Citizen science mitigates the lack of distributional data on Nigerian birds.

Citizen science projects are expanding globally, with the African continent, particularly Nigeria, registering significant growth. Here, we document and analyse novel operations of the Nigerian Bird Atlas Project (NIBAP), 2015-2022. This project has employed the use of ornithologists, mainly trained at the A. P. Leventis Ornithological Research Institute (APLORI) located in Jos, Nigeria, and its 28 bird clubs established across Nigeria to enlist 827 bird enthusiasts that contribute regular and near real-time data about bird distribution and relative abundance in the country. Interestingly, NiBAP has recorded about 75% of the bird species known from Nigeria in only about 50% of Nigeria's total surface area, including 39 nationally threatened species. The Common Bulbul Pycnonotus barbatus, Laughing Dove Spilopelia senegalensis, and Grey-backed Camaroptera Camaroptera brevicaudata were the most commonly recorded species, while Amurum Forest Reserve, Rennajj Fish Farm, and Obudu Cattle Ranch were the most surveyed sites during the period. Thus, our approach reveals how to increase involvement of nature enthusiasts, ornithologists, and a regional research institute to build local capacity and contribute rich information necessary to alleviate the lack of distributional data about Afrotropical avifauna. We strongly recommend our approach to boost other citizen science projects across Africa and beyond to address the huge lack of biodiversity data, create public awareness, and foster conservation education.

Adjuvant proton beam therapy in patients with grade 2 meningiomas.

Background: The World Health Organization (WHO) grade 2 meningiomas behave aggressively with a high proclivity toward recurrence despite maximal surgical resection. Our institution, a pioneer of proton therapy, uses exclusively proton beam radiation, and thus, we present a retrospective cohort analysis of patients with WHO grade 2 meningiomas treated with adjuvant proton beam therapy (PBT) at our institution between 2007 and 2019. The effects of adjuvant PBT were evaluated. Methods: Data collected include diagnosis, gender, histological subtype, WHO grade, the extent of surgical resection, adjuvant PBT radiation, details of the PBT radiation, recurrence, any additional PBT radiation, systemic medical therapy, and disease-specific survival. Results: Among the WHO grade 2 meningiomas (n = 50) recommended PBT, 80% and 78% of patients with gross-total resection (GTR) and subtotal resection (STR), respectively, followed through with PBT. The median radiation dose of PBT was 59.5 Gy and 59.92 Gy for patients with GTR and STR, respectively, with a median of 33 fractions delivered in 1.8 Gy doses for both groups. Combined 3-year progression-free survival (PFS) was 96%, and 5-year PFS was 92%. Combined overall survival was 95% at five years. Minimal radiation side effects were reported with no grade 3 or higher toxicities. Conclusion: Our results suggest that adjuvant PBT is well tolerated with minimal radiation toxicity. Alternative to photon radiation, PBT may be considered at least as safe and effective for adjuvant treatment of WHO grade 2 meningiomas when it is available.

Idiopathic pathological ketotic hypoglycemia: finding the needle in a haystack.

Sick children often have a decreased appetite and experience vomiting and diarrhea; however, hypoglycemia (plasma glucose concentration ≤50 mg/dL or 2.8 mmol/L) is rare. Ketotic hypoglycemia (KH) is the most common cause of hypoglycemia presenting to an Emergency Department in a previously healthy child between 6 months and 6 years of age. Ketosis and hypoglycemia are now well understood to be normal physiologic responses of young children to prolonged fasting. There is now substantial evidence that the term KH describes a variety of conditions including both the lower end of the normal distribution of fasting tolerance in young children as well as numerous rare disorders that impair fasting adaptation. Recent advances in molecular genetic testing have led to the discovery of these rare disorders. Idiopathic pathological KH is a diagnosis of exclusion that describes rare children who have abnormally limited fasting tolerance, experience recurrent episodes of KH, or develop symptoms of hypoglycemia despite elevated ketone levels, and in whom an explanation cannot be found despite extensive investigation. This review provides an approach to distinguishing between physiological KH and pathological KH and includes recommendations for management.

