Sex affects transcriptional associations with schizophrenia across the dorsolateral prefrontal cortex, hippocampus, and caudate nucleus.

Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.

Patterns of unwanted biological and technical expression variation among 49 human tissues.

Tissue gene expression studies are impacted by biological and technical sources of variation, which can be broadly classified into wanted and unwanted variation. The latter, if not addressed, results in misleading biological conclusions. Methods have been proposed to reduce unwanted variation, such as normalization and batch correction. A more accurate understanding of all causes of variation could significantly improve the ability of these methods to remove unwanted variation while retaining variation corresponding to the biological question of interest. We used 17,282 samples from 49 human tissues in the Genotype Tissue Expression (GTEx) dataset (v8) to investigate patterns and causes of expression variation. Transcript expression was transformed to z-scores and only the most variable 2% of transcripts were evaluated and clustered based on co-expression patterns. Clustered gene sets were assigned to different biological or technical causes based on histologic appearances and metadata elements. We identified 522 variable transcript clusters (median 11 per tissue) among the samples. Of these, 63% were confidently explained, 16% were likely explained, 7% were low confidence explanations and 14% had no clear cause. Histologic analysis annotated 46 clusters. Other common causes of variability included sex, sequencing contamination, immunoglobulin diversity, and compositional tissue differences. Less common biological causes included death interval (Hardy score), disease status, and age. Technical causes included blood draw timing and harvesting differences. Many of the causes of variation in bulk tissue expression were identifiable in the Tabula Sapiens dataset of single cell expression. This is among the largest explorations of the underlying sources of tissue expression variation. It uncovered expected and unexpected causes of variable gene expression and demonstrated the utility of matched histologic specimens. It further demonstrated the value of acquiring meaningful tissue harvesting metadata elements to use for improved normalization, batch correction, and analysis of both bulk and single cell RNA-seq data.

Navigating the Potential Energy Surface of CdSe Magic-Sized Clusters: Synthesis and Interconversion of Atomically Precise Nanocrystal Polymorphs.

Magic-sized clusters (MSCs) are kinetically stable, atomically precise intermediates along the quantum dot (QD) reaction potential energy surface. Literature precedent establishes two classes of cadmium selenide MSCs with QD-like inorganic cores: one class is proposed to be cation-rich with a zincblende crystal structure, while the other is proposed to be stoichiometric with a "wurtzite-like" core. However, the wide range of synthetic protocols used to access MSCs has made direct comparisons of their structure and surface chemistry difficult. Furthermore, the physical and chemical relationships between MSC polymorphs are yet to be established. Here, we demonstrate that both cation-rich and stoichiometric CdSe MSCs can be synthesized from identical reagents and can be interconverted through the addition of either excess cadmium or selenium precursor. The structural and compositional differences between these two polymorphs are contrasted using a combination of 1H NMR spectroscopy, X-ray diffraction (XRD), pair distribution function (PDF) analysis, inductively coupled plasma optical emission spectroscopy, and UV-vis transient absorption spectroscopy. The subsequent polymorph interconversion reactions are monitored by UV-vis absorption spectroscopy, with evidence for an altered cluster atomic structure observed by powder XRD and PDF analysis. This work helps to simplify the complex picture of the CdSe nanocrystal landscape and provides a method to explore structure-property relationships in colloidal semiconductors through atomically precise synthesis.

Patterns of unwanted biological and technical expression variation across 49 human tissues.

