bluuebunny/crossref_metadata_2025 huggingface dataset:
Septoria tritici blotch resistance geneStb15encodes a lectin receptor-like kinase
Authors: Hafeez Amber N. , Chartrain Laetitia , Feng Cong , Cambon Florence , Clarke Martha , Griffiths Simon , Hayta Sadiye , Jiang Mei , Keller Beat , Kirby Rachel , Kolodziej Markus C. , Powell Oliver R. , Smedley Mark , Steuernagel Burkhard , Xian Wenfei , Wingen Luzie U. , Cheng Shifeng , Saintenac Cyrille , Wulff Brande B. H. , Brown James K. M.
Published: September 2023

Septoria tritici blotch (STB), caused by the Dothideomycete fungusZymoseptoria tritici, is of one of the most damaging diseases of bread wheat (Triticum aestivum)1and the target of costly fungicide applications2. In line with the fungus’ apoplastic lifestyle, STB resistance genes isolated to date encode receptor-like kinases (RLKs) including a wall-associated kinase (Stb6) and a cysteine-rich kinase (Stb16q)3,4. Here, we used genome-wide association studies (GWAS) on a panel of 300 whole-genome shotgun-sequenced diverse wheat landraces (WatSeq consortium) to identify a 99 kb region containing six candidates for theStb15resistance gene. Mutagenesis and transgenesis confirmed a gene encoding an intronless G-type lectin RLK (LecRK) asStb15. The characterisation ofStb15exemplifies the unexpected diversity of RLKs conferringZ. triticiresistance in wheat.
Dual inhibition of coronavirus Mproand PLproenzymes by phenothiazines and their antiviral activity
Authors: Forrestall Katrina , Pringle Eric S. , Sands Dane , Duguay Brett A. , Farewell Brett , Woldemariam Tekeleselassie , Falzarano Darryl , Pottie Ian , McCormick Craig , Darvesh Sultan
Published: September 2023

Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle formation, viral RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two viral cysteine proteases, main protease (Mpro) and papain-like protease (PLpro), that mediate polyprotein cleavage. Using a structure-guided approach, a phenothiazine urea derivative that inhibits both SARS-CoV-2 Mproand PLproprotease activityin vitrowas identified.In silicodocking studies also predicted binding of the phenothiazine to the active sites of Mproand PLprofrom distantly related alphacoronavirus, HCoV-229E (229E) and the betacoronavirus, HCoV-OC43 (OC43). The lead phenothiazine urea derivative displayed broad antiviral activity against all three HCoVs tested in cell culture infection models. It was further demonstrated that the compound inhibited 229E and OC43 at an early stage of viral replication, with diminished formation of viral replication organelles and the RNAs that are made within them, as expected following viral protease inhibition. These observations suggest that the phenothiazine urea derivative inhibits viral replication and may broadly inhibit proteases of diverse coronaviruses.

Graphical Abstract

Highlights

Coronavirus cysteine proteases Mproand PLproare targets for novel antiviral agents

Phenothiazine ureas inhibit SARS-CoV-2 Mproand PLproprotease activity

Some phenothiazine ureas inhibit replication of diverse coronaviruses with minimal cytotoxicity

Phenothiazine ureas inhibit early stages of coronavirus replication consistent with failure of viral polyprotein cleavage
Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-cage Behavior
Authors: Krishnan Vaishnav , Wu Jun , Mazumder Arindam Ghosh , Kamen Jessica L. , Schirmer Catharina , Adhyapak Nandani , Bass John Samuel , Lee Samuel C. , Maheshwari Atul , Molinaro Gemma , Gibson Jay R. , Huber Kimberly M. , Minassian Berge A
Published: September 2023

Lafora Disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD, as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6-7 months and ∼12 months of age, malin deficient mice (“KO”) and wild type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age dependent LB accumulation, gliosis and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. Using anin vitroassay of neocortical function, paroxysmal increases in network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but were similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced post-ictal suppression of movement, feeding and drinking behavior. Together, these results highlight a stark clinicopathologic dissociation in a mouse model of LD, where LBs accrue substantially without clinically meaningful changes in overall wellbeing. Our findings allude to a delay between LB accumulation and neurobehavioral decline: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.
On the Rotational Structure in Neural Data
Authors: Kuzmina Ekaterina , Kriukov Dmitrii , Lebedev Mikhail
Published: September 2023

Spatiotemporal properties of the activity of neuronal populations in cortical motor areas have been the subject of many experimental and theoretical investigations, which generated numerous inter-pretations regarding the mechanisms of preparing and executing limb movements. Two competing models, namely representational and dynamical models, strive to explain the temporal course of neuronal activity and its relationship to different parameters of movements. One proposed dynamical model employs the jPCA method, a dimensionality reduction technique, to holistically characterize oscillatory activity in a population of neurons by maximizing rotational dynamics that are present in the data. Different interpretations have been proposed for the rotational dynamics revealed with jPCA approach in various brain areas. Yet, the nature of such dynamics remains poorly understood. Here we conducted a comprehensive analysis of several neuronal-population datasets. We found that rotational dynamics were consistently accounted for by a travelling wave pattern. To quantify the rotation strength, we developed a complex-valued measure termed the gyration number. Additionally, we identified the parameters influencing the extent of rotation in the data. Overall, our findings suggest that rotational dynamics and travelling waves are the same phenomena, which requires reevaluation of the previous interpretations where they were considered as separate entities.
Prenatal vitamin D deficiency alters immune cell proportions of young adult offspring through alteration of long-term stem cell fates
Authors: Ueda Koki , Chin Shu Shien , Sato Noriko , Nishikawa Miyu , Yasuda Kaori , Miyasaka Naoyuki , Bera Betelehem Solomon , Chorro Laurent , Doña-Termine Reanna , Koba Wade R , Reynolds David , Steidl Ulrich G. , Lauvau Gregoire , Greally John M. , Suzuki Masako
Published: September 2023

