bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcending Markov: non-Markovian rate processes of thermosensitive TRP ion channels
Authors: Ben-Abu Yuval , Tucker Stephen J , Contera Sonia
Published: August 2023

The Markov state model (MSM) is a popular theoretical tool for describing the hierarchy of time scales involved in the function of many proteins especially ion channel gating. An MSM is a particular case of the general non-Markovian model, where the rate of transition from one state to another does not depend on the history of state occupancy within the system, i.e. it only includes reversible, non-dissipative processes. However, an MSM requires knowledge of the precise conformational state of the protein and is not predictive when those details are not known. In the case of ion channels, this simple description fails in real (non-equilibrium) situations, for example when local temperature changes, or when energy losses occur during channel gating. Here, we show it is possible to use non-Markovian equations (i.e. offer a general description that includes the MSM as a particular case) to develop a relatively simple analytical model that describes the non-equilibrium behaviour of the temperature-sensitive transient receptor potential (TRP) ion channels, TRPV1 and TRPM8. This model accurately predicts asymmetrical opening and closing rates, infinite processes and the creation of new states, as well as the effect of temperature changes throughout the process. This approach therefore overcomes the limitations of the MSM and allows us to go beyond a mere phenomenological description of the dynamics of ion channel gating towards a better understanding of the physics underlying these processes.
Bold-shy personality traits of globally invasive, native and hatchery-reared fish
Authors: Sales Ellie , Rogers Leia , Freire Rafael , Luiz Osmar , Kopf R. Keller
Published: August 2023

Bold behaviour of non-native species is hypothesized to facilitate invasion success, yet extreme boldness in wild and domesticated animals can be maladaptive. The purpose of this study was to compare individual behaviour among Australian native hatchery-reared (n= 33) and wild (n= 38) Murray cod (Maccullochella peelii) with invasive common carp (Cyprinus carpio;n= 30). Three laboratory tests measured individual behaviour: (1) emergence from a shelter, (2) exploration of a novel environment, and (3) approaching a predator. Wild invasive carp and hatchery-reared cod were generally faster and more likely to emerge and explore novel environments when compared with wild Murray cod. The ‘bold-type’ behaviours of hatchery-reared native cod were more like invasive carp than they were to ‘shy-type’ wild conspecifics, yet an important difference was that hatchery-reared cod spent substantially more time near a large predator while carp rapidly escaped. We suggest that these results are consistent with a bold-type invasion syndrome in invasive carp and learned boldness of hatchery-reared Murray cod. The propensity of invasive carp to rapidly explore and enter new environments, along with a fast predator escape response may have been important to their invasion success, while extreme risk-taking and predator naivety of hatchery-reared Murray cod may exacerbate post-release mortality rates in fisheries and conservation stocking programmes.
Phenological mismatch affects individual fitness and population growth in the winter moth
Authors: van Dis Natalie E. , Sieperda Geert-Jan , Bansal Vidisha , van Lith Bart , Wertheim Bregje , Visser Marcel E.
Published: August 2023

Climate change can severely impact species that depend on temporary resources by inducing phenological mismatches between consumer and resource seasonal timing. In the winter moth, warmer winters caused eggs to hatch before their food source, young oak leaves, became available. This phenological mismatch changed the selection on the temperature sensitivity of egg development rate. However, we know little about the fine-scale fitness consequences of phenological mismatch at the individual level and how this mismatch affects population dynamics in the winter moth. To determine the fitness consequences of mistimed egg hatching relative to timing of oak budburst, we quantified survival and pupation weight in a feeding experiment. We found that mismatch greatly increased mortality rates of freshly hatched caterpillars, as well as affecting caterpillar growth and development time. We then investigated whether these individual fitness consequences have population-level impacts by estimating the effect of phenological mismatch on population dynamics, using our long-term data (1994–2021) on relative winter moth population densities at four locations in The Netherlands. We found a significant effect of mismatch on population density with higher population growth rates in years with a smaller phenological mismatch. Our results indicate that climate change-induced phenological mismatch can incur severe individual fitness consequences that can impact population density in the wild.
A gradual migratory divide determines not only the direction of migration but also migration strategy of a social migrant bird
Authors: Piironen Antti , Laaksonen Toni
Published: August 2023

Migratory divides separate populations of migratory animals, facilitating the evolution of intraspecific differences in migration strategies. Migration strategies are expected to be different for birds using different flyways and environments, but the knowledge regarding the impact of the flyway on individual migration strategies is scarce. By using satellite tracking and neckband resightings, we reveal the existence and structure of a gradual migratory divide between two European flyway populations of greylag geeseAnser anser. Birds breeding at the far end of the Gulf of Bothnia in the Baltic Sea coast use the Western Flyway, those breeding in the Gulf of Finland the Central Flyway and those breeding between these extremes scatter to the two flyways. By using Gaussian process modelling, we show that migration strategies differed between the flyways. The birds using the Western Flyway migrated earlier in autumn, performed longer annual migration and made a clear stopover during migration, whereas the birds using the Central Flyway flew directly to their wintering sites. The gradual migratory divide that also divides migration strategies provides insights into migratory divides on birds with learned migration. Distinct migration strategies in different flyways provide exciting possibilities to further study the factors driving migration strategies.
Effectiveness of communications in enhancing adherence to public health behavioural interventions: a COVID-19 evidence review
Authors: Williams Simon N. , Dienes Kimberly , Jaheed Jemma , Wardman Jamie K. , Petts Judith
Published: August 2023