Edge-wise analysis reveals white matter connectivity associated with focal to bilateral tonic-clonic seizures.

OBJECTIVE: Focal to bilateral tonic-clonic seizures (FBTCS) represent a challenging subtype of focal temporal lobe epilepsy (TLE) in terms of both severity and treatment response. Most studies have focused on regional brain analysis that is agnostic to the distribution of white matter (WM) pathways associated with a node. We implemented a more selective, edge-wise approach that allowed for identification of the individual connections unique to FBTCS. METHODS: T1-weighted and diffusion-weighted images were obtained from 22 patients with solely focal seizures (FS), 43 FBTCS patients, and 65 age/sex-matched healthy participants (HPs), yielding streamline (STR) connectome matrices. We used diffusion tensor-derived STRs in an edge-wise approach to determine specific structural connectivity changes associated with seizure generalization in FBTCS compared to matched FS and HPs. Graph theory metrics were computed on both node- and edge-based connectivity matrices. RESULTS: Edge-wise analyses demonstrated that all significantly abnormal cross-hemispheric connections belonged to the FBTCS group. Abnormal connections associated with FBTCS were mostly housed in the contralateral hemisphere, with graph metric values generally decreased compared to HPs. In FBTCS, the contralateral amygdala showed selective decreases in the structural connection pathways to the contralateral frontal lobe. Abnormal connections in TLE involved the amygdala, with the ipsilateral side showing increases and the contralateral decreases. All the FS findings indicated higher graph metrics for connections involving the ipsilateral amygdala. Data also showed that some FBTCS connectivity effects are moderated by aging, recent seizure frequency, and longer illness duration. SIGNIFICANCE: Data showed that not all STR pathways are equally affected by the seizure propagation of FBTCS. We demonstrated two key biases, one indicating a large role for the amygdala in the propagation of seizures, the other pointing to the prominent role of cross-hemispheric and contralateral hemisphere connections in FBTCS. We demonstrated topographic reorganization in FBTCS, pointing to the specific WM tracts involved.

Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19.

BACKGROUNDSurvivors of pneumonia, including SARS-CoV-2 pneumonia, are at increased risk for cognitive dysfunction and dementia. In rodent models, cognitive dysfunction following pneumonia has been linked to the systemic release of lung-derived pro-inflammatory cytokines. Microglia are poised to respond to inflammatory signals from the circulation, and their dysfunction has been linked to cognitive impairment in murine models of dementia and in humans.METHODSWe measured levels of 55 cytokines and chemokines in bronchoalveolar lavage fluid and plasma from 341 patients with respiratory failure and 13 healthy controls, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. We used flow cytometry to sort neuroimmune cells from postmortem brain tissue from 5 patients who died from COVID-19 and 3 patients who died from other causes for single-cell RNA-sequencing.RESULTSMicroglia from patients with COVID-19 exhibited a transcriptomic signature suggestive of their activation by circulating pro-inflammatory cytokines. Peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, but cumulative cytokine exposure was higher in patients with COVID-19. Treatment with corticosteroids reduced expression of COVID-19-specific cytokines.CONCLUSIONProlonged lung inflammation results in sustained elevations in circulating cytokines in patients with SARS-CoV-2 pneumonia compared with those with pneumonia secondary to other pathogens. Microglia from patients with COVID-19 exhibit transcriptional responses to inflammatory cytokines. These findings support data from rodent models causally linking systemic inflammation with cognitive dysfunction in pneumonia and support further investigation into the role of microglia in pneumonia-related cognitive dysfunction.FUNDINGSCRIPT U19AI135964, UL1TR001422, P01AG049665, P01HL154998, R01HL149883, R01LM013337, R01HL153122, R01HL147290, R01HL147575, R01HL158139, R01ES034350, R01ES027574, I01CX001777, U01TR003528, R21AG075423, T32AG020506, F31AG071225, T32HL076139.

No evidence for a role of MHC class II genotype in the chemical encoding of heterozygosity and relatedness in Antarctic fur seals.

