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The green algal genus Picochlorum is of biotechnological interest because of its robust response to multiple environmental stresses. We compared the metabolic performance of P. SE3 and P. oklahomense to diverse microbial phototrophs and observed exceptional performance of photosystem II (PSII) in light energy conversion in both Picochlorum species. The quantum yield (QY) for O 2 evolution is the highest of any phototroph yet observed, 32% (20%) by P. SE3 (P. okl) when normalized to total PSII subunit PsbA (D1) protein, and 80% (75%) normalized per active PSII, respectively. Three factors contribute: (1) an efficient water oxidizing complex (WOC) with the fewest photochemical misses of any organism; (2) faster reoxidation of reduced (PQH 2 ) B in P. SE3 than in P. okl. (period-2 Fourier amplitude); and (3) rapid reoxidation of the plastoquinol pool by downstream electron carriers (Cyt b 6 f/PETC) that regenerates PQ faster in P. SE3. This performance gain is achieved without significant residue changes around the Q B site and thus points to a pull mechanism involving faster PQH 2 reoxidation by Cyt b 6 f/PETC that offsets charge recombination. This high flux in P. SE3 may be explained by genomically encoded plastoquinol terminal oxidases 1 and 2, whereas P. oklahomense has neither. Our results suggest two distinct types of PSII centers exist, one specializing in linear electron flow and the other in PSII-cyclic electron flow. Several amino acids within D1 differ from those in the low-light-descended D1 sequences conserved in Viridiplantae, and more closely match those in cyanobacterial high-light D1 isoforms, including changes near tyrosine Y z and a water/proton channel near the WOC. These residue changes may contribute to the exceptional performance of Picochlorum at high-light intensities by increasing the water oxidation efficiency and the electron/proton flux through the PSII acceptors (Q A Q B )., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The association between Medically Assisted Reproduction (MAR) and thromboembolic complications has been reported widely in multiple published studies. Although venous thromboembolism (VTE) is not thought to be a common complication of MAR, it is associated with high morbidity and is often preventable. Since VTE usually occurs after completion of MAR treatment and is often managed outside of the treating fertility unit, these complications are likely to be underreported and there may be limited awareness of the risks among clinicians. As we continue to see a rise in the total number of MAR treatment cycles, particularly in women over 40 years of age, along with a steady increase in the number of fertility preservation cycles for both medical and social indications, it is likely that we will see an increase in absolute numbers of VTE complications. Currently, there is a lack of management guidance and reporting of VTE events associated with assisted conception treatment. The aim of this guidance is to provide clinicians with information on VTE risk factors, guidance on assessing VTE risk and the best practice recommendations on risk reducing strategies for individuals at risk of VTE undergoing ovarian stimulation and embryo transfer cycles.

Background: Self-harm is a major public health challenge, and repeated self-harm is common in those attending hospital following an episode. Evidence suggests psychological interventions could help people who self-harm, but few definitive studies have assessed their clinical and cost-effectiveness. Repeated self-harm is associated with poor quality of life, depression, suicide and increased health service costs which justify the development of psychotherapeutic interventions tailored for people with repeated self-harm., Methods: FReSH START is a multicentre individually 1:1 randomised controlled trial evaluating the clinical and cost-effectiveness of standard care plus psychological therapy or standard care alone for adults (≥ 18 years) presenting at an emergency department (ED) with repeated self-harm. Recruiting 630 participants, it includes an internal pilot, economic evaluation and process evaluation. The intervention will be delivered by mental health staff working in acute settings, with experience of assessing and managing risk in people presenting to emergency services with self-harm. Staff will be trained and supervised to deliver one of three specially adapted therapies: psychodynamic interpersonal therapy, cognitive behavioural therapy or acceptance and commitment therapy. Participants allocated to the intervention will receive one of the adapted therapies according to therapist allocation for up to 6 months via 12 weekly, one to one, 45-50-min sessions. The primary outcome is quality of life measured by the Clinical Outcomes in Routine Evaluation Outcome Measure at 12 months post-randomisation. Secondary outcomes include suicidal intent, depression and cost-effectiveness. Data are collected using hospital attendance records and online/postal/telephone questionnaires at 6 and 12 months post-randomisation, with resource use additionally collected at 3 and 9 months., Discussion: This protocol outlines a randomised controlled trial to investigate whether modified therapies are cost-effective and improve quality of life for people who repeatedly self-harm. Few interventions are proven to be deliverable in the NHS for this population. This study is strengthened by the involvement of qualified mental health workers experienced in managing risk as therapists., Trial Registration: Registered on August 03, 2021. IRAS number: 297939. ISRCTN: https://doi.org/10.1186/ISRCTN73357210 . REC reference: 21/EE/0145., Sponsor: University of Leeds., (© 2024. The Author(s).)

Abstract: In newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumab-containing arm showed a significant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% (P = .0002); 24 months, 36% vs 52% (P = .0001); and 30 months, 27% vs 41% (P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were significantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369)., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Primary human airway epithelial cells demonstrate altered rhythmic gene expression in cytokine-related pathways in asthma with intact core circadian gene expression https://bit.ly/3v9lOC6., Competing Interests: Conflicts of interest: All authors declare no conflicts of interest., (Copyright ©The authors 2024.)

Absorption spectroscopy probing transitions from shallow-core d and f orbitals in lanthanides and actinides reveals information about bonding and the electronic structure in compounds containing these elements. However, spectroscopy in this photon energy range is challenging because of the limited availability of light sources and extremely short penetration depths. In this work, we address these challenges using a tabletop extreme ultraviolet (XUV), ultrafast, laser-driven, high harmonic generation light source, which generates femtosecond pulses in the 40-140 eV range. We present reflection spectroscopy measurements at the N 4,5 (i.e., predominantly 4d to 5f transitions) and O 4,5 (i.e., 5d to 5f transitions) absorption edges on several lanthanide and uranium oxide crystals. We compare these results to density functional theory calculations to assign the electronic transitions and predict the spectra for other lanthanides. This work paves the way for laboratory-scale XUV absorption experiments for studying crystalline and molecular f-electron systems, with applications ranging from surface chemistry, photochemistry, and electronic or chemical structure determination to nuclear forensics.