Vitamin D deficiency is a common deficiency worldwide, particularly among women of reproductive age. During pregnancy, it increases the risk of immune-related diseases in offspring later in life. However, exactly how the body remembers exposure to an adverse environment during development is poorly understood. Herein, we explore the effects of prenatal vitamin D deficiency on immune cell proportions in offspring using vitamin D deficient mice established by dietary manipulation. We found that prenatal vitamin D deficiency alters immune cell proportions in offspring by changing the transcriptional properties of genes downstream of vitamin D receptor signaling in hematopoietic stem and progenitor cells of both the fetus and adults. Our results suggest the role of cellular differentiation properties of the hematopoiesis as the long-term memories of prenatal exposure at the adult stage. Moreover, further investigations of the associations between maternal vitamin D levels and cord blood immune cell profiles from 75 healthy pregnant women and their term babies also confirm that maternal vitamin D levels in the second trimester significantly affect immune cell proportions in the babies. This highlights the importance of providing vitamin D supplementation at specific stages of pregnancy.
An obligate aerobe adapts to hypoxia by hybridising fermentation with carbon storage
Authors: Gillett David L , Hutchinson Tess , Mudaliyar Manasi , Watts Thomas D. , Wong Wei Wen , Locop Jake , Jimenez Luis , Hanchapola Iresha , Lee Han-Chung , Tanuwidjaya Erwin , Steele Joel R. , Schittenhelm Ralf B. , Barlow Christopher K. , Grinter Rhys , Ghosal Debnath , Cook Perran L. M. , Greening Chris
Published: September 2023

In soil ecosystems, obligately aerobic bacteria survive oxygen deprivation (hypoxia) by entering non-replicative persistent states. Little is known about how these bacteria rewire their metabolism to stay viable in these states. The model obligate aerobeMycobacterium smegmatismaintains redox homeostasis during hypoxia by mediating fermentative hydrogen production. However, the fate of organic carbon during fermentation, and the associated remodeling of carbon metabolism, is unresolved. Here we systematically profiled the metabolism ofM. smegmatisduring aerobic growth, hypoxic persistence, and the transition between these states. Using differential isotope labelling, and paired metabolomics and proteomics, we observed rerouting of central carbon metabolism through the pentose phosphate pathway and Entner-Doudoroff pathway during hypoxia. We show thatM. smegmatisexcretes high levels of hydrogen concurrently with upregulating triacylglyceride synthases and accumulating glycerides as carbon stores. Using electron cryotomography (cryo-ET), we observed the presence of large spheroid structures consistent with the appearance of lipid droplets. Thus, in contrast to obligately and facultative anaerobic fermentative bacteria,M. smegmatisstores rather than excretes organic carbon during hypoxia. This novel hybrid metabolism likely provides a competitive advantage in resource-variable environments by allowingM. smegmatisto simultaneously dispose excess reductant during hypoxia and maintain carbon stores to rapidly resume growth upon reoxygenation.
WELPCR: Low-cost polymerase chain reaction (PCR) thermal cycler for nucleic acid amplification and sensing
Authors: Mandal Poulami , Dhakane Vivekanand , Kulkarni Avani , Tallur Siddharth
Published: September 2023

The COVID-19 pandemic highlighted the need for sensitive and cost-effective diagnostics. The gold standard test to diagnose infectious diseases such as COVID-19 is quantitative polymerase chain reaction (qPCR). Although there have been multiple advances in nucleic acid testing, PCR thermocyclers are expensive and typically not affordable for offering hands-on training to PCR in instructional laboratory courses in undergraduate colleges. We introduce a low-cost, portable, and automated real-time PCR device designed at the Wadhwani Electronics Lab (WEL) at IIT Bombay, christened WELPCR. WELPCR is an open-source design, and capable of reverse transcription PCR (RT-PCR) for complementary DNA synthesis, as well as end-point PCR of small amount of DNA in a test sample. The WELPCR design enables ramp rate up to 2 °C/s, weighs less than 2 kg, and is easy to assemble. The built-in LED display and keypad provides an intuitive and seamless user interface to configure and set up WELPCR. With bill of materials (BOM) cost less than INR Rs. 10 000, WELPCR is an attractive solution for bringing PCR technology to instructional and research laboratories in a cost-effective manner.
Investigating potential myopia risk factors, including chronotype, in Estonian adolescents
Authors: Palumaa Teele , Linntam Delis , Rebane Reili , Tammaru Marika , Palumaa Kadi
Published: September 2023

Purpose

To evaluate chronotype, lifestyle factors, and parental myopia in relation to myopia, and characterise the effect of cycloplegia on spherical equivalent refraction (SER) in Estonian secondary school students.