Despite decades of research, surprisingly little is known about the mechanism(s) by which an individual's genotype is encoded in odour. Many studies have focused on the role of the major histocompatibility complex (MHC) owing to its importance for survival and mate choice. However, the salience of MHC-mediated odours compared to chemicals influenced by the rest of the genome remains unclear, especially in wild populations where it is challenging to quantify and control for the effects of the genomic background. We addressed this issue in Antarctic fur seals by analysing skin swabs together with full-length MHC DQB II exon 2 sequences and data from 41 genome-wide distributed microsatellites. We did not find any effects of MHC relatedness on chemical similarity and there was also no relationship between MHC heterozygosity and chemical diversity. However, multilocus heterozygosity showed a significant positive association with chemical diversity, even after controlling for MHC heterozygosity. Our results appear to rule out a dominant role of the MHC in the chemical encoding of genetic information in a wild vertebrate population and highlight the need for genome-wide approaches to elucidate the mechanism(s) and specific genes underlying genotype-odour associations.

A Bifactor Evaluation of Self-Report and Clinician-Administered Measures of PTSD in Veterans.

The PTSD Checklist for DSM-5 (PCL-5) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) are two of the most widely used and well-validated PTSD measures providing total and subscale scores that correspond with DSM-5 PTSD symptoms. However, there is little information about the utility of subscale scores above and beyond the total score for either measure. The current study compared the proposed DSM-5 four-factor model to a bifactor model across both measures using a sample of veterans (N = 1,240) presenting to a Veterans Affairs (VA) PTSD specialty clinic. The correlated factors and bifactor models for both measures evidenced marginal-to-acceptable fit and were retained for further evaluation. Bifactor specific indices suggested that both measures exhibited a strong general factor but weak lower-order factors. Structural regressions revealed that most of the lower-order factors provided little utility in predicting relevant outcomes. Although additional research is needed to make definitive statements about the utility of PCL-5 and CAPS-5 subscales, study findings point to numerous weaknesses. As such, caution should be exercised when using or interpreting subscale scores in future research.

Prophylactic tranexamic acid for reducing intraoperative blood loss during cesarean section in women at high risk of postpartum hemorrhage: A double-blind placebo randomized controlled trial.

BACKGROUND: Postpartum hemorrhage remains a leading cause of maternal mortality especially in developing countries. The majority of previous trials on the effectiveness of tranexamic acid in reducing blood loss were performed in low-risk women for postpartum hemorrhage. A recent Cochrane Systematic Review recommended that further research was needed to determine the effects of prophylactic tranexamic acid for preventing intraoperative blood loss in women at high risk of postpartum hemorrhage. OBJECTIVE: This study aimed to evaluate the effectiveness and safety of tranexamic acid in reducing intraoperative blood loss when given prior to cesarean delivery in women at high risk of postpartum hemorrhage. STUDY DESIGN: The study is a double-blind randomized controlled trial. METHODS: The study consisted of 200 term pregnant women and high-risk preterm pregnancies scheduled for lower-segment cesarean delivery at Enugu State University of Science and Technology, Teaching Hospital, Parklane, Enugu, Nigeria. The participants were randomized into two arms (intravenous 1 g of tranexamic acid or placebo) in a ratio of 1:1. The participants received either 1 g of tranexamic acid or placebo (20 mL of normal saline) intravenously at least 10 min prior to commencement of the surgery. The primary outcome measures were the mean intraoperative blood loss and hematocrit change 48 h postoperatively. RESULTS: The baseline sociodemographic characteristics were similar in both groups. The tranexamic acid group when compared to the placebo group showed significantly lower mean blood loss (442.94 ± 200.97 versus 801.28 ± 258.68 mL; p = 0.001), higher mean postoperative hemoglobin (10.39 + 0.96 versus 9.67 ± 0.86 g/dL; p = 0.001), lower incidence of postpartum hemorrhage (1.0% versus 19.0%; p = 0.001), and lower need for use of additional uterotonic agents after routine management of the third stage of labor (39.0% versus 68.0%; p = 0.001), respectively. However, there was no significant difference in the mean preoperative hemoglobin (11.24 ± 0.88 versus 11.15 ± 0.90 g/dL; p = 0.457), need for other surgical intervention for postpartum hemorrhage (p > 0.05), and reported side effect, respectively, between the two groups. CONCLUSION: Prophylactic administration of tranexamic acid significantly decreases postpartum blood loss, improves postpartum hemoglobin, decreases the need for additional uterotonics, and prevents postpartum hemorrhage following cesarean section in pregnant women at high risk of postpartum hemorrhage. Its routine use during cesarean section in high-risk women may be encouraged.The trial was registered in the Pan-African Clinical Trial Registry with approval number PACTR202107872851363.