Background: Mesenchymal stem cells (MSCs) have alluring interest for clinical use in orthopaedics based on their therapeutic potential through directed pluripotent differentiation. While many studies and reviews have discussed the importance of this approach, few have reduced it to practice using reproducible criteria. This study was designed to systematically review and synthesize current evidence regarding clinical use of clearly defined MSCs in orthopaedics., Methods: Studies of any level of evidence and sample size, regardless of MSC source, orthopaedic pathology, and patient population, were reviewed. In vitro and animal studies, and articles written in a language other than English, were excluded. Studies were then screened for final inclusion based on documented MSC verification using testing of the therapeutic cellular population for at least one of the following phenotypic markers: CD 73, CD 90, and CD 105. In addition, therapeutic cellular populations could not have higher percentages of CD34, CD45, CD14, HLA-DR, CD11b, or CD19 markers compared to the aforementioned markers. From each studies' results, sample size, procedural methods, radiographic outcomes, clinical outcomes, patient-report outcomes (PROs), and adverse events were tabulated., Results: Overall, 43 studies were included. Twenty-three studies (53.5 %) derived their MSCs from iliac crest bone marrow while 12 (27.9 %) studied adipose-derived MSCs. Included studies explored MSC use in Osteoarthritis, Cartilage Defects, Osteonecrosis, Bone Defects and Nonunions, Spine, and Other. MSC use in all pathologies led to improvement of studied radiographic, clinical, and patient-reported outcomes., Conclusions: Mesenchymal stem cells have proven to have successful and safe uses in multiple orthopaedic applications, including treating chondral defects, osteoarthritis, and osteonecrosis. A stringent and reproducible process for evaluating obtained human stem cells using CD markers for clinical use is necessary to both evaluate previous studies and continue to evaluate for future uses., Level of Evidence: Level V., Competing Interests: None., (© 2024 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Optimal secondary prevention antithrombotic therapy for patients with antiphospholipid syndrome (APS)-associated ischemic stroke, transient ischemic attack, or other ischemic brain injury is undefined. The standard of care, warfarin or other vitamin K antagonists at standard or high intensity (international normalized ratio (INR) target range 2.0-3.0/3.0-4.0, respectively), has well-recognized limitations. Direct oral anticoagulants have several advantages over warfarin, and the potential role of high-dose direct oral anticoagulants vs high-intensity warfarin in this setting merits investigation., Objectives: The Rivaroxaban for Stroke patients with APS trial (RISAPS) seeks to determine whether high-dose rivaroxaban could represent a safe and effective alternative to high-intensity warfarin in adult patients with APS and previous ischemic stroke, transient ischemic attack, or other ischemic brain manifestations., Methods: This phase IIb prospective, randomized, controlled, noninferiority, open-label, proof-of-principle trial compares rivaroxaban 15 mg twice daily vs warfarin, target INR range 3.0-4.0. The sample size target is 40 participants. Triple antiphospholipid antibody-positive patients are excluded. The primary efficacy outcome is the rate of change in brain white matter hyperintensity volume on magnetic resonance imaging, a surrogate marker of presumed ischemic damage, between baseline and 24 months follow-up. Secondary outcomes include additional neuroradiological and clinical measures of efficacy and safety. Exploratory outcomes include high-dose rivaroxaban pharmacokinetic modeling., Conclusion: Should RISAPS demonstrate noninferior efficacy and safety of high-dose rivaroxaban in this APS subgroup, it could justify larger prospective randomized controlled trials., (© 2024 The Author(s).)

U(VI) peroxide phases (studtite and meta-studtite) are found throughout the nuclear fuel cycle and exist as corrosion products in high radiation fields. Peroxides are part of a family of reactive oxygen species (ROS) that include hydroperoxyl and superoxide species and are produced during alpha radiolysis of water. While U(VI) peroxides have been thoroughly investigated, the incorporation and stability of ROS species within studtite have not been validated. In the current study, electron paramagnetic resonance (EPR) spectroscopy was used to identify the presence of free radicals within a series of U(VI) peroxide samples containing depleted, highly enriched, and natural uranium. Density functional theory calculations indicated that the predicted EPR signals matched well with a superoxide (O 2 - ⋅) species incorporated into the studtite structure, confirming the presence of ROS in the material. Further analysis of samples that were synthesized between 1945 and 2023 indicated that there is a correlation between the radical signal and the product of specific activity multiplied by age of the sample., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G&#95;{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G&#95;{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Purpose: To evaluate the impact of an evidence-based standardized bedside report within a pediatric ambulatory surgery center on length of handoff time, registered nurse (RN) workflow, and patient and family satisfaction., Design: Quality improvement project using an evidence-based standardized bedside report intervention with pre- and postimplementation evaluation of process and outcome measures., Methods: In January 2019, a unit-based task force evaluated ways to improve current report process and consistency of communication between staff and families. Time from admit into Phase II until nursing handoff was measured pre- and postimplementation. Nursing workflow was measured by time to first RN assessment after admit to Phase II and the postimplementation nursing survey. Patient and family satisfaction were measured pre- and postimplementation from National Research Council Health., Findings: Postimplementation, average handoff times decreased by 30%; average time from admit to the Phase II unit until the nursing handoff decreased by 28%. From the postimplementation RN survey, 100% RNs: (1) felt standardized bedside report had a positive impact on their workflow, (2) expressed confidence in giving and receiving reports, and (3) reported they had critical information to safely care for patients. Overall patient satisfaction was measured by How likely would you be to recommend this facility to your family and friends; 11.6% improvement over baseline scores was reported. Improved percentages of score improvement from baseline included: nurses explained things (4.42%), nurses listened carefully (4.3%), patient and family received consistent information (2.46%), care providers explained things (2.22%), and patient and family trusted nurses with care (1.74%)., Conclusions: Implementation of standardized bedside report resulted in (1) more expeditious times to handoff and first RN assessment, (2) overall positive impact on nursing workflow, and (3) improvements in patient and family satisfaction., (Published by Elsevier Inc.)

Many sexual health programs transitioned to virtual implementation during the COVID-19 pandemic. Despite its devastation, the pandemic provided an opportunity to learn about virtual compared to in-person implementation of a sexual health promotion program-El Camino. This study assessed differences in program attendance, engagement, quality, and student ratings for virtual versus in-person implementation of El Camino as part of a rigorous evaluation in high schools with high Latino populations in Maryland. Drawing on positive youth development practices, El Camino helps participants identify personal goals and learn about sexual reproductive health and healthy relationships. This mixed-methods study incorporates data from performance measures, baseline and post-intervention participant surveys, observations, monthly implementation reports, and debriefs with facilitators to describe and compare virtual and in-person program implementation. At baseline, participants were an average of 16.2 years old; between 8 and 12 th grade; 61% female; 79% Hispanic, Latino, or of Spanish origin; and 54% spoke mostly Spanish at home. Recruitment and retention of students outside of school classes were challenging for both forms of implementation. However, attendance was higher during in-person implementation and in schools where the organization implementing El Camino had a strong presence before the pandemic. Findings indicate high fidelity, excellent quality ratings, and positive student perceptions of the program and facilitators in both the virtual and in-person cohorts, which suggest that both forms of implementation were comparable and furthermore highlight the strength of the virtual adaptation of the El Camino program., (© 2023. The Author(s).)

