The Scalable Variant Call Representation: Enabling Genetic Analysis Beyond One Million Genomes.

Motivation: The Variant Call Format (VCF) is widely used in genome sequencing but scales poorly. For instance, we estimate a 150,000 genome VCF would occupy 900 TiB, making it costly and complicated to produce, analyze, and store. The issue stems from VCF's requirement to densely represent both reference-genotypes and allele-indexed arrays.

Botulinum toxin injection for retrograde cricopharyngeal muscle dysfunction syndrome.

Retrograde cricopharyngeal dysfunction (RCPD) syndrome renders patients unable to belch, causing disabling symptoms that impact quality of life. Injection of botulinum toxin into the cricopharyngeal muscle has been reported as a trial treatment for both therapeutic and diagnostic purposes. We describe the injection technique, under general anesthesia using endoscopy or by transcutaneous injection with electromyographic control.

First example of airway restoration using cryopreserved aortic allograft after total laryngectomy: CARE case report.

Case Description: A 70 year-old woman presenting T4aN2cM0 laryngeal carcinoma first underwent total laryngectomy with airway reconstruction by cryopreserved aortic allograft. Six months after chemoradiotherapy, she underwent endoscopic surgery to create a neo-laryngopharynx.

Results: At 13 months after primary surgery, day- and night-time breathing was effectively restored, with a little persistent salivary false passage, and a whispering but comprehensible voice after tracheostomy closure.

A Genetically Encoded Redox-Active Nicotinamide Amino Acid.

Nicotinamide-containing cofactors play an essential role in many enzymes that catalyze two-electron redox reactions. However, it is difficult to engineer nicotinamide binding sites into proteins due to the extended nature of the cofactor-protein interface and the precise orientation of the nicotinamide moiety required for efficient electron transfer to or from the substrate. To address these challenges, we genetically encoded a noncanonical amino acid (ncAA) bearing a nicotinamide side chain in bacteria.

Impact of facial nerve resection in parotid cancer abutting the facial nerve without preoperative paralysis: A multicentric propensity score-based analysis.

Objectives: The management of the facial nerve (FN) is a major issue in parotid cancer, especially when there is no preoperative facial palsy and FN invasion is discovered intraoperatively. The aim of this study was to assess the impact of FN resection in patients with parotid cancer abutting the FN, without pretreatment facial palsy, using a propensity score matching.

Materials And Methods: Data from all patients treated between 2009 and 2020 for a primary parotid cancer abutting or invading the FN but without pretreatment facial palsy were extracted from the national multicentric REFCOR database.

Recent advances in the expanding genetic code.

For over a billion years, the central dogma of biology has been limited largely to 20 canonical amino acids with relatively simple functionalities. The ability to rationally add new building blocks to the genetic code has enabled the site-specific incorporation of hundreds of noncanonical amino acids (ncAAs) with novel properties into proteins in living organisms. Recent technological advances have enabled high level mammalian expression of proteins containing ncAAs, the use of unique codons to direct ncAA incorporation, extension of this methodology to a range of eukaryotic organisms, and the ability to encode building blocks beyond α-amino acids.

Using ground state and excited state density functional theory to decipher 3dopant defects in GaN.

Using ground state density functional theory (DFT) and implementing an occupation-constrained DFT (occ-DFT) for self-consistent excited state calculations, we decipher the electronic structure of the Mn dopant and other 3defects in GaN across the band gap. Our analysis, validated with broad agreement with defect levels (ground-state calculations) and photoluminescence data (excited-state calculations), mandates reinterpretation and reassignment of 3defect data in GaN. The Mndefect is determined to span stable charge states from (1-) in-type GaN through (2+) in-type GaN.

Validation of Autism Stigma Knowledge - Questionnaire (ASK-Q) for Brazilian Portuguese.

Background: Low levels of knowledge among health professionals about autism spectrum disorders (ASD) can impair the care provided to people with autism. In Brazil, there are still no validated instruments that assess the knowledge of pharmacy students and pharmacists regarding ASD.

Objective: This study aimed to carry out the cross-cultural adaptation of the Autism Stigma Knowledge Questionnaire (ASK-Q) into Brazilian Portuguese and to evaluate the evidence of content validity.

An Orthogonal T7 Replisome for Continuous Hypermutation and Accelerated Evolution in .