Annotating Macromolecular Complexes in the Protein Data Bank: Improving the FAIRness of Structure Data.

Macromolecular complexes are essential functional units in nearly all cellular processes, and their atomic-level understanding is critical for elucidating and modulating molecular mechanisms. The Protein Data Bank (PDB) serves as the global repository for experimentally determined structures of macromolecules. Structural data in the PDB offer valuable insights into the dynamics, conformation, and functional states of biological assemblies. However, the current annotation practices lack standardised naming conventions for assemblies in the PDB, complicating the identification of instances representing the same assembly. In this study, we introduce a method leveraging resources external to PDB, such as the Complex Portal, UniProt and Gene Ontology, to describe assemblies and contextualise them within their biological settings accurately. Employing the proposed approach, we assigned standard names to over 90% of unique assemblies in the PDB and provided persistent identifiers for each assembly. This standardisation of assembly data enhances the PDB, facilitating a deeper understanding of macromolecular complexes. Furthermore, the data standardisation improves the PDB's FAIR attributes, fostering more effective basic and translational research and scientific education.

Erratum: Role of adipocyte Na,K-ATPase oxidant amplification loop in cognitive decline and neurodegeneration.

[This corrects the article DOI: 10.1016/j.isci.2021.103262.].

Feats: A database of semantic features for early produced noun concepts.

Semantic feature production norms have several desirable characteristics that have supported models of representation and processing in adults. However, several key challenges have limited the use of semantic feature norms in studies of early language acquisition. First, existing norms provide uneven and inconsistent coverage of early-acquired concepts that are typically produced and assessed in children under the age of three, which is a time of tremendous growth of early vocabulary skills. Second, it is difficult to assess the degree to which young children may be familiar with normed features derived from these adult-generated datasets. Third, it has been difficult to adopt standard methods to generate semantic network models of early noun learning. Here, we introduce Feats-a tool that was designed to make headway on these challenges by providing a database, the Language Learning and Meaning Acquisition (LLaMA) lab Noun Norms that extends a widely used set of feature norms McRae et al. Behavior Research Methods 37, 547-559, (2005) to include full coverage of noun concepts on a commonly used early vocabulary assessment. Feats includes several tools to facilitate exploration of features comprising early-acquired nouns, assess the developmental appropriateness of individual features using toddler-accessibility norms, and extract semantic network statistics for individual vocabulary profiles. We provide a tutorial overview of Feats. We additionally validate our approach by presenting an analysis of an overlapping set of concepts collected across prior and new data collection methods. Furthermore, using network graph analyses, we show that the extended set of norms provides novel, reliable results given their enhanced coverage.

Predicting Post-Traumatic Stress Disorder Treatment Response Using Heart Rate Variability to Virtual Reality Environment and Modified Stroop Task: An Exploratory Study.

Predicting treatment response can inform treatment decisions, expectations, and optimize use of mental health treatment resources. This study examined heart rate (HR), heart rate variability (HRV), and a modified Stroop task (mStroop) to predict post-traumatic stress disorder (PTSD) treatment response. We report on an observational, longitudinal study with 45 U.S. veterans in outpatient PTSD care, who had deployed to Iraq or Afghanistan. HR and HRV were collected before, during, and after virtual reality (VR) combat and civilian scenes. HRV recovery was defined as HRV after a 3-minute VR simulation minus HRV during a VR scene. mStroop threat variables included index scores for combat and general threat. Self-report data were collected at baseline and 6 months later. The outcome variable was the 17-item Clinician Administered PTSD Scale (CAPS). Controlling for baseline CAPS and number of combat experiences, the following baseline HRV recovery variables were significant predictors of 6-month CAPS: standard deviation of normal beat to beat interval (SDNN) after combat scene minus SDNN during combat scene and low-frequency (LF HRV) after civilian scene minus LF during civilian scene. HRV at rest, HR reactivity, HR recovery, and mStroop scores did not predict treatment response. In conclusion, HRV recovery variables in the context of a standardized VR stressor were significant predictors of PTSD treatment response after controlling for baseline CAPS and number of combat experiences. The direction of this relationship indicates that greater baseline HRV recovery predicts lower 6-month PTSD symptom severity. This was an exploratory study in need of replication.