All tissue-based gene expression studies are impacted by biological and technical sources of variation. Numerous methods are used to normalize and batch correct these datasets. A more accurate understanding of all causes of variation could further optimize these approaches. We used 17,282 samples from 49 tissues in the Genotype Tissue Expression (GTEx) dataset (v8) to investigate patterns and causes of expression variation. Transcript expression was normalized to Z-scores and only the most variable 2% of transcripts were evaluated and clustered based on co-expression patterns. Clustered gene sets were solved to different biological or technical causes related to metadata elements and histologic images. We identified 522 variable transcript clusters (median 11 per tissue) across the samples. Of these, 64% were confidently explained, 15% were likely explained, 7% were low confidence explanations and 14% had no clear cause. Common causes included sex, sequencing contamination, immunoglobulin diversity, and compositional tissue differences. Less common biological causes included death interval (Hardy score), muscle atrophy, diabetes status, and menopause. Technical causes included brain pH and harvesting differences. Many of the causes of variation in bulk tissue expression were identifiable in the Tabula Sapiens dataset of single cell expression. This is the largest exploration of the underlying sources of tissue expression variation. It uncovered expected and unexpected causes of variable gene expression. These identified sources of variation will inform which metadata to acquire with tissue harvesting and can be used to improve normalization, batch correction, and analysis of both bulk and single cell RNA-seq data.

Developments in Pb-210 methodologies to provide chronologies for environmental change.

Chronologies generated from core profiles to apply dates to environmental changes commonly use the measurement of the activity of radionuclides deposited and stratified with physical environmental material. The most commonly reported nuclide to define chronologies covering the last 150 years is Pb-210, for which accepted data processing methodologies in the literature have focussed on the constant rate of supply (CRS) model and the more recently published Bayesian Plum model. This short communication describes a validation approach using defined sediment layers referred to as 'varve' counting, which provide known points of reference to account for uncertainty between generated dates from each model using published Pb-210 measurements. A significant improvement in the chronologies was observed when applying reference date corrections to the models. This was shown to be essential in providing confidence in reported datasets and accuracy of predicted chronologies, which will better inform the interpretation of environmental change, e.g. sedimentation rates, climate change, pollution pathways and land degradation. Generated chronologies from both the CRS and Plum methods showed good agreement with the established varve dates (typically < 4-year difference).

Photochemical and Electrochemical Applications of Proton-Coupled Electron Transfer in Organic Synthesis.

We present here a review of the photochemical and electrochemical applications of multi-site proton-coupled electron transfer (MS-PCET) in organic synthesis. MS-PCETs are redox mechanisms in which both an electron and a proton are exchanged together, often in a concerted elementary step. As such, MS-PCET can function as a non-classical mechanism for homolytic bond activation, providing opportunities to generate synthetically useful free radical intermediates directly from a wide variety of common organic functional groups. We present an introduction to MS-PCET and a practitioner's guide to reaction design, with an emphasis on the unique energetic and selectivity features that are characteristic of this reaction class. We then present chapters on oxidative N-H, O-H, S-H, and C-H bond homolysis methods, for the generation of the corresponding neutral radical species. Then, chapters for reductive PCET activations involving carbonyl, imine, other X═Y π-systems, and heteroarenes, where neutral ketyl, α-amino, and heteroarene-derived radicals can be generated. Finally, we present chapters on the applications of MS-PCET in asymmetric catalysis and in materials and device applications. Within each chapter, we subdivide by the functional group undergoing homolysis, and thereafter by the type of transformation being promoted. Methods published prior to the end of December 2020 are presented.

Spinal Cord Stimulation via Percutaneous and Open Implantation: Systematic Review and Meta-Analysis Examining Complication Rates.

BACKGROUND: Spinal cord stimulation (SCS) has become a successful therapeutic option for combating chronic pain and can be implanted via percutaneous or open (laminotomy/laminectomy) techniques. This study aimed to systematically review the complications that occur after SCS placement via percutaneous and open (laminotomy/laminectomy) in failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), and chronic back (lumbosacral)/leg pain. METHODS: The PubMed and Embase databases were searched from inception to June 2020; prospective studies using SCS in patients with FBSS, CRPS, and chronic low back pain that reported both complications and the implantation method used were included. Effects and results from each study were combined using a random-effects model and were structured for subgroup analysis between open implantation and percutaneous implantation. Meta-regression was performed by calculating a mean difference and weighted by inverse variance and 95% confidence intervals (CIs). RESULTS: Thirty-two articles were included in this systematic review and meta-analysis. Using several different patient- and event-based metrics, our meta-analysis revealed an overall average complication rate of 21.1% (95% CI, 14.9-27.2). Equipment, technical, and medical complications occurred at rates of 12.1%, 1.1%, and 6.3%, respectively. Lead migration and infection rates were 5.6% and 3.8%, respectively. When comparing the 2 implant techniques, medical-related surgical reinterventions and explants due to infection were more common in open compared with percutaneous SCS procedures. CONCLUSIONS: Equipment-related complications accounted for the majority of SCS complications. Percutaneous SCS resulted in less reintervention and fewer explants caused by medical-related complications and infection, respectively. These conclusions may provide a general understanding of the SCS complications profile for physicians who care for SCS patients.