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Despite the availability of multiple screening options, CRC screening is underutilized. We conducted a survey of patients (n = 2973) who were prescribed the multi-target stool DNA (mt-sDNA) screening test (commercialized as Cologuard ® and manufactured by Exact Sciences Corporation) to understand attitudes and experiences that influence test completion and likelihood of future test completion. Using exploratory factor analyses, we developed three scales: Perceived Effectiveness, Perceived Ease of Use, and Perceived Comfort., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Chloride (Cl - ) is essential for O 2 evolution during photosynthetic water oxidation. Two chlorides near the water-oxidizing complex (WOC) in Photosystem II (PSII) structures from Thermosynechococcus elongatus (and T. vulcanus) have been postulated to transfer protons generated from water oxidation. We monitored four criteria: primary charge separation flash yield (P* → P + Q A - ), rates of water oxidation steps (S-states), rate of proton evolution, and flash O 2 yield oscillations by measuring chlorophyll variable fluorescence (P* quenching), pH-sensitive dye changes, and oximetry. Br-substitution slows and destabilizes cellular growth, resulting from lower light-saturated O 2 evolution rate (-20 %) and proton release (-36 % ΔpH gradient). The latter implies less ATP production. In Br- cultures, protonogenic S-state transitions (S 2  → S 3  → S 0 ') slow with increasing light intensity and during O 2 /water exchange (S 0 ' → S 0  → S 1 ), while the non-protonogenic S 1  → S 2 transition is kinetically unaffected. As flash rate increases in Cl - cultures, both rate and extent of acidification of the lumen increase, while charge recombination is suppressed relative to Br - . The Cl - advantage in rapid proton escape from the WOC to lumen is attributed to correlated ion-pair movement of H 3 O + Cl - in dry water channels vs. separated Br - and H + ion movement through different regions (>200-fold difference in Bronsted acidities). By contrast, at low flash rates a previously unreported reversal occurs that favors Br - cultures for both proton evolution and less PSII charge recombination. In Br - cultures, slower proton transfer rate is attributed to stronger ion-pairing of Br - with AA residues lining the water channels. Both anions charge-neutralize protons and shepherd them to the lumen using dry aqueous channels., Competing Interests: Declaration of competing interest G. Charles Dismukes reports financial support was provided by US Department of Energy. G. Charles Dismukes reports financial support was provided by National Science Foundation., (Copyright © 2023. Published by Elsevier B.V.)

We have shown previously that expression of R345W-Fibulin-3 induces epithelial-mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells. The purpose of the current study was to determine if extracellular vesicles (EVs) derived from RPE cells expressing R345W-Fibulin-3 mutation are sufficient to induce EMT in recipient cells. ARPE-19 cells were infected with luciferase-tagged wild-type (WT)- Fibulin-3 or luciferase-tagged R345W-Fibulin-3 (R345W) using lentiviruses. EVs were isolated from the media by ultracentrifugation or density gradient ultracentrifugation. Transmission electron microscopy and cryogenic electron microscopy were performed to study the morphology of the EVs. The size distribution of EVs were determined by nanoparticle tracking analysis (NTA). EV cargo was analysed using LC-MS/MS based proteomics. EV-associated transforming growth factor beta 1 (TGFβ1) protein was measured by enzyme-linked immunosorbent assay. The capacity of EVs to stimulate RPE migration was evaluated by treating recipient cells with WT- or R345W-EVs. The role of EV-bound TGFβ was determined by pre-incubation of EVs with a pan-TGFβ blocking antibody or IgG control. EM imaging revealed spherical vesicles with two subpopulations of EVs: a group with diameters around 30 nm and a group with diameters over 100 nm, confirmed by NTA analysis. Pathway analysis revealed that members of the sonic hedgehog pathway were less abundant in R345W- EVs, while EMT drivers were enriched. Additionally, R345W-EVs had higher concentrations of TGFβ1 compared to control. Critically, treatment with R345W-EVs was sufficient to increase EMT marker expression, as well as cell migration in recipient cells. This EV-increased cell migration was significantly inhibited by pre-incubation of EVs with pan-TGFβ-neutralising antibody. In conclusion, the expression of R345W-Fibulin-3 alters the size and cargo of EVs, which are sufficient to enhance the rate of cell migration in a TGFβ dependent manner. These results suggest that EV-bound TGFβ plays a critical role in the induction of EMT in RPE cells., (© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

KappaMab (KM; formerly MDX-1097) is a monoclonal antibody specific for the kappa myeloma antigen (KMA), a cell-surface antigen expressed on malignant plasma cells in kappa-restricted multiple myeloma (κMM), some lymphomas, occasional tonsillar B cells and in vitro activated B cells, but not on normal B cells in bone marrow. Phase I/IIa studies of single-agent KM confirmed a favourable toxicity profile and evidence of anti-myeloma activity. Ex-vivo studies demonstrating upregulation of KMA by lenalidomide, and enhanced effector-cell cytotoxicity provided the rationale for this phase IIb study where KM or KM in combination with lenalidomide and dexamethasone (KM-Rd) was administered in relapsed, refractory κMM patients. In addition, outcomes for a real-world matched case-control cohort from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) who received Rd were compared to the KM-Rd cohort. KM-Rd demonstrated an overall response rate of 82.5% which compared favourably to the Rd-MRDR cohort of 45.1%. Both single-agent KM and KM-Rd regimens were well tolerated, with the KM-Rd safety profile similar to patients given only Rd in other clinical settings. Based on the excellent safety profile and significant efficacy, further clinical trials escalating the KM dose and pairing KM with other standard-of-care treatments are planned., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Ultrapurified Photosystem II complexes crystalize as uniform microcrystals (PSIIX) of unprecedented homogeneity that allow observation of details previously unachievable, including the longest sustained oscillations of flash-induced O 2 yield over > 200 flashes and a novel period-4.7 water oxidation cycle. We provide new evidence for a molecular-based mechanism for PSII-cyclic electron flow that accounts for switching from linear to cyclic electron flow within PSII as the downstream PQ/PQH 2 pool reduces in response to metabolic needs and environmental input. The model is supported by flash oximetry of PSIIX as the LEF/CEF switch occurs, Fourier analysis of O 2 flash yields, and Joliot-Kok modeling. The LEF/CEF switch rebalances the ratio of reductant energy (PQH 2 ) to proton gradient energy (H + o /H + i ) created by PSII photochemistry. Central to this model is the requirement for a regulatory site (Q C ) with two redox states in equilibrium with the dissociable secondary electron carrier site Q B . Both sites are controlled by electrons and protons. Our evidence fits historical LEF models wherein light-driven water oxidation delivers electrons (from Q A - ) and stromal protons through Q B to generate plastoquinol, the terminal product of PSII-LEF in vivo. The new insight is the essential regulatory role of Q C . This site senses both the proton gradient (H + o /H + i ) and the PQ pool redox poise via e - /H + equilibration with Q B . This information directs switching to CEF upon population of the protonated semiquinone in the Qc site (Q - H + ) C , while the WOC is in the reducible S2 or S3 states. Subsequent photochemical primary charge separation (P + Q A - ) forms no (QH 2 ) B , but instead undergoes two-electron backward transition in which the Q C protons are pumped into the lumen, while the electrons return to the WOC forming (S1/S2). PSII-CEF enables production of additional ATP needed to power cellular processes including the terminal carboxylation reaction and in some cases PSI-dependent CEF., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