Health communication has relevance for virtually every aspect of health and well-being, including disease prevention. This review explored the effectiveness of communications in enhancing the adoption of or adherence to behavioural interventions (non-pharmaceutical interventions (NPIs)) related to COVID-19. The review takes the UK as a case study and focuses on self-reported behaviours (e.g. social distancing). It also reviews the psychosocial determinants of adherence. Searches were conducted using PubMed, Scopus, CINAL, ASSIA and iCite databases. Eleven thousand five hundred records were identified and 13 were included in the final sample. Included studies suggest that NPI adoption or adherence was generally high, and communication had significant impacts, with key themes including clarity and consistency, trust and control. Based on the evidence in this review, features of effective communication in the context of NPI adoption or adherence are (i) information should be conveyed clearly and conflicting (mixed) messages should be avoided; (ii) information should be conveyed by trusted sources (e.g. health authorities) and (iii) communication should strike a balance between being authoritative but avoiding language seen as controlling (e.g. ‘you must’). Future research should prioritize quantitative, experimental and longitudinal study designs, that focus specifically on communication as an intervention, and which measure behaviour.

This article is part of the theme issue 'The effectiveness of non-pharmaceutical interventions on the COVID-19 pandemic: the evidence'.
A Systematic Background Check of TRICARE Provider Names
Authors: Bychkov David
Published: August 2023

During Covid-19, the Defense Health Agency’s TRICARE insurance plan expanded its coverage to include 30.1% additional civilian healthcare providers. The DHA’s Annual Report, however, states that TRICARE’s provider directories are only 80% accurate. Although the DHA’s 9.6 million beneficiaries need expanded access to care, they also require protection from misleading information, medical fraud, patient abuse, and identity theft. Since 2013, the Department of Health and Human Services’ Office of the Inspector General has excluded 17,706 physicians from federal health programs due to misconduct. Patients who receive care from excluded providers experience worse medical outcomes. To determine if any excluded provider names were found on TRICARE’s website, we performed background checks on TRICARE West’s healthcare provider directory between January 1 and March 2023. Out of 39,463 provider names sampled from 22 states, there were 2,398 matches (6.08%) with individuals and businesses found in the OIG List of Excluded Individuals and Entities (OIG-LEIE), the GSA-SAM, the HHS HIPAA Breach Report, the International Trade Administration’s Consolidated Screening List, the OIG-HHS Fugitive List, the FBI’s January 6th Capitol Violence List of Charged Defendants, State Medicaid Exclusion Lists, and FDA Debarment Lists. Our study includes demographic analysis of the matching names and recommendations for an Insider Threat Management model. We recommend that DHA officials publish the National Provider Identification (NPI) numbers of all TRICARE providers. NPI numbers facilitate more accurate background checks of healthcare providers.
High proportions of post-exertional malaise and orthostatic intolerance in people living with post-COVID-19 condition: the PRIME post-COVID study
Authors: Pagen Demi M. E. , Herck Maarten Van , van Bilsen Céline J. A. , Brinkhues Stephanie , Konings Kevin , den Heijer Casper D. J. , Spruit Martijn A. , Hoebe Christian J. P. A. , Dukers-Muijrers Nicole H. T. M.
Published: August 2023

Background

Exercise-based treatments can be harmful in people who were SARS-CoV-2 positive and living with post-COVID-19 condition (PL-PCC) and who have post-exertional malaise (PEM) or orthostatic intolerance (OI). Nevertheless, PEM and OI are not routinely assessed by clinicians. We estimated PEM and OI proportions in PL-PCC, as well in people not living with PCC (PnL-PCC) and negatives (i.e., never reported a SARS-CoV-2 positive test), and identified associated factors.

Methods

Participants from the PRIME post-COVID study were included. PEM and OI were assessed using validated questionnaires. PCC was defined as feeling unrecovered after SARS-CoV-2 infection. Multivariable regression analyses to study PEM and OI were stratified for sex.

Results

Data from 3,783 participants was analyzed. In PL-PCC, proportion of PEM was 48.1% and 41.2%, and proportion of OI was 29.3% and 27.9% in women and in men, respectively. Proportions were higher in PL-PCC compared to negatives, for PEM in women OR=4.38 [95%CI:3.01-6.38]; in men OR=4.78 [95%CI:3.13-7.29]; for OI in women 3.06 [95%CI:1.97-4.76]; in men 2.71 [95%CI:1.75-4.21]. Associated factors were age ≤60 years, ≥1 comorbidities and living alone.

Conclusions

High proportions of PEM and OI are observed in PL-PCC. Standard screening for PEM and OI is recommended in PL-PCC, to promote appropriate therapies.

Trial registration ClinicalTrials.gov identifier:NCT05128695
A Machine Learning Model Integrated with the Clinical Workflow Detects Sepsis Early with High Sensitivity and Specificity
Authors: Mahyoub Mohammed A. , Yadav Ravi R. , Doughetry Kacie , Shukla Ajit
Published: August 2023

Background

Sepsis is a life-threatening condition caused by a dysregulated response to infection, affecting millions of people worldwide. Early diagnosis and treatment are critical for managing sepsis and reducing morbidity and mortality rates.

Materials and Methods

A systematic design approach was employed to build a model that predicts sepsis, incorporating clinical feedback to identify relevant data elements. XGBoost was utilized for prediction, and interpretability was achieved through the application of Shapely values. The model was successfully deployed within a widely used Electronic Medical Record (EMR) system.

