bluuebunny/crossref_metadata_2025 huggingface dataset:
Dexamethasone is a dose-dependent perpetrator of drug–drug interactions: implications for use in people living with HIV
Authors: Jacobs Tom G , Marzolini Catia , Back David J , Burger David M
Published: October 2021

Global use of dexamethasone in COVID-19 patients has revealed a poor understanding of the drug–drug interaction (DDI) potential of dexamethasone, particularly with antiretroviral agents (ARVs). Dexamethasone is both a substrate and a dose-dependent inducer of cytochrome P450 3A4 (CYP3A4). As many ARVs are substrates and/or inhibitors or inducers of CYP3A4, there is concern about DDIs with dexamethasone either as a perpetrator or a victim. Assessment of DDIs that involve dexamethasone is complex as dexamethasone is used at a range of daily doses (generally 0.5 up to 40 mg) and a treatment course can be short, long, or intermittent. Moreover, DDIs with dexamethasone have been evaluated only for a limited number of drugs. Here, we summarize the available in vitro and in vivo data on the interaction potential of dexamethasone and provide recommendations for the management of DDIs with ARVs, considering various dexamethasone dosages and treatment durations.
Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis
Authors: Gastine Silke , Obiero Christina , Kane Zoe , Williams Phoebe , Readman John , Murunga Sheila , Thitiri Johnstone , Ellis Sally , Correia Erika , Nyaoke Borna , Kipper Karin , van den Anker John , Sharland Mike , Berkley James A. , Standing Joseph F.
Published: October 2021

Objectives

This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis.

Methods

Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens.

Results

A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.

Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5–1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains.

Conclusions

PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.
Bringing the Animal QTLdb and CorrDB into the future: meeting new challenges and providing updated services
Authors: Hu Zhi-Liang , Park Carissa A , Reecy James M
Published: October 2021

The Animal QTLdb (https://www.animalgenome.org/QTLdb) and CorrDB (https://www.animalgenome.org/CorrDB) are unique resources for livestock animal genetics and genomics research which have been used extensively by the international livestock genome research community. This is largely due to the active development of the databases over the years to keep up with the rapid advancement of genome sciences. The ongoing development has ensured that these databases provide researchers not only with continually updated data but also with new web tools to disseminate the data. Through our continued efforts, the databases have evolved from the original Pig QTLdb for cross-experiment QTL data comparisons to an Animal QTLdb hosting 220 401 QTL, SNP association and eQTL data linking phenotype to genotype for 2210 traits. In addition, there are 23 552 correlations for 866 traits and 4273 heritability data on 1069 traits in CorrDB. All these data were curated from 3157 publications that cover seven livestock species. Along with the continued data curation, new species, additional genome builds, and new functions and features have been built into the databases as well. Standardized procedures to support data mapping on multiple species/genome builds and the ability to browse data based on linked ontology terms are highlights of the recent developments.
Impact of Streptococcus pneumoniae Urinary Antigen Testing in Patients With Community-Acquired Pneumonia Admitted Within a Large Academic Health System
Authors: Greenfield Adam , Marsh Kassandra , Siegfried Justin , Zacharioudakis Ioannis , Ahmed Nabeela , Decano Arnold , Aguero-Rosenfeld Maria E , Inglima Kenneth , Papadopoulos John , Dubrovskaya Yanina
Published: October 2021

Background

Limited data support use of pneumococcal urinary antigen testing (PUAT) for patients with community-acquired pneumonia (CAP) as an antimicrobial stewardship tool. At our institution, CAP guidelines and admission order set were standardized to include universal PUAT.

Methods

This was a retrospective study of adults hospitalized in 2019 who had PUAT performed. We compared incidence and timing of de-escalation in PUAT- positive vs -negative groups and described patients’ outcomes.

Results

We evaluated 910 patients, 121 (13.3%) of whom were PUAT positive. No difference in baseline characteristics, including severity of illness, was observed between groups. Initial de-escalation occurred in 82.9% and 81.2% of PUAT-positive and -negative patients, respectively (P = .749). Median time to de-escalation was shorter in the PUAT-positive group (1 [interquartile range {IQR}, 0–2] day vs 1 [IQR, 1–2] day, P = .01). Within 24 hours of PUAT, more patients in the PUAT-positive group had atypical coverage discontinued (61.3% vs 47.2%, P = .026) without difference in methicillin-resistant Staphylococcus aureus (MRSA) agent discontinuation (or antipseudomonal de-escalation). Among the PUAT-positive group, unadjusted analysis demonstrated shorter median length of stay in patients who were de-escalated compared to those who were not (6 [IQR, 4–10] vs 8 [IQR, 7–12] days, P = .0005), without difference in the incidence of Clostridioides difficile, in-hospital mortality, or 30-day infection-related readmission.