Systems that perform continuous hypermutation of designated genes without compromising the integrity of the host genome can dramatically accelerate the evolution of new or enhanced protein functions. We describe an orthogonal DNA replication system in based on the controlled expression of the replisome of bacteriophage T7. The system replicates circular plasmids that enable high transformation efficiencies and seamless integration into standard molecular biology workflows.

Synthesis at the Interface of Chemistry and Biology.

ConspectusChemical synthesis as a tool to control the structure and properties of matter is at the heart of chemistry─from the synthesis of fine chemicals and polymers to drugs and solid-state materials. But as the field evolves to tackle larger and larger molecules and molecular complexes, the traditional tools of synthetic chemistry become limiting. In contrast, Mother Nature has developed very different strategies to create the macromolecules and molecular systems that make up the living cell.

An unnatural amino acid dependent, conditional Pseudomonas vaccine prevents bacterial infection.

Live vaccines are ideal for inducing immunity but suffer from the need to attenuate their pathogenicity or replication to preclude the possibility of escape. Unnatural amino acids (UAAs) provide a strategy to engineer stringent auxotrophies, yielding conditionally replication incompetent live bacteria with excellent safety profiles. Here, we engineer Pseudomonas aeruginosa to maintain auxotrophy for the UAA p-benzoyl-L-phenylalanine (BzF) through its incorporation into the essential protein DnaN.

Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention.

In efforts towards eliminating malaria, a discovery program was initiated to identify a novel antimalarial using KAF156 as a starting point. Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment (∼40-106 mg) and one-month chemoprevention (∼96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156.

A Prodrug Strategy to Reposition Atovaquone as a Long-Acting Injectable for Malaria Chemoprotection.

Recent malaria drug discovery approaches have been extensively focused on the development of oral, smallmolecule inhibitors for disease treatment whereas parenteral routes of administration have been avoided due to limitations in deploying a shelf-stable injectable even though it could be dosed less frequently. However, an updated target candidate profile from Medicines for Malaria Venture (MMV) and stakeholders have advocated for long-acting injectable chemopreventive agents as an important interventive tool to improve malaria prevention. Here, we present strategies for the development of a long-acting, intramuscular, injectable atovaquone prophylactic therapy.

Principled distillation of UK Biobank phenotype data reveals underlying structure in human variation.

Data within biobanks capture broad yet detailed indices of human variation, but biobank-wide insights can be difficult to extract due to complexity and scale. Here, using large-scale factor analysis, we distill hundreds of variables (diagnoses, assessments and survey items) into 35 latent constructs, using data from unrelated individuals with predominantly estimated European genetic ancestry in UK Biobank. These factors recapitulate known disease classifications, disentangle elements of socioeconomic status, highlight the relevance of psychiatric constructs to health and improve measurement of pro-health behaviours.

Discovering type I cis-AT polyketides through computational mass spectrometry and genome mining with Seq2PKS.

Type 1 polyketides are a major class of natural products used as antiviral, antibiotic, antifungal, antiparasitic, immunosuppressive, and antitumor drugs. Analysis of public microbial genomes leads to the discovery of over sixty thousand type 1 polyketide gene clusters. However, the molecular products of only about a hundred of these clusters are characterized, leaving most metabolites unknown.

TERT activation targets DNA methylation and multiple aging hallmarks.

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade.

Corrected speciation and gyromitrin content of false morels linked to ALS patients with mostly slow-acetylator phenotypes.

A case-control study of sporadic amyotrophic lateral sclerosis (ALS) in a mountainous village in the French Alps discovered an association of cases with a history of eating wild fungi (false morels) collected locally and initially identified and erroneously reported as . Specialist re-examination of dried specimens of the ALS-associated fungi demonstrated they were members of the group, namely , species that have been reported to contain substantially higher concentrations of gyromitrin than present in . Gyromitrin is metabolized to monomethylhydrazine, which is responsible not only for the acute oral toxic and neurotoxic properties of false morels but also has genotoxic potential with proposed mechanistic relevance to the etiology of neurodegenerative disease.

Nanoscale Three-Dimensional Imaging of Integrated Circuits Using a Scanning Electron Microscope and Transition-Edge Sensor Spectrometer.

X-ray nanotomography is a powerful tool for the characterization of nanoscale materials and structures, but it is difficult to implement due to the competing requirements of X-ray flux and spot size. Due to this constraint, state-of-the-art nanotomography is predominantly performed at large synchrotron facilities. We present a laboratory-scale nanotomography instrument that achieves nanoscale spatial resolution while addressing the limitations of conventional tomography tools.