A monoclinic polymorph of chloro-thia-zide.

A new polymorph of the diuretic chloro-thia-zide, 6-chloro-1,1-dioxo-2H-1,2,4-benzo-thia-zine-7-sulfonamide, C7H6ClN3O4S2, is described. Crystallized from basic aqueous solution, this monoclinic polymorph is found to be less thermodynamically favoured than the known triclinic polymorph and to feature only N-H⋯O type inter-molecular hydrogen bonds as opposed to the N-H⋯O and N-H⋯N type hydrogen bonds found in the P1 form.

DNA metabarcoding analysis of the bare-nosed wombat (Vombatus ursinus) diet.

Wombats are native herbivorous grazers that have adapted to Australia's low-quality forage. Studies on diet selection by bare-nosed wombats (Vombatus ursinus) are limited and are either observational or based on microhistological studies. The current study determined the diet of wombats through DNA metabarcoding across five study sites in New South Wales over a one-year period. Metabarcoding was chosen as it is non-invasive, less time consuming and more specific than traditional techniques. The list of 209 plant species identified as eaten by wombats in this study is much higher than previously reported, with grasses being the most common plant group identified in all samples. Most dietary items identified were introduced plant species. Seasonal differences in plants eaten occurred at four of the five study sites and may reflect dietary abundance and floristic composition at different times of year. Further studies are required to determine if the dietary items differ markedly across the entire range of wombats, and if nutrition influences dietary preferences.

Killer whale acoustic patterns respond to prey abundance and environmental variability around the Prince Edward Islands, Southern Ocean.

Killer whales are apex predators with temporally and spatially varying distributions throughout the world's oceans. Their ecology and behaviour are poorly understood in most regions due to limited research, often because of logistical challenges. Here, we used a passive acoustic monitoring device to investigate the seasonal acoustic occurrence and diel vocalizing behaviour of killer whales around the remote sub-Antarctic Prince Edward Islands (PEIs), Southern Ocean. Killer whales showed diel vocalizing patterns that varied seasonally in relation to their prey abundance and social activities. Killer whale calls were intermittently detected year-round with a high number of hours containing calls in October to December, and a secondary peak in February to May, corresponding to seal prey abundance. Random forest modelling identified wind speed as the primary predictor of the occurrence of killer whale calls (with a negative correlation) while sea surface height, chlorophyll-a and sea surface temperature were moderately important. We provide the first acoustic evidence that killer whale occurrence around the PEIs might coincide with variability in environmental conditions and prey abundance. Our results provide the first indication of diel vocalizing pattern of killer whales in the Southern Ocean. This knowledge is important for understanding killer whale ecology and adaptation to the changing oceans.

Exploring Pseudomonas syringae pv. tomato biofilm-like aggregate formation in susceptible and PTI-responding Arabidopsis thaliana.

Bacterial biofilm-like aggregates have been observed in plants, but their role in pathogenicity is underinvestigated. In the present study, we observed that extracellular DNA and polysaccharides colocalized with green fluorescent protein (GFP)-expressing Pseudomonas syringae pv. tomato (Pst) aggregates in Arabidopsis leaves, suggesting that Pst aggregates are biofilms. GFP-expressing Pst, Pst ΔalgU ΔmucAB (Pst algU mutant), and Pst ΔalgD ΔalgU ΔmucAB (Pst algU algD mutant) were examined to explore the roles of (1) alginate, a potential biofilm component; (2) Pst AlgU, thought to regulate alginate biosynthesis and some type III secretion system effector genes; and (3) intercellular salicylic acid (SA) accumulation during pathogen-associated molecular pattern-triggered immunity (PTI). Pst formed extensive aggregates in susceptible plants, whereas aggregate numbers and size were reduced in Pst algU and Pst algD algU mutants, and both multiplied poorly in planta, suggesting that aggregate formation contributes to Pst success in planta. However, in SA-deficient sid2-2 plants, Pst algD algU mutant multiplication and aggregate formation were partially restored, suggesting plant-produced SA contributes to suppression of Pst aggregate formation. Pst algD algU mutants formed fewer and smaller aggregates than Pst algU mutants, suggesting both AlgU and AlgD contribute to Pst aggregate formation. Col-0 plants accumulated low levels of SA in response to Pst and both mutants (Pst algU and Pst algD algU), suggesting the regulatory functions of AlgU are not involved in suppressing SA-mediated plant defence. Plant PTI was associated with highly reduced Pst aggregate formation and accumulation of intercellular SA in flg22-induced PTI-responding wild-type Col-0, but not in PTI-incompetent fls2, suggesting intercellular SA accumulation by Arabidopsis contributes to suppression of Pst biofilm-like aggregate formation during PTI.