Methods

One hundred twenty-three students aged between 15 and 17 years from three secondary schools in Estonia participated in the study. They underwent a comprehensive ocular examination, including cycloplegic refraction and ocular biometry. Chronotype was evaluated with the Morningness–Eveningness Questionnaire. Participants also completed a questionnaire about their daily activities, including time spent outdoors, time spent on near-work and mid-working distance activities, and parental myopia. Myopia was defined as cycloplegic SER ≤–0.50 D. Logistic regression analysis was performed to assess the association of the studied factors with myopia.

Results

In a multivariate regression model, having two myopic parents was associated with higher odds of myopia (OR 3.78, 95% CI 1.15–12.42). We found no association between myopia and chronotype. Notably, time spent outdoors, and doing near-work and mid-working distance activities, did not affect the likelihood of having myopia. Non-cycloplegic SER was significantly more myopic than cycloplegic SER on average by 0.86 D (p< 0.0001, Wilcoxon matched-pairs signed rank test).

Conclusion

Consistent with previous reports, we identified parental myopia as a myopia risk factor. Chronotype was not associated with myopia in our study sample. Interestingly, there was no association between myopia and time spent outdoors or near work. Using non-cycloplegic refraction would lead to a significant overestimation of myopia.
Randomized Controlled Trials Evaluating AI in Clinical Practice: A Scoping Evaluation
Authors: Han Ryan , Acosta Julián N. , Shakeri Zahra , Ioannidis John P.A. , Topol Eric J. , Rajpurkar Pranav
Published: September 2023

Background

Artificial intelligence (AI) has emerged as a promising tool in healthcare, with numerous studies indicating its potential to perform as well or better than clinicians. However, a considerable portion of these AI models have only been tested retrospectively, raising concerns about their true effectiveness and potential risks in real-world clinical settings.

Methods

We conducted a systematic search for randomized controlled trials (RCTs) involving AI algorithms used in various clinical practice fields and locations, published between January 1, 2018, and August 18, 2023. Our study included 84 trials and focused specifically on evaluating intervention characteristics, study endpoints, and trial outcomes, including the potential of AI to improve care management, patient behavior and symptoms, and clinical decision-making.

Results

Our analysis revealed that 82·1% (69/84) of trials reported positive results for their primary endpoint, highlighting AI’s potential to enhance various aspects of healthcare. Trials predominantly evaluated deep learning systems for medical imaging and were conducted in single-center settings. The US and China had the most trials, with gastroenterology being the most common field of study. However, we also identified areas requiring further research, such as multi-center trials and diverse outcome measures, to better understand AI’s true impact and limitations in healthcare.

Conclusion

The existing landscape of RCTs on AI in clinical practice demonstrates an expanding interest in applying AI across a range of fields and locations. While most trials report positive outcomes, more comprehensive research, including multi-center trials and diverse outcome measures, is essential to fully understand AI’s impact and limitations in healthcare.
Artificial Intelligence methods for Improved Detection of undiagnosed Heart Failure with Preserved Ejection Fraction (HFpEF)
Authors: Wu Jack , Biswas Dhruva , Ryan Matthew , Bernstein Brett , Rizvi Maleeha , Fairhurst Natalie , Kaye George , Baral Ranu , Searle Tom , Melikian Narbeh , Sado Daniel , Lüscher Thomas F , Grocott-Mason Richard , Carr-White Gerald , Teo James , Dobson Richard , Bromage Daniel I , McDonagh Theresa A , Shah Ajay M , O’Gallagher Kevin
Published: September 2023

Background and aim

Heart Failure with preserved Ejection Fraction (HFpEF) remains under-diagnosed in clinical practice despite accounting for nearly half of all Heart Hailure (HF) cases. Accurate and timely diagnosis of HFpEF is crucial for proper patient management and treatment. In this study, we explored the potential of natural language processing (NLP) to improve the detection and diagnosis of HFpEF according to the European Society of Cardiology (ESC) diagnostic criteria.

Methods

In a retrospective cohort study, we used an NLP pipeline applied to the Electronic Health Record (EHR) to identify patients with a clinical diagnosis of HF between 2010-2022. We collected demographic, clinical, echocardiographic and outcome data from the EHR. Patients were categorised according to the left ventricular ejection fraction (LVEF). Those with LVEF ≥ 50% were further categorised based on whether they had a clinician-assigned diagnosis of HFpEF and if not, whether they met the ESC diagnostic criteria. Results were validated in a second, independent centre.

Results

We identified 8606 patients with HF. Of 3727 consecutive patients with HF and LVEF ≥ 50% on echocardiogram, only 8.3% had a clinician-assigned diagnosis of HFpEF, while 75.4% met ESC criteria but did not have a formal diagnosis of HFpEF. Patients with confirmed HFpEF were hospitalised more frequently; however the ESC criteria group had a higher 5-year mortality, despite being less co-morbid and experiencing fewer acute cardiovascular events.