The functional annotation of gene lists is a common analysis routine required for most genomics experiments, and bioinformatics core facilities must support these analyses. In contrast to methods such as the quantitation of RNA-Seq reads or differential expression analysis, our research group noted a lack of consensus in our preferred approaches to functional annotation. To investigate this observation, we selected 4 experiments that represent a range of experimental designs encountered by our cores and analyzed those data with 6 tools used by members of the Association of Biomolecular Resource Facilities (ABRF) Genomic Bioinformatics Research Group (GBIRG). To facilitate comparisons between tools, we focused on a single biological result for each experiment. These results were represented by a gene set, and we analyzed these gene sets with each tool considered in our study to map the result to the annotation categories presented by each tool. In most cases, each tool produces data that would facilitate identification of the selected biological result for each experiment. For the exceptions, Fisher's exact test parameters could be adjusted to detect the result. Because Fisher's exact test is used by many functional annotation tools, we investigated input parameters and demonstrate that, while background set size is unlikely to have a significant impact on the results, the numbers of differentially expressed genes in an annotation category and the total number of differentially expressed genes under consideration are both critical parameters that may need to be modified during analyses. In addition, we note that differences in the annotation categories tested by each tool, as well as the composition of those categories, can have a significant impact on results., Competing Interests: Conflict of Interest Disclosure: The authors have no financial support or associations that pose a conflict of interest., (Copyright © 2023 Association of Biomolecular Resource Facilities. All rights reserved.)

Background: Previous population health studies examining adults with acute myeloid leukemia (AML); however many of these, such as the Cancer Genome Atlas, are derived from databases collected by large urban centers. Due to its unique industry and environmental exposures, we hypothesized the West Virginia Appalachian population may have different mutational trends and clinical outcomes., Aims: To address the concern of under-representation of rural minorities in cancer genomic databases, we performed exploratory whole exome sequencing in patients with newly diagnosed AML in rural Appalachia., Methods & Results: Correlations between genetic variants and clinical outcome variables were examined via retrospective chart review. A total of 26 patients were identified and whole exome sequencing was performed. Median age was 68 years old. Twenty-one patients had de novo AML (84%). As per European LeukemiaNet (ELN) criteria, 8 patients were favorable (32%), 12 were intermediate (48%), and 5 were adverse risk (20%). Eight patients proceeded to transplant. The median progression-free survival and overall survival were 16.5 months and 26.6 months, respectively. We noted an increased tumor mutation burden and a higher frequency of specific known driver mutations when compared to The Cancer Genome Atlas database; we also found novel mutations in MUC3A, MUC5AC, HCAR3, ORT2B, and PABPC. Survival outcomes were slightly lower than national average and BCOR mutation correlated with inferior outcomes., Conclusion: Our findings provide novel insight into detrimental mutations in AML in a rural, underrepresented population. We discovered several novel mutations and higher frequency of some known driver mutations, which will help us identify therapeutic targets to improve patient outcomes., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Retinal diseases like diabetic retinopathy and age-related macular degeneration affect millions of individuals worldwide and often lead to vision loss. Vitreous fluid abuts the retina, is accessible for sampling, and contains many proteins related to retinal disease. Therefore, analysis of vitreous is an important tool for studying retinal disease. Because it is rich in proteins and extracellular vesicles, mass spectrometry-based proteomics is an excellent method for vitreous analysis. Here, we discuss important variables to consider when performing vitreous proteomics via mass spectrometry., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The complex [TEA][Tp*Mo IV (O)(S 2 BMOPP)] ( 1 ) [TEA = tetraethylammonium, Tp* = tris(3,5-dimethylpyrazolyl)hydroborate, and BMOPP = 6-(3-butynyl-2-methyl-2-ol)-2-pivaloyl pterin] is a structural analogue of the molybdenum cofactor common to all pyranopterin molybdenum enzymes because it possesses a pyranopterin-ene-1,2-dithiolate ligand (S 2 BMOPP) that exists primarily in the ring-closed pyrano structure as a resonance hybrid of ene-dithiolate and thione-thiolate forms. Compound 1 , the protonated [Tp*Mo IV (O)(S 2 BMOPP-H)] ( 1-H ) and one-electron-oxidized [Tp*Mo V (O)(S 2 BMOPP)] [ 1-Mo(5+) ] species have been studied using a combination of electrochemistry, electronic absorption, and electron paramagnetic resonance (EPR) spectroscopy. Additional insight into the nature of these molecules has been derived from electronic structure computations. Differences in dithiolene C-S bond lengths correlate with relative contributions from both ene-dithiolate and thione-thiolate resonance structures. Upon protonation of 1 to form 1-H , large spectroscopic changes are observed with transitions assigned as Mo(xy) → pyranopterin metal-to-ligand charge transfer and dithiolene → pyranopterin intraligand charge transfer, respectively, and this underscores a dramatic change in electronic structure between 1 and 1-H . The changes in electronic structure that occur upon protonation of 1 are also reflected in a large >300 mV increase in the Mo(V/IV) redox potential for 1-H , resulting from the greater thione-thiolate resonance contribution and decreased charge donation that stabilize the Mo(IV) state in 1-H with respect to one-electron oxidation. EPR spin Hamiltonian parameters for one-electron-oxidized 1-Mo(5+) and uncyclized [Tp*Mo V (O)(S 2 BDMPP)] [ 3-Mo(5+) ] [BDMPP = 6-(3-butynyl-2,2-dimethyl)-2-pivaloyl pterin] are very similar to each other and to those of [Tp*Mo V O(bdt)] (bdt = 1,2-ene-dithiolate). This indicates that the dithiolate form of the ligand dominates at the Mo(V) level, consistent with the demand for greater S → Mo charge donation and a corresponding increase in Mo-S covalency as the oxidation state of the metal is increased. Protonation of 1 represents a simple reaction that models how the transfer of a proton from neighboring acidic amino acid residues to the Mo cofactor at a nitrogen atom within the pyranopterin dithiolene (PDT) ligand in pyranopterin molybdenum enzymes can impact the electronic structure of the Mo-PDT unit. This work also illustrates how pyran ring-chain tautomerization drives changes in resonance contributions to the dithiolene chelate and may adjust the reduction potential of the Mo ion.

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest Form (available upon request from the corresponding author) and declare no conflicts of interest.