Conclusions

We observed earlier de-escalation in the PUAT-positive group. This seems to be due to discontinuation of atypical rather than anti-MRSA or antipseudomonal coverage. Further antimicrobial stewardship interventions are warranted.
The Big Boom Theory: The Common Nighthawk wing-boom display delineates exclusive nesting territories
Authors: Knight Elly C , Brigham R Mark , Bayne Erin M
Published: October 2021

Understanding the functional significance of bird sounds can provide valuable insight into the behavior and how birds use habitat. We show that the Common Nighthawk (Chordeiles minor) wing-boom display is a territorial signal associated with the nest location that can be used to identify territorial habitat use. In other words, the Common Nighthawk wing-boom display can be considered analogous to song due to its potential function in territoriality. We captured, tagged, and tracked 21 male Common Nighthawks in northeastern Alberta to confirm the functional significance of the wing-boom display and describe Common Nighthawk territoriality. Mean wing-boom use density (hereafter “area”) size was 10.2 ha (SD = 11.7 ha). We found minimal overlap in the wing-boom area (5 of 15 neighboring male pairs, 0.2–4.5% overlap), suggesting the wing-boom display represents an exclusive territory. Comparison of wing-boom locations and random points within the wing-boom area confirmed that male Common Nighthawks select areas near the nest to perform wing-boom displays. There was high wing-boom area overlap for the same individual between years. Differences between years reflected shifts in nest location, suggesting that the wing-boom display is a good indicator of the nest location and territory. Future Common Nighthawk surveys should record the type of acoustic signal observed to differentiate territorial habitat use from other functions. Many taxa that produce non-vocal sounds as part of breeding displays could similarly benefit from a functional understanding to provide insight into habitat use.
Genetic and environmental influences on sleep-wake behaviors in adolescence
Authors: O’Callaghan Victoria S , Hansell Narelle K , Guo Wei , Carpenter Joanne S , Shou Haochang , Strike Lachlan T , Crouse Jacob J , McAloney Kerrie , McMahon Katie L , Byrne Enda M , Burns Jane M , Martin Nicholas G , Hickie Ian B , Merikangas Kathleen R , Wright Margaret J
Published: October 2021

Study Objectives

To investigate the influence of genetic and environmental factors on sleep-wake behaviors across adolescence.

Methods

Four hundred and ninety-five participants (aged 9–17; 55% females), including 93 monozygotic and 117 dizygotic twin pairs, and 75 unmatched twins, wore an accelerometry device and completed a sleep diary for 2 weeks.

Results

Individual differences in sleep onset, wake time, and sleep midpoint were influenced by both additive genetic (44%–50% of total variance) and shared environmental (31%–42%) factors, with a predominant genetic influence for sleep duration (62%) and restorative sleep (43%). When stratified into younger (aged 9–14) and older (aged 16–17) subsamples, genetic sources were more prominent in older adolescents. The moderate correlation between sleep duration and midpoint (rP = −.43, rG = .54) was attributable to a common genetic source. Sleep-wake behaviors on school and nonschool nights were correlated (rP = .44–.72) and influenced by the same genetic and unique environmental factors. Genetic sources specific to night-type were also identified, for all behaviors except restorative sleep.

Conclusions

There were strong genetic influences on sleep-wake phenotypes, particularly on sleep timing, in adolescence. Moreover, there may be common genetic influences underlying both sleep and circadian rhythms. The differences in sleep-wake behaviors on school and nonschool nights could be attributable to genetic factors involved in reactivity to environmental context.
Divine Warning or Prelude to Secularization? Religion, Politics, and the COVID-19 Pandemic in Turkey
Authors: Altınordu Ateş
Published: October 2021

Religion was a major pillar in the government’s pandemic management and featured centrally in a string of public controversies in the course of the coronavirus crisis in Turkey. This article analyzes the role of Islam in the political and social responses to the COVID-19 pandemic in Turkey, with a focus on four dimensions: (1) religion as a tool of governance, (2) the regulation of collective religious practices, (3) religious interpretations of the pandemic, and (4) predictions about the future impact of the coronavirus crisis on religion. Based on this analysis, the study concludes that the salience and political function of religion in the course of pandemics are contingent upon the place of religious mobilization in the political repertoire of the ruling party and the balance of power between the government and the religious field, respectively. The government's extensive instrumentalization of religion in pandemic management, on the other hand, is likely to give rise to a political backlash against organized religion.
Language, Publication, and the Advancement of Feminist Praxis
Authors: Wentworth Chelsea , Clark Dessie
Published: October 2021