Conclusions

This study demonstrates that patients with undiagnosed HFpEF are an at-risk group with high mortality. It is possible to use NLP methods to identify likely HFpEF patients from EHR data who would likely then benefit from expert clinical review and complement the use of diagnostic algorithms.

Graphical Abstract

Of 3727 consecutive patients with a clinical diagnosis of HF and left ventricular ejection fraction (LVEF) >50% on echocardiogram, only 8.3% had a clinician-assigned diagnosis of HFpEF, while 75.4% met ESC criteria but did not have a formal diagnosis of HFpEF. The two groups had similar rates of hospitalisation however the ESC criteria group had a higher 5-year mortality.
Spinocerebellar ataxia type 2 has multiple ancestral origins
Authors: Sena Lucas Schenatto , Furtado Gabriel Vasata , Pedroso José Luiz , Barsottini Orlando , Cornejo-Olivas Mario , Nóbrega Paulo Ribeiro , Neto Pedro Braga , Soares Danyela Martins Bezerra , Vargas Fernando Regla , Godeiro Clecio , Medeiros Paula Frassinetti Vasconcelos de , Camejo Claudia , Toralles Maria Betania Pereira , Fagundes Nelson Jurandi Rosa , Jardim Laura Bannach , Saraiva-Pereira Maria Luiza
Published: September 2023

Spinocerebellar ataxia type 2 (SCA2) is an adult onset, dominant neurodegenerative disorder due to expansions of a CAG repeat tract at theATXN2gene. A few studies on ancestral haplotypes were performed so far, and the allele C at rs695871 was always found in SCA2 carriers. We aimed to describe SCA2 ancestral haplotypes constructed based on the SNPs rs9300319, rs3809274, rs695871, rs1236900 and rs593226, using the STRs D12S1329, D12S1333, D12S1672 and D12S1332 to determine their genetic variation. Seventy-seven SCA2 families were recruited from Brazil, Peru, and Uruguay; 162 chromosomes from the Brazilian general population and the chromosomes with normal repeats from 101 SCA2 carriers were used as 263 controls. Eleven ancestral haplotypes were found in SCA2 families. The most frequent ones were A-G-C-C-C (46.7% of families), G-C-C-C-C (24.6%) and A-C-C-C-C (10.3%), with assigned risks of being associated with disease of δ = 0.326, 0.197 and 0, respectively. Their mean (sd) CAGexp were 41.68 (3.55), 40.42 (4.11) and 45.67 (9.70) (p= 0.055), while the mean (sd) CAG lengths at normal alleles were 23.85 (3.59), 22.97 (3.93) and 30.81 (4.27) (p< 0.001), respectively. The other SCA2 haplotypes were rare: among them, a G-C-G-A-T was found, evidencing a G allele in rs695871. In summary, our work identified eleven distinct SCA2 haplotypes in Brazilian, Uruguayan, and Peruvian families, including an unexpected SCA2 haplotype with a G allele at rs695871. These results suggest that SCA2 has multiple origins in these populations.
A PrEP Decision Aid for Women Survivors of Intimate Partner Violence: Task-Shifting Implementation to Domestic Violence Service Settings
Authors: Meyer Jaimie P. , Lazarus Elizabeth , Phillips Karlye , Watts Z. Thomasina , Duroseau Brenice , Carlson Cindy , Price Carolina R. , Kershaw Trace , Willie Tiara C.
Published: September 2023

Background

Women exposed to intimate partner violence (IPV) experience multiple social and structural barriers to accessing HIV pre-exposure prophylaxis (PrEP), despite being at increased risk for HIV. In addition, few existing HIV prevention interventions address IPV. A recently developed PrEP decision aid for women has the potential to reach IPV survivors at risk for HIV if it could be integrated into existing domestic violence agencies that prioritize trust and rapport with female IPV survivors. Leveraging non-traditional service delivery mechanisms in the community could expand reach to women who are IPV survivors for PrEP.

Methods

We conducted qualitative interviews and online qualitative surveys with 33 IPV survivors and 9 domestic violence agency staff at two agencies in Connecticut. We applied the Consolidated Framework for Implementation Research (CFIR) to understand barriers and facilitators to delivering a novel PrEP decision aid to IPV survivors in the context of domestic violence service agencies.

Results

Most IPV survivors and agency staff thought the PrEP decision aid intervention could be compatible with agencies’ existing practices, especially if adapted to be trauma-responsive and delivered by trusted counselors and staff members. PrEP conversations could be packaged into already well-developed safety planning and wellness practices. Agency staff noted some concerns about prioritizing urgent safety needs over longer-term preventive health needs during crisis periods and expressed interest in receiving further training on PrEP to provide resources for their clients.

Conclusions

IPV survivors and agency staff identified key intervention characteristics of a PrEP decision aid and inner setting factors of the service agencies that are compatible. Any HIV prevention intervention in this setting would need to be adapted to be trauma-responsive and staff would need to be equipped with proper training to be successful.
Effectiveness of Online Training in Improving Primary Care Doctors’ Competency in Brief Tobacco Interventions: A Cluster Randomised Controlled Trial of WHO Modules in Delta State, Nigeria
Authors: Moeteke Nnamdi Stephen , Oyibo Patrick , Ochei Oboratare , Ntaji Maureen Iru , Awunor Nyemike Simeon , Adeyemi Mitchell Oritsewino , Enemuwe Ibobo Mike , Agbatutu Eseoghene , Adesoye Oluwaseun Opeyemi
Published: September 2023

Background

The World Health Organisation (WHO) strongly recommends that brief tobacco interventions should be routinely offered in primary care. However, medical doctors do not consistently and effectively intervene during their encounters with cigarette smokers. There is a paucity of studies assessing the effect of training on the tobacco intervention competency of primary care doctors in Nigeria.