Abstract: Myxedema coma (MC) develops from a long-standing, unrecognized, or untreated hypothyroidism. This article discusses the pathophysiology, clinical manifestations, treatment, and nursing considerations for patients with MC., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The zam gene mediating resistance to acetazolamide in cyanobacteria was discovered thirty years ago during a drug tolerance screen. We use phylogenetics to show that Zam proteins are distributed across cyanobacteria and that they form their own unique clade of the ribonuclease II/R (RNB) family. Despite being RNB family members, multiple sequence alignments reveal that Zam proteins lack conservation and exhibit extreme degeneracy in the canonical active site-raising questions about their cellular function(s). Several known phenotypes arise from the deletion of zam , including drug resistance, slower growth, and altered pigmentation. Using room-temperature and low-temperature fluorescence and absorption spectroscopy, we show that deletion of zam results in decreased phycocyanin synthesis rates, altered PSI:PSII ratios, and an increase in coupling between the phycobilisome and PSII. Conserved cysteines within Zam are identified and assayed for function using in vitro and in vivo methods. We show that these cysteines are essential for Zam function, with mutation of either residue to serine causing phenotypes identical to the deletion of Zam. Redox regulation of Zam activity based on the reversible oxidation-reduction of a disulfide bond involving these cysteine residues could provide a mechanism to integrate the 'central dogma' with photosynthesis in cyanobacteria.

Background: Low- and middle-income countries face distinct challenges in providing health care services and training. The community of practice (CoP) has been described as a method of facilitating much-needed connections and conversations on this topic and has been adapted over time to include virtual CoPs. We describe the development and evaluation of a global Clinical Lead Forum (CLF) using a CoP framework to structure informal continuing professional development (CPD) and enhance the capacity of health care professionals in low- and middle-income countries., Methods: Baylor College of Medicine International Pediatric AIDS Initiative (BIPAI) and its network of affiliated, independent non-governmental organizations (NGOs) provide paediatric and maternal health care for vulnerable populations around the world. We established virtual sessions across the network to discuss clinical topics, which evolved based on the need to include a COVID-19 series. We collected demographic, participation, participant and facilitator assessments, as well as leadership notes from each session as part of an educational quality improvement study. We developed and evaluated the program using the Logic Model and used the Kirkpatrick Model to assess learning outcomes., Results: A total of 299 unique participants engaged in sessions, representing a total of 10 disciplines. There were a total of 1295 participants who joined for the 11 sessions in the regular CLF series and the 23 sessions in the COVID-19 series. Survey responses were overall consistent with a value-added intervention., Conclusions: The CLF, via both the regular sessions and the COVID-19 series, served as an impactful global health CoP for CPD. By focusing on creating a safe and inviting space, ensuring equity and inclusion, activating champions, fostering engagement, and promoting innovation and adaptability, this program decreased professional isolation, strengthened peer relationships, and enhanced the knowledge and practices of health care professionals. Our model may be scaled to other systems across the world to bridge divides and create similarly meaningful communities., Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest Form (available upon request from the corresponding author) and declare no conflicts of interest., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

All contemporary oxygenic phototrophs─from primitive cyanobacteria to complex multicellular plants─split water using a single invariant cluster comprising Mn 4 CaO 5 (the water oxidation catalyst ) as the catalyst within photosystem II, the universal oxygenic reaction center of natural photosynthesis. This cluster is unstable outside of PSII and can be reconstituted, both in vivo and in vitro, using elemental aqueous ions and light, via photoassembly. Here, we demonstrate the first functional substitution of manganese in any oxygenic reaction center by in vitro photoassembly. Following complete removal of inorganic cofactors from cyanobacterial photosystem II microcrystal (PSIIX), photoassembly with free cobalt (Co 2+ ), calcium (Ca 2+ ), and water (OH - ) restores O 2 evolution activity. Photoassembly occurs at least threefold faster using Co 2+ versus Mn 2+ due to a higher quantum yield for PSIIX-mediated charge separation (P*): Co 2+ → P* → Co 3+ Q A - . However, this kinetic preference for Co 2+ over native Mn 2+ during photoassembly is offset by significantly poorer catalytic activity (∼25% of the activity with Mn 2+ ) and ∼3- to 30-fold faster photoinactivation rate. The resulting reconstituted Co-PSIIX oxidizes water by the standard four-flash photocycle, although they produce 4-fold less O 2 per PSII, suggested to arise from faster charge recombination (Co 3+ Q A ← Co 4+ Q A - ) in the catalytic cycle. The faster photoinactivation of reconstituted Co-PSIIX occurs under anaerobic conditions during the catalytic cycle, suggesting direct photodamage without the involvement of O 2 . Manganese offers two advantages for oxygenic phototrophs, which may explain its exclusive retention throughout Darwinian evolution: significantly slower charge recombination (Mn 3+ Q A ← Mn 4+ Q A - ) permits more water oxidation at low and fluctuating solar irradiation (greater net energy conversion) and much greater tolerance to photodamage at high light intensities (Mn 4+ is less oxidizing than Co 4+ ). Future work to identify the chemical nature of the intermediates will be needed for further interpretation.

Background: Vitreous is an accessible, information-rich biofluid that has recently been studied as a source of retinal disease-related proteins and pathways. However, the number of samples required to confidently identify perturbed pathways remains unknown. In order to confidently identify these pathways, power analysis must be performed to determine the number of samples required, and sample preparation and analysis must be rigorously defined., Methods: Control (n = 27) and proliferative diabetic retinopathy (n = 23) vitreous samples were treated as biologically distinct individuals or pooled together and aliquoted into technical replicates. Quantitative mass spectrometry with tandem mass tag labeling was used to identify proteins in individual or pooled control samples to determine technical and biological variability. To determine effect size and perform power analysis, control and proliferative diabetic retinopathy samples were analyzed across four 10-plexes. Pooled samples were used to normalize the data across plexes and generate a single data matrix for downstream analysis., Results: The total number of unique proteins identified was 1152 in experiment 1, 989 of which were measured in all samples. In experiment 2, 1191 proteins were identified, 727 of which were measured across all samples in all plexes. Data are available via ProteomeXchange with identifier PXD025986. Spearman correlations of protein abundance estimations revealed minimal technical (0.99-1.00) and biological (0.94-0.98) variability. Each plex contained two unique pooled samples: one for normalizing across each 10-plex, and one to internally validate the normalization algorithm. Spearman correlation of the validation pool following normalization was 0.86-0.90. Principal component analysis revealed stratification of samples by disease and not by plex. Subsequent differential expression and pathway analyses demonstrated significant activation of metabolic pathways and inhibition of neuroprotective pathways in proliferative diabetic retinopathy samples relative to controls., Conclusions: This study demonstrates a feasible, rigorous, and scalable method that can be applied to future proteomic studies of vitreous and identifies previously unrecognized metabolic pathways that advance understanding of diabetic retinopathy., (© 2021. The Author(s).)