The effect of prey abundance and fisheries on the survival, reproduction, and social structure of killer whales (Orcinus orca) at subantarctic Marion Island.

Most marine apex predators are keystone species that fundamentally influence their ecosystems through cascading top-down processes. Reductions in worldwide predator abundances, attributed to environmental- and anthropogenic-induced changes to prey availability and negative interactions with fisheries, can have far-reaching ecosystem impacts. We tested whether the survival of killer whales (Orcinus orca) observed at Marion Island in the Southern Indian Ocean correlated with social structure and prey variables (direct measures of prey abundance, Patagonian toothfish fishery effort, and environmental proxies) using multistate models of capture-recapture data spanning 12 years (2006-2018). We also tested the effect of these same variables on killer whale social structure and reproduction measured over the same period. Indices of social structure had the strongest correlation with survival, with higher sociality associated with increased survival probability. Survival was also positively correlated with Patagonian toothfish fishing effort during the previous year, suggesting that fishery-linked resource availability is an important determinant of survival. No correlation between survival and environmental proxies of prey abundance was found. At-island prey availability influenced the social structure of Marion Island killer whales, but none of the variables explained variability in reproduction. Future increases in legal fishing activity may benefit this population of killer whales through the artificial provisioning of resources they provide.

The effect of supine cycling and progressive lower body negative pressure on cerebral blood velocity responses.

Moderate-intensity aerobic exercise increases cerebral blood velocity (CBv) primarily due to hyperpnea-induced vasodilation; however, the integrative control of cerebral blood flow (CBF) allows other factors to contribute to the vasodilation. Although lower body negative pressure (LBNP) can reduce CBv, the exact LBNP intensity required to blunt the aforementioned exercise-induced CBv response is unknown. This could hold utility for concussion recovery, allowing individuals to exercise at higher intensities without symptom exacerbation. Thirty-two healthy adults (age: 20-33 yr; 19 females/13 males) completed a stepwise maximal exercise test during a first visit to determine each participant's wattage associated with their exercise-induced maximal CBv increase. During the second visit, following supine rest, participants completed moderate-intensity exercise at their determined threshold, while progressive LBNP was applied at 0, -20, -40, -60, -70, -80, and ∼88 Torr. Bilateral middle cerebral artery blood velocities (MCAvs), mean arterial pressure (MAP), heart rate, respiratory rate, and end-tidal carbon dioxide levels were measured continuously. Two-way analysis of variance with effect sizes compared between sexes and stages. Compared with resting supine baseline, averaged MCAv was elevated during 0 and -20 Torr LBNP (q value > 7.73; P < 0.001); however, no differences were noted between baseline and -40 to -70 Torr (q value < |4.24|; P > 0.262). Differences were present between females and males for absolute MCAv measures (q value > 11.2; P < 0.001), but not when normalized to baseline (q value < 0.03; P > 0.951). Supine cycling-elicited increases in MCAv are able to be blunted during the application of LBNP ranging from -40 to -70 Torr. The blunted CBv response demonstrates the potential benefit of allowing individuals to aerobically train (moderate-intensity supine cycling with LBNP) without exacerbating symptoms during the concussion recovery phase.NEW & NOTEWORTHY The current investigation demonstrated that moderate-intensity supine cycling-induced increases in cerebral blood velocities were balanced by the lower body negative pressure-induced decreases in cerebral blood velocity. Although performed in a healthy population, the results may lend themselves to a potential treatment option for individuals recovering from concussion or experience persistent concussion symptoms.