Results

The developed model demonstrated robust performance pre-operations, with a sensitivity of 92%, specificity of 93%, and a false positive rate of 7%. Following deployment, the model maintained comparable performance, with a sensitivity of 91% and specificity of 94%. Notably, the post-deployment false positive rate of 6% represents a substantial reduction compared to the currently deployed commercial model in the same health system, which exhibits a false positive rate of 30%.

Conclusions

These findings underscore the effectiveness and potential value of the developed model in improving timely sepsis detection and reducing unnecessary alerts in clinical practice. Further investigations should focus on its long-term generalizability and impact on patient outcomes.
Whole-of-School Physical Activity Implementation in the Context of the Dubai Fitness Challenge
Authors: McMahon Chris , Webster Collin A. , Weaver R. Glenn , Haber Christophe El , Demir Gönül Tekkurşun , Ismail Zainab Mohamed , Fatima Naqvi Syeda Zoha , Ghani Mehnaz , Kepenek Şevval , Kherraf Manel , Krishnakumar Thrisha , Prakash Pranati , Seo Yeowon
Published: August 2023

Introduction

Physical activity (PA) promotion among school-aged youth is a global health priority. Recommendations for such promotion include implementing whole-of-school approaches that maximize resources across the school environment. This study examined schools’ participation in an annual, government-led, and emirate-wide initiative in Dubai, called the Dubai Fitness Challenge, in which the goal is to accrue 30 minutes of PA every day for 30 days (as such, the initiative is colloquially referred to as “Dubai 30×30”).

Methods

A mixed-methods design was employed for this study. Three schools were recruited using convenience sampling. Participants were 18 physical education teachers, 20 classroom teachers, 2 principals and 45 students. Data sources included surveys, focus groups, and interviews. Data were analyzed using descriptive statistics, multinomial logistic regression, and open and axial coding to develop themes.

Results

School staff reported that most Dubai 30×30 activities were provided in physical education, at break times during school, and before and after school. Students reported that they mainly participated in Dubai 30×30 activities during physical education and occasionally participated in activities after school and on weekends. During school, students were more likely to reach higher PA intensity levels when they were in contexts other than the regular classroom setting. Among school staff, physical education teachers were most involved and classroom teachers were least involved in promoting Dubai 30×30. Parent engagement was high. Staff perceived that Dubai 30×30 brought the community together, but physical education teachers also indicated there was a lack of implementation guidance and they felt burdened. Participants believed Dubai 30×30 increased PA participation and helped to promote their schools.

Discussion

This study provides an initial glimpse into schools’ participation in Dubai 30×30 and suggests that a whole-of-school PA lens is useful in gleaning information that could help to increase and optimize PA opportunities for students.
Impact of preexisting dementia on in-hospital outcomes in patients with intracerebral hemorrhage stroke in China
Authors: Zuo Lijun , Hu Yang , Dong YanHong , Gu Hongqiu , Seet Raymond CS , Li Zixiao , Wang Yongjun , Zhao Xingquan
Published: August 2023

Objective

We assessed the impact of preexisting dementia on in-hospital mortality, home discharge and complications of Chinese patients with intracerebral hemorrhage (ICH).

Methods

Consecutive in-hospital data were extracted from the China Stroke Center Alliance database from August 2015 to July 2019. Patient characteristics, in-hospital mortality, and complications were compared between ICH patients with and without preexisting dementia.

Results

Out of the eligible 72,318 patients with ICH, we identified 328 patients with pre-existing dementia. Compared with patients without dementia, those in the dementia group were older, more females and a higher proportion of individuals with lower education, and a history of diabetes, myocardial infarction, stroke, heart failure, peripheral vascular disease and cigarette smoking. Those with pre-existing dementia group were more prone to a greater stroke severity as measured by the National Institute of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) at presentation. In the adjusted models, the presence of preexisting dementia was associated with an increased risk of in-hospital mortality (OR 2.31, 95% CI 1.12-4.77) and more frequent in-hospital complications of pulmonary embolism (OR 5.41, 95% CI 1.16-25.14), pneumonia (OR 1.58, 95% CI 1.08-2.33), urinary tract infection (OR 2.37; 95% CI 1.21-4.64), and gastrointestinal bleeding (OR 2.39, 95% CI 1.27-4.49).

Conclusions

ICH patients with pre-existing dementia are more prone to more severe strokes and poorer outcomes. Future studies should evaluate the value of intensive risk factor control among individuals with pre-existing dementia for stroke prevention.
Behavioral Factors Associated with Blood Pressure Control in Hypertensive Adults 35 to 64 Years of Age at Risk of Future Stroke: A cross-sectional survey study
Authors: Masson Patricia Railsback , Mawn Barbara Ellen , Leslie-Mazwi Thabele (Bay) , Sethares Kristen A. , Caruso Alyson , Rydberg Jason
Published: August 2023

BACKGROUND

The incidence of stroke has increased for those < 64 years of age over the last decade. Control of hypertension is one of the greatest modifiable risk factors for preventing stroke but remains elusive. In 2017, the American College of Cardiology and American Heart Association national blood pressure guidelines tightened the definition of a normal blood pressure to <120/80 mm Hg, which if achieved would reduce stroke incidence by up to 21%.