Despite efforts in understanding its underlying mechanisms, the etiology of chromosomal instability (CIN) remains unclear for many tumor types. Here, we identify CIN initiation as a previously undescribed function for APOBEC3A (A3A), a cytidine deaminase upregulated across cancer types. Using genetic mouse models of pancreatic ductal adenocarcinoma (PDA) and genomics analyses in human tumor cells we show that A3A-induced CIN leads to aggressive tumors characterized by enhanced early dissemination and metastasis in a STING-dependent manner and independently of the canonical deaminase functions of A3A. We show that A3A upregulation recapitulates numerous copy number alterations commonly observed in patients with PDA, including co-deletions in DNA repair pathway genes, which in turn render these tumors susceptible to poly (ADP-ribose) polymerase inhibition. Overall, our results demonstrate that A3A plays an unexpected role in PDA as a specific driver of CIN, with significant effects on disease progression and treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Retention remains a problem for postsecondary institutions and college students. To address these issues, researchers have sought to identify factors of college success and retention. Findings have consistently shown the importance of psychosocial factors and mental health on college students' academic success. As such, university and college counseling centers are well positioned to enhance students' academic success by addressing psychosocial distress. However, existing literature on the effect of counseling on college students' academic success is mixed, and limitations exist. To address previous limitations of the literature, this study utilized an interrupted time series design to examine differences in students' postcounseling academic success compared to their precounseling academic success. Additionally, we examined the association between changes in students' psychological distress and academic distress for students who endorsed clinical distress at the onset of counseling and changes in their grade point average (GPA) over time. Data for this study consisted of 1,231 clients seen by 49 therapists at a university counseling center. As hypothesized, students' GPAs increased at a greater rate postcounseling compared to precounseling. Additionally, for students who were clinically distressed at the onset of counseling, reductions in their psychological distress were associated with positive changes in their GPA over time, but the relationship between changes in their academic distress and changes in their GPA was not significant. This study suggests that counseling can be beneficial for college students' academic success, in part due to changes in students' psychological distress, but not their academic distress, specifically for clinically distressed students. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Vitreous fluid is becoming an increasingly popular medium for the study of retinal disease. Numerous studies have demonstrated that proteomic analysis of the vitreous from patients with proliferative diabetic retinopathy yields valuable molecular information regarding known and novel proteins and pathways involved in this disease. However, there is no standardized methodology for vitreous proteomic studies. Here, we share a suggested protocol for such studies and outline the various experimental and analytic methods that are currently available. We also review prior mass spectrometry-based proteomic studies of the vitreous from patients with proliferative diabetic retinopathy, discuss common pitfalls of these studies, and propose next steps for moving the field forward.

Objectives: (1) To measure caregiver satisfaction with a nonstandardized postoperative pain regimen after pediatric tonsillectomy. (2) To implement a quality improvement project (QIP) to reduce the number and volume of narcotics prescribed and to describe the effect on caregiver satisfaction., Methods: A prospective cohort study at a tertiary children's hospital examined postoperative narcotics prescribed to children following adenotonsillectomy. A QIP was implemented 3 months into the observation, with the goal to standardize nonnarcotic analgesics and reduce the volume of narcotics prescribed. Caregivers were called 2 to 3 weeks postoperatively to assess pain control and caregiver satisfaction., Results: Over an 8-month period, 118 patients were recruited (66 before the QIP, 52 after induction). Prior to the QIP, 47% of patients were prescribed postoperative narcotics, as opposed to 27% after the QIP ( P < .05). There was a significant reduction in the volume of narcotics prescribed before (mean ± SD, 300 ± 150 mL) versus after (180 ± 111 mL) the initiative ( P < .05). The per-kilogram dose did not change over the study time frame. On a 5-point Likert scale, there was no difference in the caregivers' satisfaction regarding pain control before (4.37 ± 0.85) versus after (4.35 ± 1.0) the project started., Discussion: A system shift was identified with the establishment of a posttonsillectomy pain control protocol associated with a reduction in prescribed narcotics without a significant change in caregiver satisfaction., Implications for Practice: Implementing a standardized plan for the use of nonnarcotic medications was associated with reduced frequency and volume of narcotics prescribed. Future work will further standardize our postoperative pain regimen.

Cyanobacteria possess unique intracellular organization. Many proteomic studies have examined different features of cyanobacteria to learn about the intracellular structures and their respective functions. While these studies have made great progress in understanding cyanobacterial physiology, the conventional fractionation methods used to purify cellular structures have limitations; specifically, certain regions of cells cannot be purified with existing fractionation methods. Proximity-based proteomics techniques were developed to overcome the limitations of biochemical fractionation for proteomics. Proximity-based proteomics relies on spatiotemporal protein labeling followed by mass spectrometry of the labeled proteins to determine the proteome of the region of interest. We performed proximity-based proteomics in the cyanobacterium Synechococcus sp. PCC 7002 with the APEX2 enzyme, an engineered ascorbate peroxidase. We determined the proteome of the thylakoid lumen, a region of the cell that has remained challenging to study with existing methods, using a translational fusion between APEX2 and PsbU, a lumenal subunit of photosystem II. Our results demonstrate the power of APEX2 as a tool to study the cell biology of intracellular features and processes, including photosystem II assembly in cyanobacteria, with enhanced spatiotemporal resolution.

Introduction: Public health responses often lack the infrastructure to capture the impact of public health emergencies on pregnant women and infants, with limited mechanisms for linking pregnant women with their infants nationally to monitor long-term effects. In 2019, the Centers for Disease Control and Prevention (CDC), in close collaboration with state, local, and territorial health departments, began a 5-year initiative to establish population-based mother-baby linked longitudinal surveillance, the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET)., Objectives: The objective of this report is to describe an expanded surveillance approach that leverages and modernizes existing surveillance systems to address the impact of emerging health threats during pregnancy on pregnant women and their infants., Methods: Mother-baby pairs are identified through prospective identification during pregnancy and/or identification of an infant with retrospective linking to maternal information. All data are obtained from existing data sources (e.g., electronic medical records, vital statistics, laboratory reports, and health department investigations and case reporting)., Results: Variables were selected for inclusion to address key surveillance questions proposed by CDC and health department subject matter experts. General variables include maternal demographics and health history, pregnancy and infant outcomes, maternal and infant laboratory results, and child health outcomes up to the second birthday. Exposure-specific modular variables are included for hepatitis C, syphilis, and Coronavirus Disease 2019 (COVID-19). The system is structured into four relational datasets (maternal, pregnancy outcomes and birth, infant/child follow-up, and laboratory testing)., Discussion: SET-NET provides a population-based mother-baby linked longitudinal surveillance approach and has already demonstrated rapid adaptation to COVID-19. This innovative approach leverages existing data sources and rapidly collects data and informs clinical guidance and practice. These data can help to reduce exposure risk and adverse outcomes among pregnant women and their infants, direct public health action, and strengthen public health systems.