Examining interactions between polygenic scores and interpersonal trauma exposure on alcohol consumption and use disorder in an ancestrally diverse college cohort.

Introduction: Genetic factors impact alcohol consumption and use disorder (AUD), with large-scale genome-wide association studies (GWAS) identifying numerous associated variants. Aggregate genetic methods in combination with important environmental factors (e.g., interpersonal trauma [IPT]) can be applied to expand our understanding of the ways by which genetic and environmental variables work together to influence alcohol consumption and disordered use. The present study aimed to detail the relationships between genome-wide polygenic scores (PGS) for alcohol phenotypes (i.e., alcohol consumption and AUD status) and IPT exposure as well as the interaction between them across ancestry. Methods: Data were drawn from the Spit for Science (S4S) study, a US college student population, where participants reported on IPT exposure prior to college and alcohol consumption and problems during college (N = 9,006; ancestry: 21.3% African [AFR], 12.5% Admixed Americas [AMR], 9.6% East Asian [EAS], 48.1% European [EUR], 8.6% South Asian [SAS]). Two trans-ancestry PGS were constructed, one for alcohol consumption and another for AUD, using large-scale GWAS summary statistics from multiple ancestries weighted using PRS-CSx. Regression models were applied to test for the presence of associations between alcohol-PGS and IPT main and interaction effects. Results: In the meta-analysis across ancestry groups, IPT exposure and PGS were significantly associated with alcohol consumption (ßIPT = 0.31, P IPT = 0.0002; ßPGS = 0.09, P PGS = 0.004) and AUD (ORIPT = 1.12, P IPT = 3.5 × 10-8; ORPGS = 1.02, P PGS = 0.002). No statistically significant interactions were detected between IPT and sex nor between IPT and PGS. When inspecting ancestry specific results, the alcohol consumption-PGS and AUD-PGS were only statistically significant in the EUR ancestry group (ßPGS = 0.09, P PGS = 0.04; ORPGS = 1.02, P PGS = 0.022, respectively). Discussion: IPT exposure prior to college was strongly associated with alcohol outcomes in this college-age sample, which could be used as a preventative measure to identify students at high risk for problematic alcohol use. Additionally, results add to developing evidence of polygenic score association in meta-analyzed samples, highlighting the importance of continued efforts to increase ancestral representation in genetic studies and inclusive analytic approaches to increase the generalizability of results from genetic association studies.

Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial.

PURPOSE: Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . METHODS: We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . RESULTS: Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (- 1, 21) vs 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs 0 (- 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). CONCLUSIONS: We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.

Neurovascular coupling on trial: How the number of trials completed impacts the accuracy and precision of temporally derived neurovascular coupling estimates.

Standard practices for quantifying neurovascular coupling (NVC) with transcranial Doppler ultrasound (TCD) require participants to complete one-to-ten repetitive trials. However, limited empirical evidence exists regarding how the number of trials completed influences the validity and reliability of temporally derived NVC metrics. Secondary analyses was performed on 60 young healthy participants (30 females/30 males) who completed eight cyclical eyes-closed (20-seconds), eyes-open (40-seconds) NVC trials, using the "Where's Waldo?" visual paradigm. TCD data was obtained in posterior and middle cerebral arteries (PCA and MCA, respectively). The within-day (n = 11) and between-day (n = 17) reliability were assessed at seven- and three-time points, respectively. Repeat testing from the reliability aims were also used for the concurrent validity analysis (n = 160). PCA metrics (i.e., baseline, peak, percent increase, and area-under-the-curve) demonstrated five trials produced excellent intraclass correlation coefficient (ICC) 95% confidence intervals for validity and within-day reliability (>0.900), whereas between-day reliability was good-to-excellent (>0.750). Likewise, 95% confidence intervals for coefficient of variation (CoV) measures ranged from acceptable (<20%) to excellent (<5%) with five-or-more trials. Employing fewer than five trials produced poor/unacceptable ICC and CoV metrics. Future NVC, TCD-based research should therefore have participants complete a minimum of five trials when quantifying the NVC response with TCD via a "Where's Waldo?" paradigm.