METHODS

This IRB approved cross-sectional study utilized stratified random sampling to recruit adults, 35 to 64 years of age with an active diagnosis of hypertension, no prior history of stroke or transient ischemic attack (TIA) and under current primary care. Blood pressure was dichotomized into controlled blood pressure (≤120/80 mm Hg) and uncontrolled blood pressure (>120/80 mm Hg). Guided by a modified Health Belief Model, electronic surveys assessing individual medication compliance and beliefs about future stroke risk were distributed. Bivariate and multivariate logistic regression models analyzed the data with α set at 0.05 and observational cohort guidelines were followed.

RESULTS

Of the 304 subjects, 83% (n=253) had uncontrolled blood pressure, 78% of women and 89% of men, (77% of total subjects) classified as stage 1 or stage 2 hypertension. Men and women had mean composite compliancy scores below the 50thpercentile (21.53 +/-2.89). Women with uncontrolled hypertension were statistically less likely to be compliant (p= 0.040), with lower perceived susceptibility (p= 0.04) and severity of stroke (p=0.037) and less likely to see barriers to initiating exercise (p=0.04)but did not view exercise as beneficial in preventing stroke (p=0.039).

CONCLUSION

Uncontrolled blood pressure remains problematic for both men and women. Women are known to have greater longevity and this study has identified targeted beliefs and behaviors that may more effectively address uncontrolled blood pressure in women at risk for future stroke.
Ischemic Stroke Risk in Patients on Direct Oral Anticoagulants with Levetiracetam: A Pharmacovigilance Study
Authors: Abou Kaoud Mohammed , Nissan Ran , Segev Amitai , Sabbag Avi , Orion David , Maor Elad
Published: August 2023

Background

Levetiracetam is widely used in post stroke epilepsy. However, it is suspected to possess P-glycoprotein induction properties and therefore a potential significant interaction with DOACs. Our aim was to search for ischemic stroke signals with levetiracetam and the DOACs.

Methods

In this retrospective, pharmacovigilance study, we used the Food and Drug Administration adverse event reporting system to identify ischemic stroke events associated with DOACs and concomitant use of levetiracetam. We evaluated disproportionate reporting by the reporting odds ratio adjusted to age and sex (adj.ROR) and the lower bound of the shrinkage 95% confidence interval (Ω025> 0 is deemed significant for an interaction).

Results

We identified 1,841 (1.5%), 3,731 (5.3%), 338 (4.9%), and 1,723 (1.3%), ischemic stroke reports with apixaban, dabigatran, edoxaban, and rivaroxaban respectively. When heparin/enoxaparin was used as the comparator the adjusted ROR of the interaction effect was 3.57 (95%CI, 2.81–4.58) between DOACs and levetiracetam. The shrinkage analysis detected an interaction between each of the DOACs and levetiracetam resulting in higher reports of ischemic stroke with the combination compared to each drug alone. The logistic model and shrinkage analysis failed to detect an interaction when queried for hemorrhagic stroke.

Conclusions

We show a strong signal for the levetiracetam interaction with apixaban, dabigatran, edoxaban, and rivaroxaban leading to a 3-5 folds increased reporting risk of ischemic stroke. Our findings suggest the need for pharmacodynamic monitoring, while concomitantly prescribing levetiracetam with the DOACs.
Volumetric trans-scale imaging of massive quantity of heterogeneous cell populations in centimeter-wide tissue and embryo
Authors: Ichimura Taro , Kakizuka Taishi , Taniguchi Yoshitsugu , Ejima Satoshi , Sato Yuki , Itano Keiko , Seiriki Kaoru , Hashimoto Hitoshi , Sugawara Ko , Itoga Hiroya , Onami Shuichi , Nagai Takeharu
Published: August 2023

We established a volumetric trans-scale imaging system with an ultra-large field-of-view (FOV) that enables simultaneous observation of millions of cellular dynamics in centimeter-wide three-dimensional (3D) tissues and embryos. Using a custom-made giant lens system with a magnification of 2× and a numerical aperture (NA) of 0.25, and a CMOS camera with more than 100 megapixels, we built a trans-scale scope AMATERAS-2, and realized fluorescence imaging with a transverse spatial resolution of approximately 1.1 µm across an FOV of approximately 1.5 × 1.0 cm2. The 3D resolving capability was realized through a combination of optical and computational sectioning techniques tailored for our low-power imaging system. We applied the imaging technique to 1.2 cm-wide section of mouse brain, and successfully observed various regions of the brain with sub-cellular resolution in a single FOV. We also performed time-lapse imaging of a 1-cm-wide vascular network during quail embryo development for over 24 hours, visualizing the movement of over 4.0 × 105vascular endothelial cells and quantitatively analyzing their dynamics. Our results demonstrate the potential of this technique in accelerating production of comprehensive reference maps of all cells in organisms and tissues, which contributes to understanding developmental processes, brain functions, and pathogenesis of disease, as well as high-throughput quality check of tissues used for transplantation medicine.
Heterologous sarbecovirus receptor binding domains as scaffolds for SARS-CoV-2 receptor binding motif presentation
Authors: Hauser Blake M. , Sangesland Maya , Lam Evan C. , Denis Kerri J. St. , Sheehan Maegan L. , Vu Mya L. , Cheng Agnes H. , Balazs Alejandro B. , Lingwood Daniel , Schmidt Aaron G.
Published: August 2023