Objectives: Describe the postop morbidity of adults undergoing palatopharyngoplasty (PPP)., Method: Adults who underwent PPP were studied using ACS-NSQIP (American College of Surgeons National Surgical Quality Improvement Program) database (2016-2017) via CPT code 42145. Analyzed outcomes included length of stay (LOS), readmission, reoperation, and postop complications. Predictive variables were age, gender, BMI, comorbidities., Results: A total of 1081 patients (73.7% male, mean age 42.0 years, range 18-79 years) were included. 95 (8.8%) were diabetic, 183 (16.9%) were smokers, 30 (2.8%) had preoperative dyspnea. 328 (30.3%) took medicine for hypertension. Concurrent procedures occurred in 646 (59.76%), 357 (33.02%) had nasal procedures, 320 (29.60%) had tonsil procedures, 66 (6.11%) had tongue procedures. Within 30 days postop, there were two (0.19%) mortalities. Complications included six wound infections, two dehiscences, four with pneumonia, two pulmonary embolisms, three myocardial infarctions, one DVT, three sepsis, one UTI, one who required CPR, and two who were ventilated for >48 hours. Five required reintubation. A total of 41 (3.79%) returned to OR for a related reason, at least 27 (65.90%) for bleeding. LOS ranged from 0 to 15 days, median 1 day. Overall 38 (3.52%) were readmitted for a related reason, 12 (31.58%) for bleeding and three (7.89%) for pain. Using a significance level of 0.002 (Bonferroni correction), LOS varied with presence of any concurrent procedure, BMI, and estimated probability of mortality and morbidity indices; readmission and reoperation had no significantly associated variables., Conclusion: PPP is associated with low frequency but significant morbidity and mortality.

We studied the habitat selection of pronghorn (Antilocapra americana) during seasonal migration; an important period in an animal's annual cycle associated with broad-scale movements. We further decompose our understanding of migration habitat itself as the product of both broad- and fine-scale behavioral decisions and take a multi-scale approach to assess pronghorn spring and fall migration across the transboundary Northern Sagebrush Steppe region. We used a hierarchical habitat selection framework to assess a suite of natural and anthropogenic features that have been shown to influence selection patterns of pronghorn at both broad (migratory neighborhood) and fine (migratory pathway) scales. We then combined single-scale predictions into a scale-integrated step selection function (ISSF) map to assess its effectiveness in predicting migration route habitat. During spring, pronghorn selected for native grasslands, areas of high forage productivity (NDVI), and avoided human activity (i.e., roads and oil and natural gas wells). During fall, pronghorn selected for native grasslands, larger streams and rivers, and avoided roads. We detected avoidance of paved roads, unpaved roads, and wells at broad spatial scales, but no response to these features at fine scales. In other words, migratory pronghorn responded more strongly to anthropogenic features when selecting a broad neighborhood through which to migrate than when selecting individual steps along their migratory pathway. Our results demonstrate that scales of migratory route selection are hierarchically nested within each other from broader (second-order) to finer scales (third-order). In addition, we found other variables during particular migratory periods (i.e., native grasslands in spring) were selected for across scales indicating their importance for pronghorn. The mapping of ungulate migration habitat is a topic of high conservation relevance. In some applications, corridors are mapped according to telemetry location data from a sample of animals, with the assumption that the sample adequately represents habitat for the entire population. Our use of multi-scale modelling to predict resource selection during migration shows promise and may offer another relevant alternative for use in future conservation planning and land management decisions where telemetry-based sampling is unavailable or incomplete., Competing Interests: The authors have declared that no competing interests exist.

We develop a rapid "stroboscopic" fluorescence induction method, using the fast repetition rate fluorometry (FRRF) technique, to measure changes in the quantum yield of light emission from chlorophyll in oxygenic photosynthesis arising from competition with primary photochemical charge separation (P 680 * ➔ P 680 + Q A - ). This method determines the transit times of electrons that pass through PSII during the successive steps in the catalytic cycle of water oxidation/O 2 formation (S states) and plastoquinone reduction in any oxygenic phototroph (in vivo or in vitro). We report the first measurements from intact living cells, illustrated by a eukaryotic alga (Nannochloropsis oceanica). We demonstrate that S state transition times depend strongly on the redox state of the PSII acceptor side, at both Q B and the plastoquinone pool which serve as the major locus of regulation of PSII electron flux. We provide evidence for a kinetic intermediate S3' state (lifetime 220 μs) following formation of S3 and prior to the release of O 2 . We compare the FRRF-detected kinetics to other previous spectroscopic methods (optical absorbance, EPR, and XES) that are applicable only to in vitro samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Over the last decade, the cost of -omics data creation has decreased 10-fold, whereas the need for analytical support for those data has increased exponentially. Consequently, bioinformaticians face a second wave of challenges: novel applications of existing approaches ( e.g. , single-cell RNA sequencing), integration of -omics data sets of differing size and scale ( e.g. , spatial transcriptomics), as well as novel computational and statistical methods, all of which require more sophisticated pipelines and data management. Nonetheless, bioinformatics cores are often asked to operate under primarily a cost-recovery model, with limited institutional support. Seeing the need to assess bioinformatics core operations, the Association of Biomolecular Resource Facilities Genomics Bioinformatics Research Group conducted a survey to answer questions about staffing, services, financial models, and challenges to better understand the challenges bioinformatics core facilities are currently faced with and will need to address going forward. Of the respondent groups, we chose to focus on the survey data from smaller cores, which made up the majority. Although all cores indicated similar challenges in terms of changing technologies and analysis needs, small cores tended to have the added challenge of funding their operations largely through cost-recovery models with heavy administrative burdens., (© Association of Biomolecular Resource Facilities.)

Recurrent Respiratory Papillomatosis (RRP) is a benign disease of the airway that can result in symptoms ranging from mild dysphonia to respiratory distress to respiratory failure related to colonization of the lung parenchyma. It is a disease that typically begins in childhood and can require treatment indefinitely, though may remit in adolescence. Although treatment includes surgical management, certain cases require adjuvant therapy. Many therapies have been tried over the years with varying levels of success. Our patient presented as a 7 month old male in respiratory distress, who was subsequently diagnosed with RRP. He has required a tracheostomy, ventilation, and frequent surgical debridement for the last 20 months. Due to the aggressiveness of his disease, he was started on systemic bevacizumab (Avastin) in an effort to stabilize his lesions. Though early effect seemed apparent based on Derkay scores, systemic bevacizumab has failed to elicit clinical improvement in our patient. He remains with a tracheostomy receiving bevacizumab 10 mg/kg as an intermittent infusion approximately every 4 weeks along with surgical debridement with little to no clinical improvement thus far. In light of the recent successes with bevacizumab therapy, this case highlights the difficulty in finding new treatment for this disease., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The title compound I , 2,2'-[(2-nitro-phen-yl)methyl-ene]bis-(3-hy-droxy-5,5-di-methyl-cyclo-hex-2-enone), C 23 H 27 NO 6 , features a 1,3-ketone-enol conformation which is stabilized by two intra-molecular hydrogen bonds. The most prominent inter-molecular inter-actions in compound I are C-H⋯O hydrogen bonds, which link mol-ecules into a two-dimensional network parallel to the (001) plane and a chain perpendicular to (11). Both title compounds II , ethyl 4-(4-hy-droxy-3,5-di-meth-oxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carb-oxyl-ate, C 23 H 29 NO 6 , and III , ethyl 4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, C 29 H 29 NO 3 , share the same structural features, such as a shallow boat conformation of the di-hydro-pyridine group and an orthogonal aryl group attached to the di-hydro-pyridine. Inter-molecular N-H⋯O bonding is present in the crystal packing of both compound II and III ., (© Steiger et al. 2020.)