N-Heterocyclic Carbene Ligand Stability on Gold Nanoparticles in Biological Media.

The ability to functionalize gold nanoparticle surfaces with target ligands is integral to developing effective nanosystems for biomedical applications, ranging from point-of-care diagnostic devices to site-specific cancer therapies. By forming strong covalent bonds with gold, thiol functionalities can easily link molecules of interest to nanoparticle surfaces. Unfortunately, thiols are inherently prone to oxidative degradation in many biologically relevant conditions, which limits their broader use as surface ligands in commercial assays. Recently, N-heterocyclic carbene (NHC) ligands emerged as a promising alternative to thiols since initial reports demonstrated their remarkable stability against ligand displacement and stronger metal-ligand bonds. This work explores the long-term stability of NHC-functionalized gold nanoparticles suspended in five common biological media: phosphate-buffered saline, tris-glycine potassium buffer, tris-glycine potassium magnesium buffer, cell culture media, and human serum. The NHCs on gold nanoparticles were probed with surface-enhanced Raman spectroscopy (SERS) and X-ray photoelectron spectroscopy (XPS). SERS is useful for monitoring the degradation of surface-bound species because the resulting vibrational modes are highly sensitive to changes in ligand adsorption. Our measurements indicate that imidazole-based NHCs remain stable on gold nanoparticles over the 21 days of examination in all tested environments, with no observed change in the molecule's SERS signature, XPS response, or UV-vis plasmon band.

Randomised controlled trial of oxygen therapy and high-flow nasal therapy in African children with pneumonia.

PURPOSE: The life-saving role of oxygen therapy in African children with severe pneumonia is not yet established. METHODS: The open-label fractional-factorial COAST trial randomised eligible Ugandan and Kenyan children aged > 28 days with severe pneumonia and severe hypoxaemia stratum (SpO2 < 80%) to high-flow nasal therapy (HFNT) or low-flow oxygen (LFO: standard care) and hypoxaemia stratum (SpO2 80-91%) to HFNT or LFO (liberal strategies) or permissive hypoxaemia (ratio 1:1:2). Children with cyanotic heart disease, chronic lung disease or > 3 h receipt of oxygen were excluded. The primary endpoint was 48 h mortality; secondary endpoints included mortality or neurocognitive sequelae at 28 days. RESULTS: The trial was stopped early after enrolling 1852/4200 children, including 388 in the severe hypoxaemia stratum (median 7 months; median SpO2 75%) randomised to HFNT (n = 194) or LFO (n = 194) and 1454 in the hypoxaemia stratum (median 9 months; median SpO2 88%) randomised to HFNT (n = 363) vs LFO (n = 364) vs permissive hypoxaemia (n = 727). Per-protocol 15% of patients in the permissive hypoxaemia group received oxygen (when SpO2 < 80%). In the severe hypoxaemia stratum, 48-h mortality was 9.3% for HFNT vs. 13.4% for LFO groups. In the hypoxaemia stratum, 48-h mortality was 1.1% for HFNT vs. 2.5% LFO and 1.4% for permissive hypoxaemia. In the hypoxaemia stratum, adjusted odds ratio for 48-h mortality in liberal vs permissive comparison was 1.16 (0.49-2.74; p = 0.73); HFNT vs LFO comparison was 0.60 (0.33-1.06; p = 0.08). Strata-specific 28 day mortality rates were, respectively: 18.6, 23.4 and 3.3, 4.1, 3.9%. Neurocognitive sequelae were rare. CONCLUSIONS: Respiratory support with HFNT showing potential benefit should prompt further trials.