Structure-guided rational immunogen design can generate optimized immunogens that elicit a desired humoral response. Design strategies often center upon targeting conserved sites on viral glycoproteins that will ultimately confer potent neutralization. For SARS-CoV-2 (SARS-2), the surface-exposed spike glycoprotein includes a broadly conserved portion, the receptor binding motif (RBM), that is required to engage the host cellular receptor, ACE2. Expanding humoral responses to this site may result in a more potently neutralizing antibody response against diverse sarbecoviruses. Here, we used a “resurfacing” approach and iterative design cycles to graft the SARS-2 RBM onto heterologous sarbecovirus scaffolds. The scaffolds were selected to vary the antigenic distance relative to SARS-2 to potentially focus responses to RBM. Multimerized versions of these immunogens elicited broad neutralization against sarbecoviruses in the context of preexisting SARS-2 immunity. These validated engineering approaches can help inform future immunogen design efforts for sarbecoviruses and are generally applicable to other viruses.
Contribution of bacterial and host factors to pathogen “blooming” in a gnotobiotic mouse model forSalmonella entericaserovar Typhimurium-induced enterocolitis
Authors: Beutler Markus , Eberl Claudia , Garzetti Debora , Herp Simone , Münch Philipp , Ring Diana , Dolowschiak Tamas , Brugiroux Sandrine , Schiller Patrick , Hussain Saib , Basic Marijana , Bleich Andre , Stecher Barbel
Published: August 2023

Inflammation has a pronounced impact on the intestinal ecosystem by driving an expansion of facultative anaerobic bacteria at the cost of obligate anaerobic microbiota. This pathogen “blooming” is also a hallmark of entericSalmonellaenterica serovar Typhimurium (S. Tm) infection. Here, we analyzed the contribution of bacterial and host factors toS. Tm “blooming” in a gnotobiotic mouse model forS.Tm-induced enterocolitis. Mice colonized with the Oligo-Mouse-Microbiota (OMM12), a minimal bacterial community, develop fulminant colitis by day 4 after oral infection with wild typeS. Tm but not with an avirulent mutant. Inflammation leads to pronounced reduction in overall intestinal bacterial loads, distinct microbial community shifts and pathogen blooming (relative abundance >50%).S.Tm mutants attenuated in inducing gut inflammation generally elicit less pronounced microbiota shifts and reduction in total bacterial loads. In contrast,S.Tm mutants in nitrate respiration, salmochelin production and ethanolamine utilization induced strong inflammation andS. Tm “blooming”. Therefore, individualSalmonella-specific inflammation-fitness factors seem to be of minor importance for competition against this minimal microbiota in the inflamed gut. Finally, we show that antibody-mediated neutrophil depletion normalized gut microbiota loads but not intestinal inflammation or microbiota shifts. This suggests that neutrophils equally reduce pathogen and commensal bacterial loads in the inflamed gut.
AI-based antibody discovery platform identifies novel, diverse and pharmacologically active therapeutic antibodies against multiple SARS-CoV-2 strains
Authors: Moldovan Loomis Cristina , Lahlali Thomas , Van Citters Danielle , Sprague Megan , Neveu Gregory , Somody Laurence , Siska Christine C. , Deming Derrick , Asakawa Andrew J. , Amimeur Tileli , Shaver Jeremy M. , Carbonelle Caroline , Ketchem Randal R. , Alam Antoine , Clark Rutilio H.
Published: August 2023

A critical aspect of a successful pandemic response is expedient antibody discovery, manufacturing and deployment of effective lifesaving treatments to patients around the world. However, typical drug discovery and development is a lengthy multi-step process that must align drug efficacy with multiple developability criteria and can take years to complete. In this context, artificial intelligence (AI), and especially machine learning (ML), have great potential to accelerate and improve the optimization of therapeutics, increasing their activity and safety as well as decreasing their development time and manufacturing costs. Here we present a novel, cost-effective and accelerated approach to therapeutic antibody discovery, that couples AI-designed human antibody libraries, biased for improved developability attributes with high throughput and sensitive screening technologies. The applicability of our platform for effective therapeutic antibody discovery is demonstrated here with the identification of a panel of human monoclonal antibodies that are novel, diverse and pharmacologically active. These first-generation antibodies, without the need for affinity maturation, bind to the SARS-CoV-2 spike protein with therapeutically-relevant specificity and affinity and display neutralization of SARS-CoV-2 viral infectivity across multiple strains. Altogether, this platform is well suited for rapid response to infectious threats, such as pandemic response.

IMPORTANCE

Expedient discovery and manufacturing of lifesaving therapeutics is critical for pandemic response. The recent COVID pandemic has highlighted the current inefficiencies and the need for improvements. To this end, we present our therapeutic antibody discovery platform that couples artificial intelligence (AI) and innovative high throughput technologies, and we demonstrate its applicability to rapid response. This platform enabled the isolation, characterization, and rapid identification of effective broadly neutralizing SARS-CoV-2 antibodies with good developability attributes, anticipated to fit our current process development and manufacturing platform. As such, this would benefit cost-of-goods and improve therapeutic access to patients. The AI-derived antibodies represent an advantageous therapeutic modality that can be developed and deployed fast, thus well suited for rapid response to infectious threats, such as pandemic response.
hnRNPA1 RGG-box acts a ”catalyst” in UP1-induced destabilization of RNA and DNA telomeric G-Quadruplexes
Authors: Balasubramanian Sangeetha , Roy Irawati , Appadurai Rajeswari , Srivastava Anand
Published: August 2023