Western voices from publications predominantly in English dominate conversations surrounding knowledge production, consumption, and dissemination, which in turn shapes social policy. To achieve feminist epistemological frameworks that many academic publications espouse, we call for publications that are accessible and equitable not only for academics, but also for community partners and activists. To ensure a role for diverse voices, we must remove language barriers that prioritize Western viewpoints. Feminist scholars are poised to advance the contemporary debates on the politics of the language of academic publishing, and explore ways that a decolonized, inclusive approach could benefit knowledge on a global scale.
I am Chinese: The Politics of Chinese American Lapel Buttons in Los Angeles during World War II
Authors: Gow William
Published: October 2021

This article examines the history of lapel buttons and stickers used by Chinese Americans to identify their ethnicity during World War II. Most of these buttons and stickers were produced by Chinese Consolidated Benevolent Associations (CCBAs) immediately after the attack on Pearl Harbor to differentiate their members from Japanese Americans. In examining this history, this article focuses in particular on Los Angeles, the city with the largest Japanese American population on the West Coast. In Los Angeles, U.S.-born Chinese American and Japanese American youth attended many of the same schools and often formed close friendships with one another. As a result, the questions that the buttons and stickers posed for this generation of Chinese American youth were particularly fraught. Drawing on oral history interviews, sociological studies of the Southern California Chinese American community from the period, and archival newspaper reportage, this article approaches these lapel pins and stickers as items of cultural contestation through which a variety of historical actors—from Chinese consular representatives, to immigrant leaders in the CCBAs, to Chinese American youth—negotiated questions of ethnic and national identity after the U.S. entry into World War II. I argue that rather than reflecting the complex ways that most Chinese American youth understood their own identity, the buttons and stickers represented the official viewpoints of the Chinese consulates in the United States and their allies in the nation’s CCBAs.
CSOG MFM Committee Guideline: Clinical Management Guidelines for Acute Fatty Liver of Pregnancy in China (2021)
Authors: Li Ping , Chen Yaolong , Zhang Weishe , Yang Huixia
Published: October 2021

Acute fatty liver of pregnancy (AFLP) is a rare but critical obstetric-specific disease with a high fatality rate, posing a serious threat to the safety of mothers and infants. These guidelines were specially formulated to standardize AFLP clinical pathways and to improve maternal and infant outcomes. Based on a two-round questionnaire survey, the guideline development team identified the following nine clinical issues that clinicians were most concerned about, and developed recommendations for each of them: prenatal outpatient screening for AFLP, diagnosis, preoperative risk assessment, delivery modes and timing, anesthesia methods, perinatal complications, selecting AFLP patients for artificial liver treatment, prognostic assessment, and monitoring during treatment. The guidelines cover the key issues related to AFLP diagnosis and treatment that concern clinicians.
Transfusion-free Retransplantation for Post–liver Transplantation Hepatic Artery Thrombosis: How Much Augmentation Is Too Much?
Authors: Mulgaonkar Ashwini , Horwich Brian , Kim Brian , Kahn Jeffrey A. , Kaur Navpreet , Genyk Yuri , Han Hyosun , Ahearn Aaron
Published: October 2021

Liver transplantation presents unique challenges in patients who do not accept blood transfusions. The difficulty of balancing chemical augmentation and handling the technical difficulty of the surgery make transfusion-free liver transplantation an exception rather than the norm. However, at our center, we have performed 27 successful living donor liver transplants in transfusion-free patients. We describe a case of hepatic artery thrombosis (HAT) after living donor liver transplantation requiring retransplantation. This first report of safe retransplantation without blood products demonstrates that even graft-threatening complications can be safely managed in a transfusion-free setting. However, it remains unclear if the medical augmentation to meet hematologic and coagulation parameters before transfusion-free transplantation may increase the risk of postoperative HAT and other thrombotic complications. Although it is our center’s experience that the thrombosis rate is comparable with the published rate in standard transfusion-eligible living donor liver transplantations and this case demonstrates that HAT can be safely managed in this setting, further study on the risks and benefits of hematopoietic stimulants as pretransplant optimization is warranted.
Psychological distress of healthcare workers in Québec (Canada) during the second and the third pandemic waves
Authors: Carazo Sara , Pelletier Mariève , Talbot Denis , Jauvin Nathalie , De Serres Gaston , Vézina Michel
Published: October 2021

Objective

We aimed to measure the prevalence of psychological distress among Quebec healthcare workers (HCWs) during the second and third pandemic waves and to assess the effect of psychosocial risk factors (PSRs) on work-related psychological distress among SARS-CoV-2 infected (cases) and non-infected (controls) HCWs.

Methods

A self-administered survey was used to measure validated indicators of psychological distress (K6 scale) and PSR (questions based on Karasek and Siegrist models, value conflicts and work-life balance). Adjusted robust Poisson models were used to estimate prevalence ratios.