Imidazolinium N-Heterocyclic Carbene Ligands for Enhanced Stability on Gold Surfaces.

N-heterocyclic carbenes (NHCs) have emerged as versatile and robust ligands for noble metal surface modifications due to their ability to form compact, self-assembled monolayers. Despite a growing body of research, previous NHC surface modification schemes have employed just two structural motifs: the benzimidazolium NHC and the imidazolium NHC. However, different NHC moieties, including saturated NHCs, are often more effective in homogenous catalysis chemistry than these aforementioned motifs and may impart numerous advantages to NHC surfaces, such as increased stability and access to chiral groups. This work explores the preparation and stability of NHC-coated gold surfaces using imidazolium and imidazolinium NHC ligands. X-ray photoelectron spectroscopy and surface-enhanced Raman spectroscopy demonstrate the attachment of NHC ligands to the gold surface and show enhanced stability of imidazolinium compared to the traditional imidazolium under harsh acidic conditions.

What do "barbarians" eat? Integrating ceramic use-wear and residue analysis in the study of food and society at the margins of Bronze Age China.

The Siwa archaeological culture (ca. 3350 and 2650 cal yr BP) has often been associated with the tribes referenced in textual sources as Qiang and Rong: prized captives commonly sacrificed by the Shang and marauding hordes who toppled the Western Zhou dynasty. In early Chinese writings, food plays a key role in accentuating the 'sino-barbarian' dichotomy believed to have taken root over 3000 years ago, with the Qiang and Rong described as nomadic pastoralists who consumed more meat than grain and knew little of proper dining etiquette. To date, however, little direct archaeological evidence has allowed us to reconstruct the diet and foodways of the groups who occupied the Loess Plateau during this pivotal period. Here we present the results of the first ceramic use-wear study performed on the Siwa ma'an jars from the site of Zhanqi, combined with the molecular and isotopic characterization of lipid residues from foodcrusts, and evidence from experimental cooking. We report molecular data indicating the preparation of meals composed of millet and ruminant dairy among the Siwa community of Zhanqi. Use-wear analysis shows that Zhanqi community members were sophisticated creators of ceramic equipment, the ma'an cooking pot, which allowed them to prepare a wide number of dishes with limited fuel. These findings support recent isotope studies at Zhanqi as well as nuance the centrality of meat in the Siwa period diet.

The lipid phosphatase-like protein PLPPR1 associates with RhoGDI1 to modulate RhoA activation in response to axon growth inhibitory molecules.

Phospholipid Phosphatase-Related Protein Type 1 (PLPPR1) is a member of a family of lipid phosphatase related proteins, integral membrane proteins characterized by six transmembrane domains. This family of proteins is enriched in the brain and recent data indicate potential pleiotropic functions in several different contexts. An inherent ability of this family of proteins is to induce morphological changes, and we have previously reported that members of this family interact with each other and may function co-operatively. However, the function of PLPPR1 is not yet understood. Here we show that the expression of PLPPR1 reduces the inhibition of neurite outgrowth of cultured mouse hippocampal neurons by chondroitin sulfate proteoglycans and the retraction of neurites of Neuro-2a cells by lysophosphatidic acid (LPA). Further, we show that PLPPR1 reduces the activation of Ras homolog family member A (RhoA) by LPA in Neuro-2a cells, and that this is because of an association of PLPPR1with the Rho-specific guanine nucleotide dissociation inhibitor (RhoGDI1). These results establish a novel signaling pathway for the PLPPR1 protein.

The Role of Chondroitin Sulfate Proteoglycans in Nervous System Development.