hnRNPA1, a protein from the heterogeneous-nuclear ribonucleoprotein fam-ily, mediates cellular processes such as RNA metabolism and DNA telomere maintenance. Besides the folded RNA recognition motifs, hnRNPA1 has a ∼ 135 amino-acids long low-complexity domain (LCD) consisting of an RGG-rich region and a prion-like domain (PrLD). Biochemical data suggest that RGG-rich region modulates recognition of G-quadruplexes (GQs) in the telomeric repeats. Here, we utilize an in-house developed replica exchange technique (REHT) to generate the heterogeneous conformation ensemble of hnRNPA1-RGG and explore its functional significance in telomere maintenance. Single chain statistics and abundance of structural motifs, as well as consistency with experimentally reported struc-tural data, suggest faithful recapitulation of local interactions. We also introduce a protocol to generate functionally significant IDP-nucleic acid complex structures that corroborate well with the experimental knowledge of their binding. We find that RGG-box preferentially binds to the grooves and loops of GQs providing specificity towards certain GQ structures with its Phe, Tyr, and Asn residues forming essential hydrogen bonds and electrostatic interactions. Several of these residues were also identified as important by the reported HSQC chemical shift data. Our binding and simulations studies also revealed that a minor population of the RGG-box can destabilize telomeric GQs, thereby expediting the unfolding activities of hnRNPA1-UP1 at the telomeric end.
Spatiotemporal modelling of cholera and implications for its control, Uvira, Democratic Republic of the Congo
Authors: Ratnayake Ruwan , Knee Jacqueline , Cumming Oliver , Saidi Jaime Mufitini , Rumedeka Baron Bashige , Finger Flavio , Azman Andrew S. , Edmunds W. John , Checchi Francesco , Gallandat Karin
Published: August 2023

The African Great Lakes region including Eastern Democratic Republic of the Congo is a hotspot for cholera transmission. We evaluated the local and global clustering of cholera using 5 years (2016—2020) of suspected cases positive by rapid diagnostic test in Uvira, South Kivu to detect spatiotemporal clusters and the extent of zones of increased risk around cases. We detected 26 clusters (mean radius 652m and mean duration 24.8 days) which recurred annually in three locations and typically preceded seasonal outbreaks. We found a 1100m zone of increased infection risk around cases during the 5 days following clinic attendance for the 2016—2020 period and a 600m radius risk zone for 2020 alone. These risk zone sizes correspond with the area typically used for targeted intervention in the Democratic Republic of the Congo. Our findings underscore the value of the site-specific evaluation of clustering to guide targeted control efforts.
Pathogenic paralogous variants can be used to apply the ACMG PS1 and PM5 variant interpretation criteria
Authors: Brünger Tobias , Ivaniuk Alina , Pérez-Palma Eduardo , Montanucci Ludovica , Cohen Stacey , Smith Lacey , Parthasarathy Shridhar , Helbig Ingo , Nothnagel Michael , May Patrick , Lal Dennis
Published: August 2023

Purpose

The majority of missense variants in clinical genetic tests are classified as variants of uncertain significance. Broadening the evidence of the PS1 and PM5 criteria has the potential to increase conclusive variant interpretation.

Methods

We hypothesized that incorporation of pathogenic missense variants in conserved residues across paralogous genes can increase the number of variants where ACMG PS1/PM5 criteria can be applied. We mapped over 2.5 million pathogenic and general population variants from ClinVar, HGMD, and gnomAD databases onto 9,990 genes and aligned these by gene families. Subsequently, we developed a novel framework to extend PS1/PM5 by incorporating pathogenic paralogous variants annotations (para-PS1/PM5).

Results

We demonstrate that para-PS1/PM5 criteria increase the number of classifiable amino acids 3.6-fold compared to PS1 and PM5. Across all gene families with at least two disease-associated genes, the calculated likelihood ratios suggest moderate evidence for pathogenicity. Moreover, for 36 genes, the extended para-PS1/PM5 criteria reach strong evidence level.

Conclusion

We show that single pathogenic paralogous variants incorporation at paralogous protein positions increases the applicability of the PS1 and PM5 criteria, likely leading to a reduction of variants of uncertain significance across many monogenic disorders. Future iterations of the ACMG guidelines may consider para-PS1 and para-PM5.
Risk of long COVID and associated symptoms after acute SARS-COV-2 infection in ethnic minorities: a Danish nationwide cohort study
Authors: Mkoma George F. , Agyemang Charles , Benfield Thomas , Rostila Mikael , Cederström Agneta , Petersen Jørgen H. , Norredam Marie
Published: August 2023

Background

Ethnic minorities living in high-income countries have been disproportionately affected by COVID-19 in terms of infection rates and hospitalisations; however, less is known about long COVID in this population. Our aim was to examine the risk of long COVID and associated symptoms among ethnic minorities.

Methods and Findings

A Danish nationwide register-based cohort study of individuals diagnosed with COVID-19 aged ≥18 years (n=2 334 271) between January 2020 and August 2022. We calculated the risk of long COVID diagnosis and long COVID symptoms among ethnic minorities compared with native Danes using multivariable Cox proportional hazard regression and logistic regression, respectively.