Results

4068 cases and 4152 controls completed the survey. Prevalence of high work-related psychological distress was 42%; it was associated with PSRs (mainly work-life balance, value conflicts and high psychological demands) but not with SARS-CoV-2 infection.

Conclusion

Primary prevention measures targeting PSRs are needed to reduce mental health risks of HCWs.
Differences in COVID-19 Risk by Race and County-Level Social Determinants of Health Among Veterans
Authors: Abdel Magid Hoda S. , Ferguson Jacqueline M. , Cleve Raymond V. , Purnell Amanda L. , Osborne Thomas F.
Published: October 2021

COVID-19 disparities by area-level social determinants of health (SDH) may be impacting U.S. Veterans. This retrospective analysis utilized COVID-19 data from the U.S. Department of Veterans Affairs (VA)’s EHR and geographically linked county-level data from 18 area-based socioeconomic measures. The risk of testing positive with Veterans’ county-level SDHs adjusting for demographics, comorbidities, and facility characteristics was calculated using generalized linear models. We found an exposure-response relationship whereby individual COVID-19 infection risk increased with each increasing quartile of adverse county-level SDH such as the percentage of residents in a county without a college degree, eligible for Medicaid, and living in crowded housing.
S100A8 and S100A9, biomarkers of SARS-Cov2-infected patients, suppress HIV replication in primary macrophages
Authors: Oguariri Raphael M. , Brann Terrence W. , Adelsberger Joseph W. , Chen Qian , Goswami Suranjana , Mele Anthony R. , Imamichi Tomozumi
Published: October 2021

S100A8 and S100A9 are members of the Alarmin family; these proteins are abundantly expressed in neutrophils and form a heterodimer complex. Recently, both proteins were identified as novel biomarkers of SARS-CoV-2 infection and were shown to play key roles in inducing an aggressive inflammatory response by mediating the release of large amounts of pro-inflammatory cytokines, called the “cytokine storm.” Although co-infection with SARS-CoV-2 in people living with HIV-1 may result in an immunocompromised status, the role of the S100A8/A9 complex in HIV-1 replication in primary T cells and macrophages is still unclear. Here, we evaluated the roles of the proteins in HIV replication to elucidate their functions. We found that the complex had no impact on virus replication in both cell types; however, the subunits of S100A8 and S100A9 inhibits HIV in macrophages. These findings provide important insights into the regulation of HIV viral loads in SARS-CoV2 co-infection.
Loss of C9orf72 perturbs the Ran-GTPase gradient and generates compositionally diverse cytoplasmic Importin β-1 granules in motor and cortical neuronsin vivo
Authors: McGoldrick Philip , Lau Agnes , You Zhipeng , Durcan Thomas M , Robertson Janice
Published: October 2021

Repeat expansions inC9orf72cause Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) eliciting toxic effects through generation of RNA foci, dipeptide repeat proteins and/or loss of C9orf72 protein. Defects in nucleocytoplasmic transport (NCT) have been implicated as a pathogenic mechanism underlying repeat expansion toxicity. Here, we show that loss of C9orf72 causes neuronal specific phenotypes, disrupting the Ran-GTPase gradient bothin vitroandin vivo. We describe compositionally different types of cytoplasmic Importin β-1 granules that exhibit neuronal subtype-specific propertiesin vivo. We show that the abundance of Importin β-1 granules is increased in the context of C9orf72 deficiency, disrupting interactions with nuclear pore complex proteins. These granules appear to bud from the nuclear envelope and are co-immunoreactive for G3BP1 and K63-ubiquitin. These findings link loss of C9orf72 protein to gain-of-function mechanisms and defects in NCT.
What can astrocytes compute?
Authors: Peterson Erik J.
Published: October 2021

A foundational result in neural computation was proving the firing-rate model of neurons defines a universal function approximator. In this paper I prove it is possible for astrocytes to compute anything neurons can, by extending this original proof to a model of calcium waves in astrocytes. I confirm this in a series of computer simulations. The major limit for astrocytes, it turns out, is not their ability to learn solutions but the computational complexity of their network. I suggest some initial experiments that might be used to confirm these predictions.
Single-cell Atlas Unveils Cellular Heterogeneity and Novel Markers in Human Neonatal and Adult Intervertebral Discs
Authors: Jiang Wensen , Glaeser Juliane D. , Salehi Khosrowdad , Kaneda Giselle , Mathkar Pranav , Wagner Anton , Ho Ritchie , Sheyn Dmitriy
Published: October 2021