The orderly development of the nervous system is characterized by phases of cell proliferation and differentiation, neural migration, axonal outgrowth and synapse formation, and stabilization. Each of these processes is a result of the modulation of genetic programs by extracellular cues. In particular, chondroitin sulfate proteoglycans (CSPGs) have been found to be involved in almost every aspect of this well-orchestrated yet delicate process. The evidence of their involvement is complex, often contradictory, and lacking in mechanistic clarity; however, it remains obvious that CSPGs are key cogs in building a functional brain. This review focuses on current knowledge of the role of CSPGs in each of the major stages of neural development with emphasis on areas requiring further investigation.

Early evidence for mounted horseback riding in northwest China.

Horseback riding was a transformative force in the ancient world, prompting radical shifts in human mobility, warfare, trade, and interaction. In China, domestic horses laid the foundation for trade, communication, and state infrastructure along the ancient Silk Road, while also stimulating key military, social, and political changes in Chinese society. Nonetheless, the emergence and adoption of mounted horseback riding in China is still poorly understood, particularly due to a lack of direct archaeological data. Here we present a detailed osteological study of eight horse skeletons dated to ca. 350 BCE from the sites of Shirenzigou and Xigou in Xinjiang, northwest China, prior to the formalization of Silk Road trade across this key region. Our analyses reveal characteristic osteological changes associated with equestrian practices on all specimens. Alongside other relevant archaeological evidence, these data provide direct evidence for mounted horseback riding, horse equipment, and mounted archery in northwest China by the late first millennium BCE. Most importantly, our results suggest that this region may have played a crucial role in the spread of equestrian technologies from the Eurasian interior to the settled civilizations of early China, where horses facilitated the rise of the first united Chinese empires and the emergence of transcontinental trade networks.

Role of Chondroitin Sulfation Following Spinal Cord Injury.

Traumatic spinal cord injury produces long-term neurological damage, and presents a significant public health problem with nearly 18,000 new cases per year in the U.S. The injury results in both acute and chronic changes in the spinal cord, ultimately resulting in the production of a glial scar, consisting of multiple cells including fibroblasts, macrophages, microglia, and reactive astrocytes. Within the scar, there is an accumulation of extracellular matrix (ECM) molecules-primarily tenascins and chondroitin sulfate proteoglycans (CSPGs)-which are considered to be inhibitory to axonal regeneration. In this review article, we discuss the role of CSPGs in the injury response, especially how sulfated glycosaminoglycan (GAG) chains act to inhibit plasticity and regeneration. This includes how sulfation of GAG chains influences their biological activity and interactions with potential receptors. Comprehending the role of CSPGs in the inhibitory properties of the glial scar provides critical knowledge in the much-needed production of new therapies.

The organisation of critical care for burn patients in the UK: epidemiology and comparison of mortality prediction models.

In the UK, a network of specialist centres has been set up to provide critical care for burn patients. However, some burn patients are admitted to general intensive care units. Little is known about the casemix of these patients and how it compares with patients in specialist burn centres. It is not known whether burn-specific or generic risk prediction models perform better when applied to patients managed in intensive care units. We examined admissions for burns in the Case Mix Programme Database from April 2010 to March 2016. The casemix, activity and outcome in general and specialist burn intensive care units were compared and the fit of two burn-specific risk prediction models (revised Baux and Belgian Outcome in Burn Injury models) and one generic model (Intensive Care National Audit and Research Centre model) were compared. Patients in burn intensive care units had more extensive injuries compared with patients in general intensive care units (median (IQR [range]) burn surface area 16 (7-32 [0-98])% vs. 8 (1-18 [0-100])%, respectively) but in-hospital mortality was similar (22.8% vs. 19.0%, respectively). The discrimination and calibration of the generic Intensive Care National Audit and Research Centre model was superior to the revised Baux and Belgian Outcome in Burn Injury burn-specific models for patients managed on both specialist burn and general intensive care units.