Ethnic minorities from North Africa (adjusted hazard ratio [aHR] 1.41; 95% CI 1.12–1.79), Middle East (aHR 1.38; 95% CI 1.24–1.55), Eastern Europe (aHR 1.35; 95% CI 1.22–1.49), and Asia (aHR 1.23; 95% CI 1.09–1.40) had significantly greater risk of long COVID diagnosis than native Danes in both unadjusted and adjusted models. In the analysis by largest countries of origin, the greater risks of long COVID diagnosis were found in Iraqis (aHR 1.56; 95% CI 1.30– 1.88), Turks (aHR 1.42; 95% CI 1.24–1.63), and Somalis (aHR 1.42; 95% CI 1.07–1.91) after adjustment for confounders. Significant factor associated with an increased risk of long COVID diagnosis was COVID-19 hospitalisation. Furthermore, the odds of reporting cardiopulmonary symptoms (including dyspnoea, cough, and chest pain) andanylong COVID symptoms were higher among North African, Middle Eastern, Eastern European, and Asian than among native Danes in both unadjusted and adjusted models.

Conclusions

Belonging to an ethnic minority group was significantly associated with an increased risk of long COVID indicating the need to better understand long COVID drivers and address care and treatment strategies in this population.
Sex differences in the diagnosis of advanced cancer and subsequent outcome in people with chronic kidney disease: an analysis of a national population cohort
Authors: Shemilt R , Sullivan MK , Hanlon P , Jani B , De La Mata N , Rosales B , Elyan BMP , Wyld M , Hedley JA , Cutting R , McAllister DA , Webster AC , Mark PB , Lees JS
Published: August 2023

Background

In the general population, advanced cancer stage at presentation is associated with poorer health outcomes. People with chronic kidney disease (CKD) have increased incidence and mortality from most cancer types. We sought to determine whether people with CKD were more likely to present with advanced stage cancer, whether this was associated with survival, and whether these associations varied by sex.

Methods

Data were from Secure Anonymised Information Linkage Databank (SAIL), a Welsh primary care database with linkage to cancer and death registries. We included patients with a de- novo cancer diagnosis (2011-2017), and at least two kidney function tests in the two years prior to diagnosis. Estimated glomerular filtration rate based on serum creatinine (eGFRcr) was calculated using the CKD-EPI 2009 equation (mL/min/1.73m2). Logistic regression models determined odds of presenting with advanced cancer (stage 3 or 4 at diagnosis) by different values of eGFRcr at baseline. Cox proportional hazards models tested associations between eGFRcr at baseline and all-cause mortality risk (reference eGFR 75 to <90).

Findings

There were 66,128 patients: 30,857 (46.7%) were female, mean age was 69.1 (standard deviation [SD] 13.8) years in females and 70.6 (SD 11.1) years in males; median eGFRcr at baseline was 78 (interquartile range [IQR] 63 – 90) mL/min/1.73m2in both females and males. Over a median follow-up time of 3.1 (IQR 0.5 – 5.7) years in females and 2.9 (IQR 0.5-5.5) years in males, there were 17,303 deaths in females and 20,855 in males. An eGFRcr <30 was associated with higher odds of presenting with advanced cancer in males (OR 1.33 95% CI 1.09-1.62), but not in females (OR 1.17 95% CI 0.92-1.50); positive associations were primarily driven by prostate and breast cancers. With lower eGFRcr, hazards of cancer death increased in both sexes, but lower eGFRcr was associated with greater hazards of cancer death in females (eGFRcr <30: HR 1.71, 95% CI 1.56-1.88, p<0.001; male versus female comparison HR 0.88, 95% CI 0.78-0.90; p=0.037).

Interpretation

CKD was not associated with substantially higher odds of presenting with advanced cancer across most cancer sites (except prostate and breast), but was associated with reduced survival. Despite an initial survival advantage compared to males, females with CKD had disproportionately higher hazards of death. Though potential explanations for reduced survival after a cancer diagnosis are manifold, scrutiny of access to, efficacy, and safety of cancer treatments in people with CKD – particularly females with CKD – are warranted.

Funding

Chief Scientist Office (Scotland) Postdoctoral Lectureship (PCL/20/10) and University of Sydney/University of Glasgow Office of Global Engagement Collaboration Partnership (9241562498).
Administration of vaccine-boosted COVID-19 convalescent plasma to SARS-CoV-2 infected hamsters decreases virus replication in lungs and hastens resolution of the infection despite transiently enhancing disease and lung pathology
Authors: Carroll Timothy D. , Wong Talia , Morris Mary Kate , Germanio Clara Di , Ma Zhong-min , Stone Mars , Ball Erin , Fritts Linda , Rustagi Arjun , Simmons Graham , Busch Michael , Miller Christopher J.
Published: August 2023

The utility of COVID-19 convalescent plasma (CCP) for treatment of immunocompromised patients who are not able to mount a protective antibody response against SARS-CoV-2 and who have contraindications or adverse effects from currently available antivirals remains unclear. To better understand the mechanism of protection in CCP, we studied viral replication and disease progression in SARS-CoV-2 infected hamsters treated with CCP plasma obtained from recovered COVID patients that had also been vaccinated with an mRNA vaccine, hereafter referred to as Vaxplas. We found that Vaxplas dramatically reduced virus replication in the lungs and improved infection outcome in SARS-CoV-2 infected hamsters. However, we also found that Vaxplas transiently enhanced disease severity and lung pathology in treated animals likely due to the deposition of immune complexes, activation of complement and recruitment of increased numbers of macrophages with an M1 proinflammatory phenotype into the lung parenchyma.
Cerebral perfusion alterations in temporal lobe epilepsy: Structural underpinnings and network disruptions
Authors: Ngo Alexander , Royer Jessica , Rodríguez-Cruces Raúl , Xie Ke , DeKraker Jordan , Auer Hans , Tavakol Shahin , Lam Jack , Schrader Dewi , Dudley Roy W. R. , Bernasconi Andrea , Bernasconi Neda , Frauscher Birgit , Larivière Sara , Bernhardt Boris C.
Published: August 2023