Enhanced sensitivity of electrocorticography during awake craniotomy using a novel circular grid electrode.

PURPOSE: Awake craniotomy with intraoperative functional brain mapping (FBM) bedside neurological testing is an important technique used to optimize resective brain surgeries near eloquent cortex. Awake craniotomy performed with electrocorticography (ECoG) and direct electrical stimulation (DES) for FBM can delineate eloquent cortex from lesions and epileptogenic regions. However, current electrode technology demonstrates spatial limitations. Our group has developed a novel circular grid with the goal of improving spatial recording of ECoG to enhance detection of ictal and interictal activity. METHODS: This retrospective study was approved by the institutional review board at Mayo Clinic Florida. We analyzed patients undergoing awake craniotomy with ECoG and DES and compared ECoG data obtained using the 22 contact circular grid to standard 6 contact strip electrode. RESULTS: We included 144 cases of awake craniotomy with ECoG, 73 using circular grid and 71 with strip electrode. No significant differences were seen regarding preoperative clinical and demographic data, duration of ECoG recording (p = 0.676) and use of DES (p = 0.926). Circular grid was more sensitive in detecting periodic focal epileptiform discharges (PFEDs) (p = 0.004), PFEDs plus (p = 0.032), afterdischarges (ADs) per case (p = 0.022) at lower minimum (p = 0.012) and maximum (p < 0.0012) intensity stimulation, and seizures (p = 0.048). PFEDs (p < 0.001), PFEDs plus (p < 0.001), and HFOs (p < 0.001) but not ADs (p = 0.255) predicted electrographic seizures. CONCLUSION: We demonstrate higher sensitivity in detecting ictal and interictal activity on ECoG during awake craniotomy with a novel circular grid compared to strip electrode, likely due to better spatial sampling during ECoG. We also found association between PFEDs and intraoperative seizures.

Ninety years of change, from commercial extinction to recovery, range expansion and decline for Antarctic fur seals at South Georgia.

With environmental change, understanding how species recover from overharvesting and maintain viable populations is central to ecosystem restoration. Here, we reconstruct 90 years of recovery trajectory of the Antarctic fur seal at South Georgia (S.W. Atlantic), a key indicator species in the krill-based food webs of the Southern Ocean. After being harvested to commercial extinction by 1907, this population rebounded and now constitutes the most abundant otariid in the World. However, its status remains uncertain due to insufficient and conflicting data, and anthropogenic pressures affecting Antarctic krill, an essential staple for millions of fur seals and other predators. Using integrated population models, we estimated simultaneously the long-term abundance for Bird Island, northwest South Georgia, epicentre of recovery of the species after sealing, and population adjustments for survey counts with spatiotemporal applicability. Applied to the latest comprehensive survey data, we estimated the population at South Georgia in 2007-2009 as 3,510,283 fur seals [95% CI: 3,140,548-3,919,604] (ca. 98% of global population), after 40 years of maximum growth and range expansion owing to an abundant krill supply. At Bird Island, after 50 years of exponential growth followed by 25 years of slow stable growth, the population collapsed in 2009 and has thereafter declined by -7.2% [-5.2, -9.1] per annum, to levels of the 1970s. For the instrumental record, this trajectory correlates with a time-varying relationship between coupled climate and sea surface temperature cycles associated with low regional krill availability, although the effects of increasing krill extraction by commercial fishing and natural competitors remain uncertain. Since 2015, fur seal longevity and recruitment have dropped, sexual maturation has retarded, and population growth is expected to remain mostly negative and highly variable. Our analysis documents the rise and fall of a key Southern Ocean predator over a century of profound environmental and ecosystem change.

