (CL) with or without alveolar cleft (CLA) or +/- cleft palate (CLP).

Design: Retrospective study of children with CL/P in a tertiary children's Hospital.

Setting: Single-center cohort study conducted in a tertiary pediatric Hospital.

Outcomes and Reliability of Perforator Flaps in the Reconstruction of Hidradenitis Suppurativa Defects: A Systemic Review and Meta-Analysis.

Introduction: Hidradenitis suppurativa (HS) is a common and debilitating disease, in which the only effective treatment involves a wide excision of the affected skin. Secondary wound healing and skin grafting are two well-known options for managing these defects, but perforator flaps provide a new therapeutic alternative by ensuring reconstructions of large defects, reducing donor site morbidity, and enhancing functional recovery. The aim of this study was to achieve a systematic review of perforator flaps use in HS.

A Gardos channelopathy associated with nonimmune hydrops and fetal loss.

Dehydrated hereditary stomatocytosis (DHS) (MIM#194380) is a rare autosomal dominant disorder of red blood cell permeability, characterized by a partially or fully compensated nonimmune hemolytic anemia. PIEZO1 is the major gene involved with hundreds of families described, some of which present transient perinatal edema of varying severity. A smaller subset of individuals harbors pathogenic variants in KCNN4, sometimes referred as "Gardos channelopathy.

Painters in chromatin: a unified quantitative framework to systematically characterize epigenome regulation and memory.

In eukaryotes, many stable and heritable phenotypes arise from the same DNA sequence, owing to epigenetic regulatory mechanisms relying on the molecular cooperativity of 'reader-writer' enzymes. In this work, we focus on the fundamental, generic mechanisms behind the epigenome memory encoded by post-translational modifications of histone tails. Based on experimental knowledge, we introduce a unified modeling framework, the painter model, describing the mechanistic interplay between sequence-specific recruitment of chromatin regulators, chromatin-state-specific reader-writer processes and long-range spreading mechanisms.

[The multiple perspectives of the multipurpose home care service].

The Cosi home nursing service (Ssiad), created in 2000, is committed to working in partnership, considering that cooperation and good coordination are at the origin of a sustainable and quality home care. With this in mind, the directors of Ssiad took over the management of a home assistance and support service in 2011 in order to offer personal assistance and care, and thus to provide comprehensive care. Now a multi-purpose home help and care service, Cosi continues to evolve to best meet the needs of users.

Driving Performance after Bedtime Administration of Daridorexant, Assessed in a Sensitive Simulator.

Use of hypnotics is often associated with next-morning residual effects and a higher risk of motor vehicle accidents. Measuring next-morning effects on driving performance is therefore advised by regulatory agencies. Here, we examined driving performance following administration of daridorexant, a new dual orexin receptor antagonist developed to treat insomnia.

The first two non-Finnish HYLS1 variants: Expanding the phenotypic spectrum of hydrolethalus syndrome.

Hydrolethalus syndrome (HLS) is a rare lethal fetal malformation disorder related to ciliogenesis disruption. This condition is more frequent in Finland where a founder missense variant in the HYLS1 gene was identified. No other HYLS1 variant has hitherto been implicated in HLS.

Coupling between Sequence-Mediated Nucleosome Organization and Genome Evolution.

The nucleosome is a major modulator of DNA accessibility to other cellular factors. Nucleosome positioning has a critical importance in regulating cell processes such as transcription, replication, recombination or DNA repair. The DNA sequence has an influence on the position of nucleosomes on genomes, although other factors are also implicated, such as ATP-dependent remodelers or competition of the nucleosome with DNA binding proteins.

Cardiac rhabdomyoma with hydrops fetalis: Prenatal management by abdominal drainage.

Objective: We described a case of fetal cardiac rhabdomyoma complicated by hydrops. And we discussed our approach during pregnancy.

Case Report: A 23-year-old woman primigravida was referred at 29 weeks of gestation (WG) to prenatal unit for a large hyperechogenic intracardiac mass associated with fetal hydrops.

Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders.

Introduction: The last two decades have witnessed a rapid increase in the knowledge about the role of the orexin system, particularly in the regulation of wakefulness and arousal. Dual orexin receptor antagonists (DORAs) have been approved for the treatment of insomnia disorders (suvorexant, lemborexant) and drugs with a distinctive profile (daridorexant) or orexin-2 receptor selectivity (seltorexant) are in development.

Areas Covered: This review discusses pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety properties of orexin receptor antagonists (ORAs).