Anxiety disorders and trauma- and stressor-related disorders, such as posttraumatic stress disorder (PTSD), are common and are associated with significant economic and social burdens. Although trauma and stressor exposure are recognized as a risk factors for development of anxiety disorders and trauma or stressor exposure is recognized as essential for diagnosis of PTSD, the mechanisms through which trauma and stressor exposure lead to these disorders are not well characterized. An improved understanding of the mechanisms through which trauma or stressor exposure leads to development and persistence of anxiety disorders or PTSD may result in novel therapeutic approaches for the treatment of these disorders. Here, we review the current state-of-the-art theories, with respect to mechanisms through which stressor exposure leads to acute or chronic exaggeration of avoidance or anxiety-like defensive behavioral responses and fear, endophenotypes in both anxiety disorders and trauma- and stressor-related psychiatric disorders. In this chapter, we will explore physiological responses and neural circuits involved in the development of acute and chronic exaggeration of anxiety-like defensive behavioral responses and fear states, focusing on the role of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid hormones.

Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR 1a , mGLuR 5 or mGluR 8 . Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR 5 site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR 2 and mGluR 4 are distinct: the compounds which select for mGluR 2 all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABA A, nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn's mGluR 1 crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The current mainstay of the treatment and secondary thromboprophylaxis of thrombotic antiphospholipid syndrome (APS) is anticoagulation with warfarin or other vitamin K antagonists (VKAs). In addition to their well-known limitations, VKAs are often problematic in APS patients because of the variable sensitivity of thromboplastins to lupus anticoagulant. As a result, the international normalized ratio may not accurately reflect the intensity of anticoagulation. Direct oral anticoagulants (DOACs) are established as therapeutic alternatives to VKAs for a wide range of indications, including the treatment and secondary prevention of venous thromboembolism. Definition of the role of DOACs in the treatment of thrombotic APS is emerging with the results of recent and ongoing clinical studies. This review focuses on the current situation with regard to DOACs for secondary thromboprophylaxis in APS and issues pertinent to DOAC use in APS patients, as well as potential future directions., Competing Interests: Hannah Cohen reports receiving institutional research support and honoraria (diverted to local Charity) for lectures and Advisory Board from Bayer. Maria Efthymiou, Carolyn Gates, and David Isenberg had no conflicts of interest to disclose., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background : Evidence-based interventions have been developed and tested to promote physical activity, but fewer studies have focused on identifying effective intervention strategies for mid-size rural communities, especially new immigrant destinations. We report here on the design and implementation of Active Ottumwa, a community-wide intervention using a lay health advisor approach to increase physical activity in a micropolitan new destination community in the rural state of Iowa. Methods : The Active Ottumwa study is part of a community-academic partnership in Ottumwa, IA. Evidence-based strategies recommended by the Community Guide for Preventive Services guided study implementation and included behavioral and social, campaign and informational, and environmental and policy approaches. Evaluation methods for this study are multi-faceted and include a cross-sectional community survey, longitudinal cohort assessment, observational data, key informant interviews, and project records. Results : We are currently in our second year of intervention implementation, with 45 lay health advisors (termed physical activity leaders here) trained to carry out behavioral and social intervention approaches, including walking groups, tai chi, and yoga. We have completed a communication and informational campaign utilizing five channels. Our longitudinal cohort has been recruited, with baseline and 12-month data collection completed. Conclusions : This study will assess the effectiveness and impact of a community-wide intervention to support physical activity.

Finding patterns in graphs has become a vital challenge in many domains from biological systems, network security, to finance (e.g., finding money laundering rings of bankers and business owners). While there is significant interest in graph databases and querying techniques, less research has focused on helping analysts make sense of underlying patterns within a group of subgraph results. Visualizing graph query results is challenging, requiring effective summarization of a large number of subgraphs, each having potentially shared node-values, rich node features, and flexible structure across queries. We present VIGOR, a novel interactive visual analytics system, for exploring and making sense of query results. VIGOR uses multiple coordinated views, leveraging different data representations and organizations to streamline analysts sensemaking process. VIGOR contributes: (1) an exemplar-based interaction technique, where an analyst starts with a specific result and relaxes constraints to find other similar results or starts with only the structure (i.e., without node value constraints), and adds constraints to narrow in on specific results; and (2) a novel feature-aware subgraph result summarization. Through a collaboration with Symantec, we demonstrate how VIGOR helps tackle real-world problems through the discovery of security blindspots in a cybersecurity dataset with over 11,000 incidents. We also evaluate VIGOR with a within-subjects study, demonstrating VIGOR's ease of use over a leading graph database management system, and its ability to help analysts understand their results at higher speed and make fewer errors.

The desert microalga Chlorella ohadii was reported to grow at extreme light intensities with minimal photoinhibition, tolerate frequent de/re-hydrations, yet minimally employs antenna-based non-photochemical quenching for photoprotection. Here we investigate the molecular mechanisms by measuring Photosystem II charge separation yield (chlorophyll variable fluorescence, Fv/Fm) and flash-induced O 2 yield to measure the contributions from both linear (PSII-LEF) and cyclic (PSII-CEF) electron flow within PSII. Cells grow increasingly faster at higher light intensities (μE/m 2 /s) from low (20) to high (200) to extreme (2000) by escalating photoprotection via shifting from PSII-LEF to PSII-CEF. This shifts PSII charge separation from plastoquinone reduction (PSII-LEF) to plastoquinol oxidation (PSII-CEF), here postulated to enable proton gradient and ATP generation that powers photoprotection. Low light-grown cells have unusually small antennae (332 Chl/PSII), use mainly PSII-LEF (95%) and convert 40% of PSII charge separations into O 2 (a high O 2 quantum yield of 0.06mol/mol PSII/flash). High light-grown cells have smaller antenna and lower PSII-LEF (63%). Extreme light-grown cells have only 42 Chl/PSII (no LHCII antenna), minimal PSII-LEF (10%), and grow faster than any known phototroph (doubling time 1.3h). Adding a synthetic quinone in excess to supplement the PQ pool fully uncouples PSII-CEF from its natural regulation and produces maximum PSII-LEF. Upon dark adaptation PSII-LEF rapidly reverts to PSII-CEF, a transient protection mechanism to conserve water and minimize the cost of antenna biosynthesis. The capacity of the electron acceptor pool (plastoquinone pool), and the characteristic times for exchange of (PQH 2 ) B with PQ pool and reoxidation of (PQH 2 ) pool were determined., (Copyright © 2017. Published by Elsevier B.V.)