The evolution of antiseizure medication therapy selection in adults: Is artificial intelligence -assisted antiseizure medication selection ready for prime time?

Antiseizure medications (ASMs) are the mainstay of symptomatic epilepsy treatment. The primary goal of pharmacotherapy with ASMs in epilepsy is to achieve complete seizure remission while minimizing therapy-related adverse events. Over the years, more ASMs have been introduced, with approximately 30 now in everyday use. With such a wide variety, much guidance is needed in choosing ASMs for initial therapy, subsequent replacement monotherapy, or adjunctive therapy. The specific ASMs are typically tailored by the patient's related factors, including epilepsy syndrome, age, sex, comorbidities, and ASM characteristics, including the spectrum of efficacy, pharmacokinetic properties, safety, and tolerability. Weighing these key clinical variables requires experience and expertise that may be limited. Furthermore, with this approach, patients may endure multiple trials of ineffective treatments before the most appropriate ASM is found. A more reliable way to predict response to different ASMs is needed so that the most effective and tolerated ASM can be selected. Soon, alternative approaches, such as deep machine learning (ML), could aid the individualized selection of the first and subsequent ASMs. The recognition of epilepsy as a network disorder and the integration of personalized epilepsy networks in future ML platforms can also facilitate the prediction of ASM response. Augmenting the conventional approach with artificial intelligence (AI) opens the door to personalized pharmacotherapy in epilepsy. However, more work is needed before these models are ready for primetime clinical practice.

Regulation of alternative splicing and polyadenylation in neurons.

Cell-type-specific gene expression is a fundamental feature of multicellular organisms and is achieved by combinations of regulatory strategies. Although cell-restricted transcription is perhaps the most widely studied mechanism, co-transcriptional and post-transcriptional processes are also central to the spatiotemporal control of gene functions. One general category of expression control involves the generation of multiple transcript isoforms from an individual gene, whose balance and cell specificity are frequently tightly regulated via diverse strategies. The nervous system makes particularly extensive use of cell-specific isoforms, specializing the neural function of genes that are expressed more broadly. Here, we review regulatory strategies and RNA-binding proteins that direct neural-specific isoform processing. These include various classes of alternative splicing and alternative polyadenylation events, both of which broadly diversify the neural transcriptome. Importantly, global alterations of splicing and alternative polyadenylation are characteristic of many neural pathologies, and recent genetic studies demonstrate how misregulation of individual neural isoforms can directly cause mutant phenotypes.

Risk factors for preoperative and postoperative seizures in patients with glioblastoma according to the 2021 World Health Organization classification.

OBJECTIVE: To identify risk factors for developing glioblastoma (GBM) related preoperative (PRS) and postoperative seizures (POS). Also, we aimed to analyze the impact of PRS and POS on survival in a GBM cohort according to the revised 2021 WHO glioma classification. METHODS: We performed a single-center retrospective cohort study of patients with GBM (according to the 2021 World Health Organization Classification) treated at Mayo Clinic Florida between January 2018 and July 2022. Seizures were stratified into preoperative seizures (PRS) and postoperative seizures (POS, >7 days after surgery). Associations between patients' characteristics and overall survival with PRS and POS were assessed. RESULTS: One hundred nineteen adults (mean =60.9 years), 49 (41.2 %) females, were identified. The rates of PRS and POS in the cohort were 35.3 % (n = 42) and 37.8 % (n = 45), respectively. Patients with PRS were younger (p = 0.035) and were likely to undergo intraoperative electrocorticography. The incidence of PRS (p = 0.049) and POS (p<0.001) was lower among patients with tumors located in the occipital location. PRS increased the risk of POS after adjusting for age and sex (RR: 2.59, CI = 1.44-4.65, p = 0.001). There was no association between PRS or POS and other patient-related factors, including several tumor molecular markers (TMMs) examined. PRS (p = 0.036), POS (p<0.001), and O6-Methylguanine-DNA Methyltransferase (MGMT) promotor methylation status (p = 0.032) were associated with longer survival time. CONCLUSIONS: PRS and POS are associated with non-occipital tumor location and longer survival time in patients with GBM. While younger ages predicted PRS, PRS predicted POS. Well-designed prospective studies with larger sample sizes are needed to clarify the influence of TMMs in the genesis of epileptic seizures in patients with GBM.