The origin, composition, distribution, and function of cells in the human intervertebral disc (IVD) has not been fully understood. Here, cell atlases of both human neonatal and adult IVDs have been generated and further assessed by gene ontology pathway enrichment, pseudo-time trajectory, histology, and immunofluorescence. Comparison of cell atlases revealed the presence of two sub-populations of notochordal cells (NCs) and their associated markers in both the neonatal and adult IVDs. Developmental trajectories predicted 7 different cell states that describe the developmental process from neonatal to adult cells in IVD and analyzed the NC’s role in the IVD development. A high heterogeneity and gradual transition of annulus fibrosus cells (AFCs) in the neonatal IVD was detected and their potential relevance in IVD development assessed. Collectively, comparing single-cell atlases between neonatal and adult IVDs delineates the landscape of IVD cell biology and may help discovering novel therapeutic targets for IVD degeneration.
Unravelling the role of thyroid hormones in seasonal neuroplasticity in European Starlings (Sturnus vulgaris)
Authors: Orije Jasmien , Raymaekers Sander R. , Majumadar Gaurav , De Groof Geert , Jonckers Elisabeth , Ball Gregory F. , Verhoye Marleen , Darras Veerle M. , Van der Linden Annemie
Published: October 2021

1

Thyroid hormones clearly play a role in the seasonal regulation of reproduction, but any role they might play in song behavior and the associated seasonal neuroplasticity in songbirds remains to be elucidated. To pursue this question, we first established seasonal patterns in the expression of thyroid hormone regulating genes in male European starlings employing in situ hybridization methods. Thyroid hormone transporter LAT1 expression in the song nucleus HVC was elevated during the photosensitive phase, pointing towards an active role of thyroid hormones during this window of possible neuroplasticity. In contrast DIO3 expression was high in HVC during the photostimulated phase, limiting the possible effect of thyroid hormones to maintain song stability during the breeding season. Next, we studied the effect of hypothyroidism on song behavior and neuroplasticity using in vivo MRI. Hypothyroidism inhibited the photostimulation-induced increase in testosterone, confirming the role of thyroid hormones in activating the hypothalamic–pituitary–gonadal (HPG) axis. Surprisingly, apart from the myelination of several tracts during the photostimulated phase, most neuroplasticity related to song production was unaffected by hypothyroidism. Remarkably, T3 plasma concentrations were negatively correlated to the microstructural changes in several song control nuclei. Potentially, a global reduction of circulating thyroid hormones during the photosensitive period is necessary to lift the brake imposed by the photorefractory period, whereas local fine-tuning of thyroid hormone concentrations through LAT1 could activate underlying neuroplasticity mechanisms. Given the complexity of thyroid hormone effects, this study is a steppingstone to disentangle the influence of thyroid hormones on seasonal neuroplasticity.
Engineering transcription factor BmoR mutants for constructing multifunctional alcohol biosensors
Authors: Wu Tong , Chen Zhenya , Guo Shuyuan , Zhang Cuiying , Huo Yi-Xin
Published: October 2021

Native transcription factor-based biosensors (TFBs) have the potential for in situ detection of value-added chemicals or byproducts. However, their industrial application is limited by their ligand promiscuity, low sensitivity, and narrow detection range. Alcohols exhibit similar structures, and no reported TFB can distinguish a specific alcohol from its analogs. Here, we engineered an alcohol-regulated transcription factor, BmoR, and obtained various mutants with remarkable properties. For example, the generated signal-molecule-specific BmoRs could distinguish the constitutional isomers n-butanol and isobutanol, with insensitivity up to an ethanol concentration of 800 mM (36.9 g/L). Linear detection of 0–60 mM of a specific higher alcohol could be achieved in the presence of up to 500 mM (23.0 g/L) ethanol as background noise. Notably, two mutants with raised outputs and over 1.0 × 107-fold higher sensitivity, and one mutant with an increased upper detection limit (14.8 g/L n-butanol or isobutanol) were screened out. Using BmoR as an example, this study systematically explored the ultimate detection limit of a TFB towards its small-molecule ligands, paving the way for in situ detection in the biofuel and wine industries.
The response to drought-stressed host plants varies among herbivorous mite populations from a climate gradient
Authors: Migeon Alain , Auger Philippe , Fossati-Gaschignard Odile , Hufbauer Ruth A. , Miranda Maëva , Zriki Ghais , Navajas Maria
Published: October 2021