Abstract

Objective

Neuroimaging has been the prevailing method to study brain networks in temporal lobe epilepsy (TLE), showing widespread alterations beyond the mesiotemporal lobe. Despite the critical role of the cerebrovascular system in maintaining whole-brain structure and function, changes in cerebral blood flow (CBF) remain incompletely understood in the disease.

Methods

We studied 24 individuals with pharmaco-resistant TLE and 38 healthy adults using multimodal 3T magnetic resonance imaging. We compared regional CBF changes in patients relative to controls and related our perfusion findings to morphological and microstructural metrics. We further probed inter-regional vascular networks in TLE, using graph theoretical CBF covariance analysis. Finally, we assessed the effects of disease duration to study progressive changes.

Results

Compared to controls, individuals with TLE showed widespread CBF reductions, predominantly in fronto-temporal regions, with 83% of patients showing more marked decreases ipsilateral than contralateral to the seizure focus. Parallel structural profiling and network-based models showed that cerebral hypoperfusion may be partly constrained by grey and white matter changes and topologically segregated from whole-brain perfusion networks. Negative effects of progressive disease duration further targeted regional CBF profiles in patients. Findings were confirmed in a subgroup of patients who remained seizure-free after surgery.

Interpretation

Our multimodal findings provide insights into vascular contributions to TLE pathophysiology and highlight their clinical potential in seizure lateralization.
Single-molecule analysis reveals the phosphorylation of FLS2 governs its spatiotemporal dynamics and immunity
Authors: Cui Yaning , Qian Hongping , Yin Jinhuan , Xu Changwen , Luo Pengyun , Zhang Xi , Yu Meng , Su Bodan , Li Xiaojuan , Lin Jinxing
Published: August 2023

TheArabidopsis thalianaFLAGELLIN-SENSITIVE2 (FLS2), a typical receptor kinase, recognizes the conserved 22 amino acid sequence in the N-terminal region of flagellin (flg22) to initiate plant defense pathways, which was intensively studied in the past decades. However, the dynamic regulation of FLS2 phosphorylation at the plasma membrane after flg22 recognition needs further elucidation. Through single-particle tracking, we demonstrated that upon flg22 treatment, the phosphorylation of Ser-938 in FLS2 impacts its spatiotemporal dynamics and lifetime. Following förster resonance energy transfer-fluorescence lifetime (FRET-FLIM) imaging microscopy and protein proximity indexes (PPI) assays revealed that flg22 treatment increased the co-localization of GFP-tagged FLS2/FLS2S938Dbut not FLS2S938Awith AtRem1.3-mCherry, a sterol-rich lipid marker, indicating that the phosphorylation of FLS2S938affects FLS2 sorting efficiency to AtRem1.3-associated nanodomains. Importantly, we found that the phosphorylation of Ser-938 enhanced flg22-induced FLS2 internalization and immune responses, demonstrating that the phosphorylation may activate flg22-triggered immunity through partitioning FLS2 into functionalAtRem1.3-associated nanodomains, which fills the gap between the FLS2S938phosphorylation and FLS2-mediated immunity.
Meta-omic profiling reveals ubiquity of genes encoding for the high value nitrogen rich biopolymer cyanophycin in activated sludge microbiomes
Authors: Farmer McKenna , Raj Rashmi , Tarpeh Will , Tyo Keith , Wells George
Published: August 2023

Recovering nitrogen (N) from municipal wastewater is a promising approach to prevent nutrient pollution, reduce energy use, and transition towards a circular N bioeconomy, but remains a technologically challenging endeavor. Existing N recovery techniques are optimized for high-strength, low-volume wastewater. Therefore, developing methods to concentrate dilute N from mainstream wastewater will bridge the gap between existing technologies and practical implementation. The N-rich biopolymer cyanophycin is a promising candidate for N bioconcentration and recovery due to its solubility characteristics and potential for high levels of accumulation in a limited number of bacterial isolates. However, the cyanophycin synthesis pathway is poorly explored in natural and engineered microbiomes. In this study, we analyzed over 3700 publicly available metagenome assembled genomes (MAGs) and found that the cyanophycin synthesis genecphAwas ubiquitous across common activated sludge bacteria. Surprisingly, we found thatcphAwas present in all analyzed genomes of the common phosphorus accumulating organisms (PAO)Ca. ‘Accumulibacter’ andTetrasphaera, suggesting potential for simultaneous N and P bioconcentration in the same organisms. Using metatranscriptomic data, we also confirmed the expression ofcphAin lab-scale bioreactors enriched with PAO. Our findings suggest that cyanophycin synthesis is a ubiquitous metabolic pathway in activated sludge microbiomes and therefore may have potential for integration in existing biological nutrient removal and recovery processes. We anticipate this work to be a starting point for future evaluations of combined N and P bioaccumulation, with the ultimate goal of advancing widespread adoption of nutrient recovery from municipal wastewater.