The sulfonadyns: a class of aryl sulfonamides inhibiting dynamin I GTPase and clathrin mediated endocytosis are anti-seizure in animal models.

We show that dansylcadaverine (1) a known in-cell inhibitor of clathrin mediated endocytosis (CME), moderately inhibits dynamin I (dynI) GTPase activity (IC50 45 µM) and transferrin (Tfn) endocytosis in U2OS cells (IC50 205 µM). Synthesis gave a new class of GTP-competitive dynamin inhibitors, the Sulfonadyns™. The introduction of a terminal cinnamyl moiety greatly enhanced dynI inhibition. Rigid diamine or amide links between the dansyl and cinnamyl moieties were detrimental to dynI inhibition. Compounds with in vitro inhibition of dynI activity <10 µM were tested in-cell for inhibition of CME. These data unveiled a number of compounds, e.g. analogues 33 ((E)-N-(6-{[(3-(4-bromophenyl)-2-propen-1-yl]amino}hexyl)-5-isoquinolinesulfonamide)) and 47 ((E)-N-(3-{[3-(4-bromophenyl)-2-propen-1-yl]amino}propyl)-1-naphthalenesulfonamide)isomers that showed dyn IC50 <4 µM, IC50(CME) <30 µM and IC50(SVE) from 12-265 µM. Both analogues (33 and 47) are at least 10 times more potent that the initial lead, dansylcadaverine (1). Enzyme kinetics revealed these sulfonamide analogues as being GTP competitive inhibitors of dynI. Sulfonadyn-47, the most potent SVE inhibitor observed (IC50(SVE) = 12.3 µM), significantly increased seizure threshold in a 6 Hz mouse psychomotor seizure test at 30 (p = 0.003) and 100 mg kg-1 ip (p < 0.0001), with similar anti-seizure efficacy to the established anti-seizure medication, sodium valproate (400 mg kg-1). The Sulfonadyn™ class of drugs target dynamin and show promise as novel leads for future anti-seizure medications.

Genetic diversity and demographic history of the leopard seal: A Southern Ocean top predator.

Leopard seals (Hydrurga leptonyx) are top predators that can exert substantial top-down control of their Antarctic prey species. However, population trends and genetic diversity of leopard seals remain understudied, limiting our understanding of their ecological role. We investigated the genetic diversity, effective population size and demographic history of leopard seals to provide fundamental data that contextualizes their predatory influence on Antarctic ecosystems. Ninety leopard seals were sampled from the northern Antarctic Peninsula during the austral summers of 2008-2019 and a 405bp segment of the mitochondrial control region was sequenced for each individual. We uncovered moderate levels of nucleotide (π = 0.013) and haplotype (Hd = 0.96) diversity, and the effective population size was estimated at around 24,000 individuals (NE = 24,376; 95% CI: 16,876-33,126). Consistent with findings from other ice-breeding pinnipeds, Bayesian skyline analysis also revealed evidence for population expansion during the last glacial maximum, suggesting that historical population growth may have been boosted by an increase in the abundance of sea ice. Although leopard seals can be found in warmer, sub-Antarctic locations, the species' core habitat is centered on the Antarctic, making it inherently vulnerable to the loss of sea ice habitat due to climate change. Therefore, detailed assessments of past and present leopard seal population trends are needed to inform policies for Antarctic ecosystems.

Prolonged exposure to lung-derived cytokines is associated with inflammatory activation of microglia in patients with COVID-19.

Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia1-4. Dysfunction in microglia, the primary immune cell in the brain, has been linked to cognitive impairment in murine models of dementia and in humans5. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF-α and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-196, was associated with lower levels of CXCL10, CCL8, and CCL2-molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells7. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19.