Drought associated with climate change can stress plants, altering their interactions with phytophagous arthropods. Drought not only impacts cultivated plants but also their parasites, which in some cases are favored by drought. Herbivorous arthropods feeding on drought-stressed plants typically produce bigger offspring and develop faster. However, it is unclear how much responses to drought stress differ among populations of herbivore species. Here, we evaluate variability among populations of a major agricultural pest, the two spotted spider mite,Tetranychus urticae, in response to drought stress. We compare key life history parameters of twelve populations that originate from climates ranging from wet and cool Atlantic locations to medium to dry hot Mediterranean locations. We evaluated how plant drought stress affects four life history traits: development time, fecundity, sex-ratio and emigration rate in an experiment comparing well-watered and drought-stressed bean plants. Mites feeding on drought-stressed plants developed faster and attempted to leave leaves less often, and young females were more fecund. The mites from wet temperate climates exhibited greater plasticity between the two water regimes than mites originating from dryer and hot climates, suggesting that the climate in the area of origin influences mite response to drought.
Habitat loss exacerbates pathogen spread: An Agent-based model of avian influenza infection in migratory waterfowl
Authors: Yin Shenglai , Xu Yanjie , de Jong Mart C.M. , Huisman Mees R.S. , Contina Andrea , Prins Herbert H. T. , Huang Zheng Y. X. , de Boer Willem F.
Published: October 2021

Habitat availability determines the distribution of migratory waterfowl along their flyway, which further influences the transmission and spatial spread of avian influenza viruses (AIVs). The extensive habitat loss in the East Asian-Australasian Flyway (EAAF) may have potentially altered the virus transmission and spread, but those consequences are rarely studied. We constructed 6 fall migration networks that differed in their level of habitat loss, wherein an increase in habitat loss resulted in smaller networks with fewer sites. The networks were integrated with an agent-based model and a susceptible-infected-recovered model to simulate waterfowl migration and AIV transmission. We found that extensive habitat loss in the EAAF can 1) relocate the outbreaks northwards responding to the distribution changes of wintering waterfowl geese, 2) increase the outbreak risk in remaining sites due to larger bird congregations, and 3) facilitate AIV transmission among wintering geese. Our modelling output suggested that there was a certain system resilience of migration network to confront the site removal. In addition, the outputs were in line with the predictions from the concept of “migratory escape”, affecting the pattern of infection prevalence in the waterfowl population. Our modelling shed light on the potential consequences of habitat loss in transmitting and spreading AIV at the flyway scale, and suggested the driving mechanisms behind these effects, advocating the importance of nature conservation in changing spatial and temporal patterns of AIV outbreak.

Author summary

What are the possible consequences of extensive habitat loss on the transmission and spread of avian influenza viruses (AIVs)? We used a logistic regression model to select the suitable habitats of Greater white-fronted goose in the East Asian-Australasian Flyway and treated these habitats as sites to construct 6 fall migration networks that differed in their level of habitat loss (i.e., site removal). We then simulate geese migration in these networks, and explore the impacts of habitat loss on habitat connectivity and AIV transmission. We found the extensive habitat loss can cause relocation of the outbreaks and increase the outbreak risk and AIV transmission. Our modelling outputs suggested a certain network resilience to confront the site loss, and a “migratory escape” to change the spatial and temporal pattern of infection prevalence in the population. Overall, our study showed that land use changes and habitat loss can affect disease distribution and prevalence, suggested the importance of habitat conservation in changing the spatial and temporal pattern of AIVs transmission and spread.
The 2D Ising model, criticality and AIT
Authors: Ruffini G. , Deco G.
Published: October 2021

In this short note we study the 2D Ising model, a universal computational model which reflects phase transitions and critical phenomena, as a framework for establishing links between systems that exhibit criticality with the notions of complexity. This is motivated in the context of neuroscience applications stemming from algorithmic information theory (AIT). Starting with the original 2D Ising model, we show that — together with correlation length of the spin lattice, susceptibility to a uniform external field — the correlation time of the magnetization time series, the compression ratio of the spin lattice, the complexity of the magnetization time series — as derived from Lempel-Ziv-Welch compression—, and the rate of information transmission in the lattice, all reflect the effects of the phase transition, which results in spacetime pockets of uniform magnetization at all scales. We also show that in the Ising model the insertion of sparse long-range couplings has a direct effect on the critical temperature and other parameters. The addition of positive links extends the ordered regime to higher critical temperatures, while negative links have a stronger, disordering influence at the global scale. We discuss some implications for the study of long-range (e.g., ephaptic) interactions in the human brain and the effects of weak perturbations in neural dynamics.
A comprehensive benchmark for structural assessment in bipartite networks
Authors: Palazzi María J. , Lampo Aniello , Solé-Ribalta Albert , Borge-Holthoefer Javier
Published: October 2021