PCET-Based Ligand Limits Charge Recombination with an Ir(III) Photoredox Catalyst.

Upon photoinitiated electron transfer, charge recombination limits the quantum yield of photoredox reactions for which the rates for the forward reaction and back electron transfer are competitive. Taking inspiration from a proton-coupled electron transfer (PCET) process in Photosystem II, a benzimidazole-phenol (BIP) has been covalently attached to the 2,2'-bipyridyl ligand of [Ir(dF(CF3)ppy)2(bpy)][PF6] (dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine; bpy = 2,2'-bipyridyl). Excitation of the [Ir(dF(CF3)ppy)2(BIP-bpy)][PF6] photocatalyst results in intramolecular PCET to form a charge-separated state with oxidized BIP. Subsequent reduction of methyl viologen dication (MV2+), a substrate surrogate, by the reducing moiety of the charge separated species demonstrates that the inclusion of BIP significantly slows the charge recombination rate. The effect of ∼24-fold slower charge recombination in a photocatalytic phthalimide ester reduction resulted in a greater than 2-fold increase in reaction quantum efficiency.

Genome Sequence of Lactiplantibacillus plantarum DmPark25_157, a Bacterial Strain Isolated from Drosophila melanogaster.

We present the genome sequence of a bacterial strain isolated from park25 mutants of Drosophila melanogaster as part of efforts to better understand the microbial communities in D. melanogaster We isolated and sequenced a Lactiplantibacillus plantarum strain. We present a preliminary comparative analysis with a closely related strain.

The Science and Art of Clinical Genetic Variant Classification and Its Impact on Test Accuracy.

Clinical genetic variant classification science is a growing subspecialty of clinical genetics and genomics. The field's continued improvement is essential for the success of precision medicine in both germline (hereditary) and somatic (oncology) contexts. This review focuses on variant classification for DNA next-generation sequencing tests. We first summarize current limitations in variant discovery and definition, and then describe the current five- and four-tier classification systems outlined in dominant standards and guideline publications for germline and somatic tests, respectively. We then discuss measures of variant classification discordance and the field's bias for positive results, as well as considerations for panel size and population screening in the context of estimates of positive predictive value thatincorporate estimated variant classification imperfections. Finally, we share opinions on the current state of variant classification from some of the authors of the most widely used standards and guideline publications and from other domain experts.

Container Closure and Delivery Considerations for Intravitreal Drug Administration.

Intravitreal (IVT) administration of therapeutics is the standard of care for treatment of back-of-eye disorders. Although a common procedure performed by retinal specialists, IVT administration is associated with unique challenges related to drug product, device and the procedure, which may result in adverse events. Container closure configuration plays a crucial role in maintaining product stability, safety, and efficacy for the intended shelf-life. Careful design of primary container configuration is also important to accurately deliver small volumes (10-100 µL). Over- or under-dosing may lead to undesired adverse events or lack of efficacy resulting in unpredictable and variable clinical responses. IVT drug products have been traditionally presented in glass vials. However, pre-filled syringes offer a more convenient administration option by reducing the number of steps required for dose preparation there by potentially reducing the time demand on the healthcare providers. In addition to primary container selection, product development studies should focus on, among other things, primary container component characterization, material compatibility with the formulation, formulation stability, fill volume determination, extractables/leachables, and terminal sterilization. Ancillary components such as disposable syringes and needles must be carefully selected, and a detailed administration procedure that includes dosing instructions is required to ensure successful administration of the product. Despite significant efforts in improving the drug product and administration procedures, ocular safety concerns such as endophthalmitis, increased intraocular pressure, and presence of silicone floaters have been reported. A systematic review of available literature on container closure and devices for IVT administration can help guide successful product development.