Aim

To evaluate the effectiveness of online training in improving competency in brief tobacco interventions among primary care doctors in Delta State, Nigeria.

Methods

A cluster-randomised controlled trial was conducted among eligible doctors working in government-owned facilities. The 22 eligible Local Government Areas (LGAs) served as clusters. The intervention group received a WHO six-hour online course on brief tobacco cessation intervention, delivered via Zoom. The control group received no intervention. A structured questionnaire was sent to participants via WhatsApp before and six months after the training. The primary outcome variables were scores for knowledge, attitude, self-efficacy, and practice. Differences in change of scores between intervention and control groups were assessed witht-test. To adjust for clustering, these inter-group differences were further analysed using linear mixed-effects regression modelling with study condition modelled as a fixed effect, and LGA of practice entered as a random effect.

Results

The intervention group had a significantly higher mean of change in scores for knowledge (effect size 0.344) and confidence (effect size 0.52).

Conclusion

The study shows that training, even online, positively affects clinician competency in brief tobacco intervention. This is important for primary care systems in developing countries. Mandatory in-service training and promotion of the WHO modules are recommended.
Demographic responses of oceanic island birds to local and regional ecological disruptions revealed by whole-genome sequencing
Authors: Gabrielli Maëva , Leroy Thibault , Salmona Jordi , Nabholz Benoit , Milá Borja , Thébaud Christophe
Published: September 2023

Disentangling the effects of ecological disruptions operating at different spatial and temporal scales in shaping past species’ demography is particularly important in the current context of rapid environmental changes driven by both local and regional factors. We argue that volcanic oceanic islands provide useful settings to study the influence of past ecological disruptions operating at local and regional scales on population demographic histories. We investigate potential drivers of past population dynamics for three closely related species of passerine birds from two volcanic oceanic islands, Reunion and Mauritius (Mascarene archipelago), with distinct volcanic history. Using ABC and PSMC inferences from complete genomes, we reconstructed the demographic history of the Reunion Grey White-eye (Zosterops borbonicus(Pennant, 1781)), the Reunion Olive White-eye (Z. olivaceus(Linnaeus, 1766)), and the Mauritius Grey White-eye (Z. mauritianus(Gmelin, 1789)), and searched for possible causes underlying similarities or differences between species living on the same or different islands. Both demographic inferences strongly support ancient and long-term expansions in all species. They also reveal different trajectories between species inhabiting different islands, but consistent demographic trajectories in species or populations from the same island. Species from Reunion appear to have experienced synchronous reductions in population size during the Last Glacial Maximum, a trend not seen in the Mauritian species. Overall, this study suggests that local events may have played a role in shaping population trajectories of these island species. It also highlights the potential of our conceptual framework to disentangle the effects of local and regional drivers on past species’ demography and long-term population processes.
Plasma membrane abundance dictates phagocytic capacity and functional crosstalk in myeloid cells
Authors: Winer Benjamin Y. , Settle Alexander H. , Yakimov Alexandrina M. , Jeronimo Carlos , Lazarov Tomi , Tipping Murray , Saoi Michelle , Sawh Anjelique , Sepp Anna-Liisa L. , Galiano Michael , Wong Yung Yu , Perry Justin S. A. , Geissmann Frederic , Cross Justin , Zhou Ting , Kam Lance C. , Pasoli Hilda Amalia , Hohl Tobias , Cyster Jason G. , Weiner Orion D. , Huse Morgan
Published: September 2023

Professional phagocytes like neutrophils and macrophages tightly control what they eat, how much they eat, and when they move after eating. We show that plasma membrane abundance is a key arbiter of these cellular behaviors. Neutrophils and macrophages lacking the G-protein subunit Gβ4 exhibit profound plasma membrane expansion due to enhanced production of sphingolipids. This increased membrane allocation dramatically enhances phagocytosis of bacteria, fungus, apoptotic corpses, and cancer cells. Gβ4 deficient neutrophils are also defective in the normal inhibition of migration following cargo uptake. In Gβ4 knockout mice, myeloid cells exhibit enhanced phagocytosis of inhaled fungal conidia in the lung but also increased trafficking of engulfed pathogens to other organs. These results reveal an unexpected, biophysical control mechanism lying at the heart of myeloid functional decision-making.
Protein phosphatase 1 regulates core PCP signaling
Authors: Song Song , Cho Bomsoo , Weiner Alexis T. , Nissen Silas Boye , Naharros Irene Ojeda , Bosch Pablo Sanchez , Suyama Kaye , Hu Yanhui , He Li , Svinkina Tanya , Udeshi Namrata D. , Carr Steven A. , Perrimon Norbert , Axelrod Jeffrey D.
Published: September 2023