The use of null models has been a cornerstone to assess the emergence of many network properties at different levels of organization (micro-, meso- and macroscale). Notwithstanding, the debate around which is the most appropriate randomization procedure for a given problem is far from being over. Within the ecological community, for example, the discussion around whether nestedness is –or is not– a frequent pattern in natural systems, and under which assumptions, remains open. For this particular problem, efforts have been devoted to exploring to what extent current models are vulnerable to statistical errors, or to introduce new models that employ different randomization procedures. However, few or no attention has been devoted to the performance of those null models against other architectures. Here, we show that assessing alternative structures under a single null model may produce ambiguous results, which difficult the comparison regarding the joint emergence of different arrangements within a single network. To this aim, we analyze the statistical significance –in terms ofz-scores– of nestedness, modularity, and in-block nestedness scores, employing five different null models on a benchmark of ∼ 2.5 × 104synthetic bipartite networks with prescribed levels of the mentioned patterns. We show that some null models systematically over- or underestimate the presence of one or another structural pattern. In light of these ambiguities, we introduce an alternative model (termed Corrected Probabilistic model) that reduces the observed biases towards under- and overestimation, and highlight the need for the development of new frameworks that take into account those biases.
fcfdr: an R package to leverage continuous and binary functional genomic data in GWAS
Authors: Hutchinson Anna , Liley James , Wallace Chris
Published: October 2021

GWAS discovery is limited in power to detect associations that exceed the stringent genome-wide significance threshold, but this limitation can be alleviated by leveraging relevant auxiliary data. Frameworks utilising the conditional false discovery rate (cFDR) can be used to leverage continuous auxiliary data (including GWAS and functional genomic data) with GWAS test statistics and have been shown to increase power for GWAS discovery whilst controlling the FDR. Here, we describe an extension to the cFDR framework for binary auxiliary data (such as whether SNPs reside in regions of the genome with specific activity states) and introduce an all-encompassing R package to implement the cFDR approach, fcfdr, demonstrating its utility in an application to type 1 diabetes.

Availability and implementation

The fcfdr R package is freely available at: https://github.com/annahutch/fcfdr. Scripts and data to reproduce the analysis in this paper are freely available at: https://annahutch.github.io/fcfdr/articles/t1d_app.html
Mimicked synthetic ribosomal protein complex for benchmarking crosslinking mass spectrometry workflows
Authors: Matzinger Manuel , Vasiu Adrian , Madalinski Mathias , Müller Fränze , Stanek Florian , Mechtler Karl
Published: October 2021

The field of cross-linking mass spectrometry has matured to a frequently used tool for the investigation of protein structures as well as interactome studies up to a system wide level. The growing community generated a broad spectrum of applications, linker types, acquisition strategies and specialized data analysis tools, which makes it challenging, especially for newcomers, to decide for an appropriate analysis workflow. Therefore, we here present a large and flexible synthetic peptide library as reliable instrument to benchmark crosslinkers with different reactive sites as well as acquisition techniques and data analysis algorithms. Additionally, we provide a tool, IMP-X-FDR, that calculates the real, experimentally validated, FDR, compares results across search engine platforms and analyses crosslink properties in an automated manner. The library was used with the reagents DSSO, DSBU, CDI, ADH, DHSO and azide-a-DSBSO and data were analysed using the algorithms MeroX, MS Annika, XlinkX, pLink 2, MaxLynx and xiSearch. We thereby show that the correct algorithm and search setting choice is highly important to improve ID rate and FDR in combination with software and sample-complexity specific score cut-offs. When analysing DSSO data with MS Annika, we reach high identification rates of up to ∼70 % of the theoretical maximum (i.e. 700 unique lysine-lysine cross-links) while maintaining a low real FDR of < 3 % at cross-link level and with high reproducibility, representatively showing that our test system delivers valuable and statistically solid results.

Graphical abstract
PI4P and BLOC-1 remodel endosomal membranes into tubules
Authors: Jani Riddhi Atul , Cicco Aurélie Di , Keren-Kaplan Tal , Vale-Costa Silvia , Hamaoui Daniel , Hurbain Ilse , Tsai Feng-Ching , Dimarco Mathilde , Macé Anne-Sophie , Zhu Yueyao , Amorim Maria João , Bassereau Patricia , Bonifacino Juan S. , Subtil Agathe , Marks Michael S. , Lévy Daniel , Raposo Graça , Delevoye Cédric
Published: October 2021

Intracellular trafficking is mediated by transport carriers that originate by membrane remodeling from donor organelles. Tubular carriers play major roles in the flux of membrane lipids and proteins to acceptor organelles. However, how lipids and proteins impose a tubular geometry on the carriers is incompletely understood. By exploiting imaging approaches at different scales on cells and in vitro membrane systems, we show that phosphatidylinositol-4-phosphate (PI4P) and biogenesis of lysosome-related organelles complex 1 (BLOC-1) govern the formation, stability and functions of recycling endosomal tubules. Endosomal PI4P production by type II PI4-kinases is needed to form nascent curved tubules through binding of BLOC-1 that stabilize and elongate them. Membrane remodeling by the PI4P/ BLOC-1 module functions not only in the recycling of endosomal cargoes, but also in the lifecycles of intracellular pathogens such as Chlamydia bacteria and influenza virus. This study demonstrates how a phospholipid and a protein complex coordinate as a minimal machinery to remodel cellular membranes into functional tubes.
Potassium-chelating drug sodium polystyrene sulfonate enhances lysosomal function and suppresses proteotoxicity
Authors: Arputhasamy Cyrene , Lucanic Mark , Rane Anand , Schmidt Minna , Garett Theo , Foulger Anna C. , Broussalian Michael , Battistoni Elena , Brem Rachel B. , Lithgow Gordon J. , Chamoli Manish , Andersen Julie K.
Published: October 2021