Pars Plana Vitrectomy following Traumatic Ocular Injury and Initial Globe Repair: A Retrospective Analysis of Clinical Outcomes.

INTRODUCTION: Penetrating and perforating ocular trauma are often devastating and may lead to complete visual loss in the traumatized eye and subsequent compromise of the fellow eye. A significant proportion of traumatic injuries are complex, often requiring vitreoretinal intervention to preserve vision. A retrospective analysis at a level 1 trauma center was performed to evaluate the time course, incidence, and outcomes following pars plana vitrectomy (PPV) after traumatic ocular injury and initial globe repair. MATERIALS AND METHODS: Eyes that underwent open globe repair following ocular trauma at Brooke Army Medical Center, between January 1, 2014 and December 30, 2016 were analyzed. Specific factors evaluated include mechanism of injury, defect size and complexity, ocular trauma score, zone of injury, associated orbital trauma, and time from injury to surgical intervention. A subset analysis was conducted specifically on eyes requiring subsequent PPV for vision preservation because of vitreoretinal disease. Surgical outcomes, time to secondary intervention, and complication rates were then assessed. RESULTS: In total, 70 eyes requiring open globe repair were examined, with 43 having undergone PPV. Average and median time to vitrectomy were 18.8 and 8 days, respectively. Eyes that underwent PPV were more likely to have an afferent papillary defect, vitreous hemorrhage, intraocular foreign body, and retinal detachment at the time of initial injury (although the latter two factors were not statistically significant), and were more likely to receive penetrating keratoplasty. Proliferative vitreoretinopathy occurred in 37.2% of eyes that underwent PPV, versus 3.7% of those that did not (P = 0.0013). Timing of PPV (i.e., before or after 14 days) had no statistically significant effect on the rate of PVR (Table I). Eyes that underwent PPV showed an improvement of visual acuity from average 2.5 logMAR following initial injury to 1.5 logMAR 6 months after PPV, equivalent to 18.7 Early Treatment Diabetic Retinopathy Study (ETDRS) letters gained, versus 37.7 ETDRS letters gained in eyes without PPV. Among PPV eyes, early repair (<14 days) was associated with greater improvement in visual acuity. CONCLUSION: Overall, patients requiring PPV following open globe repair generally had more severe injuries and worse 6-month postoperative visual acuity. Patients who underwent more expedited vitrectomy showed greater improvement in visual acuity as measured by ETDRS letters gained.

Predicting bioavailability of monoclonal antibodies after subcutaneous administration: Open innovation challenge.

Despite the increasing trend towards subcutaneous delivery of monoclonal antibodies, factors influencing the subcutaneous bioavailability of these molecules remain poorly understood. To address critical knowledge gaps and issues during development of subcutaneous dosage forms for monoclonal antibodies, the Subcutaneous Drug Delivery and Development Consortium was convened in 2018 as a pre-competitive collaboration of recognized industry experts. One of the Consortium's eight problem statements highlights the challenges of predicting human bioavailability of subcutaneously administered monoclonal antibodies due to a lack of reliable in vitro and preclinical in vivo predictive models. In this paper, we assess the current landscape in subcutaneous bioavailability prediction for monoclonal antibodies and discuss the gaps and opportunities associated with bioavailability models for biotherapeutics. We also issue an open challenge to industry and academia, encouraging the development of reliable models to enable subcutaneous bioavailability prediction of therapeutic large molecules in humans and improve translation from preclinical species.