Abstract

PCP signaling polarizes epithelial cells within the plane of an epithelium. Core PCP signaling components adopt asymmetric subcellular localizations within cells to both polarize and coordinate polarity between cells. Achieving subcellular asymmetry requires additional effectors, including some mediating post-translational modifications of core components. Identification of such proteins is challenging due to pleiotropy. We used mass spectrometry-based proximity labeling proteomics to identify such regulators in theDrosophilawing. We identified the catalytic subunit of Protein Phosphatase1, Pp1-87B, and show that it regulates core protein polarization. Pp1-87B interacts with the core protein Van Gogh and at least one Serine/Threonine kinase, Dco/CKIc, that is known to regulate PCP. Pp1-87B modulates Van Gogh subcellular localization and directs its dephosphorylation in vivo. PNUTS, a Pp1 regulatory subunit, also modulates PCP. While the direct substrate(s) of Pp1-87B in control of PCP is not known, our data support the model that cycling between phosphorylated and unphosphorylated forms of one or more core PCP components may regulate acquisition of asymmetry. Finally, our screen serves as a resource for identifying additional regulators of PCP signaling.
Finding Drug Repurposing Candidates for Neurodegenerative Diseases using Zebrafish Behavioral Profiles
Authors: Del Rosario Hernández Thaís , Gore Sayali V , Kreiling Jill A , Creton Robbert
Published: September 2023

Drug repurposing can accelerate drug development while reducing the cost and risk of toxicity typically associated with de novo drug design. Several disorders lacking pharmacological solutions and exhibiting poor results in clinical trials - such as Alzheimer’s disease (AD) - could benefit from a cost-effective approach to finding new therapeutics. We previously developed a neural network model, Z-LaP Tracker, capable of quantifying behaviors in zebrafish larvae relevant to cognitive function, including activity, reactivity, swimming patterns, and optomotor response in the presence of visual and acoustic stimuli. Using this model, we performed a high-throughput screening of FDA-approved drugs to identify compounds that affect zebrafish larval behavior in a manner consistent with the distinct behavior induced by calcineurin inhibitors. Cyclosporine (CsA) and other calcineurin inhibitors have garnered interest for their potential role in the prevention of AD. We generated behavioral profiles suitable for cluster analysis, through which we identified 64 candidate therapeutics for neurodegenerative disorders.
Conformation Selection by ATP-competitive Inhibitors and Allosteric Communication in ERK2
Authors: Anderson Jake W. , Vaisar David , Jones David N. , Pegram Laurel M. , Vigers Guy P. , Chen Huifen , Moffat John G. , Ahn Natalie G.
Published: September 2023

Activation of the extracellular signal regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states of the active kinase, named “L” and “R”, where R is associated with a catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site. However, the features of inhibitors important for R-state selection are unknown. Here we survey a panel of ATP-competitive ERK inhibitors using HDX-MS and NMR and identify 14 new molecules with properties of R-state selection. They reveal effects propagated to distal regions in the P+1 and helix αF segments surrounding the activation loop, as well as helix αL16. Crystal structures of inhibitor complexes with ERK2 reveal systematic shifts in the Gly loop and helix αC, mediated by a Tyr-Tyr ring stacking interaction and the conserved Lys-Glu salt bridge. The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors.
Influence of Microbiome on Withdrawal-Like Behavior in Planaria
Authors: Sosa Enrique Mentado , Pisciotta John M. , Guerra-Solano Miguel , Pagan One
Published: September 2023

The microbiome of animals can influence health status, disease susceptibility and can also influence host behavior. This study investigates the effect of microbiome alteration on animal behavior using the planarian model system. For this,Girardia tigrina(Brown Planaria) andPhagocata gracilis(Black Planaria) were investigated. These flatworms possess a primitive nervous system and exhibit similar addictive and withdrawal behaviors to mammals. Here we tested the hypothesis that alteration of planarian microbiome using the broad-spectrum antibiotics kanamycin and ampicillin could influence the worms’ behavior and withdrawal response to nicotine. After antibiotic treatment period of seven days, the behavior and withdrawal response of four groups of brown and black planaria was analyzed by recording the worms’ motility on a 1 cm2grid. Results support the hypothesis as treatment significantly altered behavior in black worms. The microbiomes of antibiotic treated planaria were analyzed using conventional culture techniques, microscopy and metagenomic methods. Alpha proteobacteria including Sphingomonadaceae were detected in both Brown and Black planarians. This study suggests chemotherapeutic alteration of an animal’s microbiome can influence motility behavior and withdrawal responses to addictive substance and sheds light on the species composition of Planarian microbiomes.
Concurrent administration of COVID-19 and influenza vaccines enhances Spike-specific antibody responses
Authors: Barouch Susanna E. , Chicz Taras M. , Blanc Ross , Barbati Domenic R. , Parker Lily J. , Tong Xin , McNamara Ryan P.
Published: September 2023

The bivalent COVID-19 mRNA boosters became available in fall 2022 and were recommended alongside the seasonal influenza vaccine. However, the immunogenicity of concurrent versus separate administration of these vaccines remains unclear. Here, we analyzed antibody responses in healthcare workers who received the bivalent COVID-19 booster and the influenza vaccine on the same day or different days. IgG1 responses to SARS-CoV-2 Spike were higher at peak immunogenicity and 6 months following concurrent administration compared with separate administration of the COVID-19 and influenza vaccines. These data suggest that concurrent administration of these vaccines may yield higher and more durable SARS-CoV-2 antibody responses.
Heterologous expression of insect IRs in transgenicDrosophila melanogaster
Authors: Cattaneo Alberto Maria , Crava Cristina M. , Walker William B
Published: September 2023

Among insect chemosensory receptors, the broadly conserved Ionotropic Receptors (IRs) remain some of the least investigated. Several studies have documented IR activation by recording insect’s neuronal activityin situ, some demonstrated their activation when expressed in oocytes fromXenopus, others made use of theDrosophila“ionotropic receptor decoders” to functionally mis-express IRs from the same species or from the closely relatedD. sechellia. Here we demonstrated that both substituting tuning IRs ofD. melanogasterand expressing heterologous IRs from other insects alongside theDrosophilanative ones result in functional heteromeric complexes. By these methods, we functionally characterized the IR41a1 subunit of the codling mothCydia pomonella, which demonstrated binding to polyamines with different pharmacological characteristics and the IR75d subunit of the spotted wing drosophilaDrosophila suzukii, which binds hexanoic acid. Then we expressed theD. suzukiiacid sensor IR64a into theD. melanogaster“ionotropic receptor decoder” neuron, which resulted in the inhibition to the main activators of other neurons housed in the same sensillum ofD. melanogaster, as an evidence of its possible functional expression, but it did not show response to acids.In situhybridization on the antennae ofD. suzukiiunveiled a wide expression of this subunit in neurons proximal to the sacculus. Structural analysis did not explain absence of IR64a binding to acids, but it identified key amino acid features that may justify possible hexanoic acid binding for IR75d. While our findings add to the derophanization efforts conducted on the chemosensors of the aforementioned pests, they demonstrated potential for the use of neurons of transgenicDrosophilaas a tool to functionally characterize IRs from different insect species.
Neuronal correlates of time integration into memories
Authors: Frantzmann Felix , Lamberty Marius , Braune Laurin , Auger Genevieve M. , Chouhan Nitin Singh , Langenhan Tobias , Selcho Mareike , Pauls Dennis
Published: September 2023

The circadian clock affects a wide range of physiological processes. Of particular interest is the influence of the clock on memory performance, as circadian dysfunction is associated with age- and disease-related decline in memory. In various species it has been shown that memory performance is regulated by the circadian clock. However, the anatomical and functional connection of the circadian clock and memory neurons has not been described in detail so far. This study now identifies that Diuretic hormone 31 (DH31)-positive clock neurons of the DN1p cluster regulate memory performance. DH31, a functional homolog of the mammalian calcitonin gene-related peptide, plays a crucial role in this process as a clock communication signal. DH31 facilitates memory performance during the night via indirect signalling, while DH31 signals directly to the mushroom bodies restricting memory performance specifically in the evening. This pleiotropic action of DH31 suggests that the circadian clock confines memory performance to a physiological dynamic range.
Bibliometric analysis of neuroscience publications quantifies the impact of data sharing
Authors: Emissah Herve , Ljungquist Bengt , Ascoli Giorgio A.
Published: September 2023

Motivation

Neural morphology, the branching geometry of neurons and glia in the nervous system, is an essential cellular substrate of brain function and pathology. Despite the accelerating production of digital reconstructions of neural morphology in laboratories worldwide, the public accessibility of data remains a core issue in neuroscience. Deficiencies in the availability of existing data create redundancy of research efforts and prevent researchers from building on others’ work. Data sharing complements the development of computational resources and literature mining tools to accelerate scientific discovery.

Results

We carried out a comprehensive bibliometric analysis of neural morphology publications to quantify the impact of data sharing in the neuroscience community. Our findings demonstrate that sharing digital reconstructions of neural morphology via the NeuroMorpho.Org online repository leads to a significant increase of citations to the original article, thus directly benefiting the authors. Moreover, the rate of data reusage remains constant for at least 16 years after sharing (the whole period analyzed), altogether nearly doubling the peer-reviewed discoveries in the field. Furthermore, the recent availability of larger and more numerous datasets fostered integrative meta-analysis applications, which accrue on average twice the citations of re-analyses of individual datasets. We also designed and deployed an open-source citation tracking web-service that allows researchers to monitor reusage of their datasets in independent peer-reviewed reports. These results and the released tool can facilitate the recognition of shared data reuse for promotion and tenure considerations, merit evaluations, and funding decisions.

Availability and implementation

The code is available athttps://github.com/HerveEmissah/nmo-authors-app(author app) andhttps://github.com/HerveEmissah/nmo-bibliometric-analysis(bibliometric analysis app).
Deep Learning disconnectomes to accelerate and improve long-term predictions for post-stroke symptoms
Authors: Matsulevits Anna , Coupe Pierrick , Nguyen Huy-Dung , Talozzi Lia , Foulon Chris , Nachev Parashkev , Corbetta Maurizio , Tourdias Thomas , Thiebaut de Schotten Michel
Published: September 2023

Deep learning as a truly transformative force is revolutionizing a wide range of fields, making a significant difference in medical imaging, where recent advancements have yielded some truly remarkable outcomes. In a connected brain, maps of white matter damage — otherwise known as disconnectomes — are essential for capturing the effects of focal lesions. However, the current tools for obtaining such information are prohibitively slow and not admitted for clinical usage. Here, we have explored the potential of deep-learning models to accurately generate disconnectomes in a population of stroke survivors. We trained a 3D U-Net algorithm to producedeep-disconnectomesfrom binary lesion masks. This artificial neural network was able to capture most information obtained in conventional disconnectomes, i.e., statistical maps filtering normative white-matter networks, but output a deep-disconnectome 170 times faster – compared to disconnectome computation with the state-of-the-art BCBToolkit software. Moreover, the deep-disconnectomes were challenged to predict cognitive and behavioral outcomes one-year post-stroke. In an additional cohort of N=139 stroke survivors, N=86 neuropsychological scores were predicted from deep-disconnectomes achieving, on average, 85.2% of accuracy and R2= 0.208. The deep-disconnectomes predictivity power outperformed the conventional disconnectome predictions for clinical scores.

In summary, we have achieved a significant milestone for clinical neuroimaging by accelerating and ameliorating the creation of disconnectome maps using deep learning. By integrating deep learning into the management of stroke, one of the most prevailing catalysts for acquired disabilities, we deepen our understanding of its impact on the brain. This novel approach may offer potential avenues for acute intervention, ultimately enhancing patients’ overall quality of life.
mTORC1 Regulates the Metabolic Switch of Postnatal Cardiomyocytes During Regeneration
Authors: Paltzer Wyatt G. , Aballo Timothy J. , Bae Jiyoung , Hubert Katharine A. , Nuttall Dakota J. , Perry Cassidy , Wanless Kayla N. , Nahlawi Raya , Ge Ying , Mahmoud Ahmed I.
Published: September 2023

The metabolic switch from glycolysis to fatty acid oxidation in postnatal cardiomyocytes contributes to the loss of the cardiac regenerative potential of the mammalian heart. However, the mechanisms that regulate this metabolic switch remain unclear. The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) is a central signaling hub that regulates cellular metabolism and protein synthesis, yet its role during mammalian heart regeneration and postnatal metabolic maturation is undefined. Here, we use immunoblotting, rapamycin treatment, myocardial infarction, and global proteomics to define the role of mTORC1 in postnatal heart development and regeneration. Our results demonstrate that the activity of mTORC1 is dynamically regulated between the regenerating and the non-regenerating hearts. Acute inhibition of mTORC1 by rapamycin or everolimus reduces cardiomyocyte proliferation and inhibits neonatal heart regeneration following injury. Our quantitative proteomic analysis demonstrates that transient inhibition of mTORC1 during neonatal heart injury did not reduce protein synthesis, but rather shifts the cardiac proteome of the neonatal injured heart from glycolysis towards fatty acid oxidation. This indicates that mTORC1 inhibition following injury accelerates the postnatal metabolic switch, which promotes metabolic maturation and impedes cardiomyocyte proliferation and heart regeneration. Taken together, our results define an important role for mTORC1 in regulating postnatal cardiac metabolism and may represent a novel target to modulate cardiac metabolism and promote heart regeneration.
A Rapid Anterior Auditory Processing Stream Through the Insulo-Parietal Auditory Field in the Rat
Authors: Jankowski Maciej M. , Karayanni Mousa , Harpaz Mor , Polterovich Ana , Nelken Israel
Published: September 2023

The insular cortex is believed to be involved in a wide range of auditory functions in the mammalian brain. We studied the organization and basic response properties of auditory neurons in insular cortex and adjacent areas by recording responses to sound stimuli in anesthetized rats. Auditory neurons were present in an insulo-parietal auditory field that spans the boundary between the posterior insula, particularly in the granular insular cortex and the ventral part of the secondary somatosensory cortex. Neurons in this field had narrow tuning, were preferentially tuned to relatively low frequencies (<16 kHz), and had short response latencies. Intriguingly, some auditory units in this insulo-parietal field displayed shorter onset latencies than the minimal latency in primary auditory cortex. At the same time, these units showed weaker sensitivity to deviance than units in primary auditory cortex. These results establish the existence of a rapid information stream through the insulo-parietal cortex that may parallel the pathway through the primary and anterior auditory fields.
Targeted Transcriptional Activation using a CRISPR-Associated Transposon System
Authors: Elizondo Andrea M. Garza , Chappell James
Published: September 2023

Synthetic perturbation of gene expression is central to our ability to reliably uncover genotype-phenotype relationships in microbes. Here, we present a novel gene transcription activation strategy that uses theVibrio choleraeCRISPR-Associated Transposon (CAST) system to selectively insert promoter elements upstream of genes of interest. Through this strategy, we show robust activation of both recombinant and endogenous genes across theE. colichromosome. We then demonstrate precise tuning of expression levels by exchanging the promoter elements being inserted. Finally, we demonstrate that CAST activation can be used to synthetically induce ampicillin-resistant phenotypes inE. coli.