Lysosomes are crucial for degradation and recycling of damaged proteins and cellular components. Therapeutic strategies enhancing lysosomal function are a promising approach for aging and age-related neurodegenerative diseases. Here, we show that an FDA approved drug sodium polystyrene sulfonate (SPS), used to reduce high blood potassium in humans, enhances lysosomal function both in C.elegans and in human neuronal cells. Enhanced lysosomal function following SPS treatment is accompanied by the suppression of proteotoxicity caused by expression of the neurotoxic peptides Aβ and TAU. Additionaly, treatment with SPS imparts health benefits as it significantly increases lifespan in C.elegans. Overall our work supports the potential use of SPS as a prospective geroprotective intervention.

HIGHLIGHTS

Sodium polystyrene sulfonate improves pH-dependent processing of lysosomal cargo, enhances proteotoxic stress resistance and extends lifespan in C. elegans

Sodium polystyrene sulfonate boosts lysosomal function in human neuronal cells and reduces level of aggregation-associated phosphorylated-TAU
Maternal SMCHD1 controls both imprinted Xist expression and imprinted X chromosome inactivation
Authors: Wanigasuriya Iromi , Kinkel Sarah A , Beck Tamara , Roper Ellise A , Breslin Kelsey , Lee Heather J , Keniry Andrew , Ritchie Matthew E , Blewitt Marnie E , Gouil Quentin
Published: October 2021

Embryonic development is dependent on the maternal supply of proteins through the oocyte, including factors setting up the adequate epigenetic patterning of the zygotic genome. We previously reported that one such factor is the epigenetic repressor SMCHD1, whose maternal supply controls autosomal imprinted expression in mouse preimplantation embryos and mid-gestation placenta. In mouse preimplantation embryos, X chromosome inactivation is also an imprinted process. Combining genomics and imaging, we show that maternal SMCHD1 is required not only for the imprinted expression of Xist in preimplantation embryos, but also for the efficient silencing of the inactive X in both the preimplantation embryo and mid-gestation placenta. These results expand the role of SMCHD1 in enforcing the silencing of Polycomb targets. The inability of zygotic SMCHD1 to fully restore imprinted X inactivation further points to maternal SMCHD1’s role in setting up the appropriate chromatin environment during preimplantation development, a critical window of epigenetic remodelling.
A Null Allele of the Pol IV Second Subunit is Viable in Oryza sativa
Authors: Chakraborty Tania , Trujillo Joshua T. , Kendall Timmy , Mosher Rebecca A.
Published: October 2021

All eukaryotes possess three DNA-dependent RNA polymerases, Pols I-III, while land plants possess two additional polymerases, Pol IV and Pol V. Derived through duplication of Pol II subunits, Pol IV produces 24-nt siRNAs that interact with Pol V transcripts to target de novo DNA methylation and silence transcription of transposons. Members of the grass family encode additional duplicated subunits of Pol IV and V, raising questions regarding the function of each paralog. In this study, we identify a null allele of the putative Pol IV second subunit, NRPD2, and demonstrate that NRPD2 is the sole subunit functioning with NRPD1 in small RNA production and CHH methylation in leaves. Homozygous nrpd2 mutants have neither gametophytic defects, nor embryo lethality, although adult plants are dwarf and sterile.
Temperature-dependent local conformations and conformational distributions of cyanine dimer labeled single-stranded – double-stranded DNA junctions by 2D fluorescence spectroscopy
Authors: Heussman Dylan , Kittell Justin , von Hippel Peter H. , Marcus Andrew H.
Published: October 2021

DNA replication, and the related processes of genome expression, require binding, assembly, and function of protein complexes at and near single-stranded (ss) – double-stranded (ds) DNA junctions. These central protein-DNA interactions are likely influenced by thermally induced conformational fluctuations of the DNA scaffold across an unknown distribution of functionally relevant states to provide regulatory proteins access to properly conformed DNA binding sites. Thus, characterizing the nature of conformational fluctuations and the associated structural disorder at ss-dsDNA junctions is likely critical for understanding the molecular mechanisms of these central biological processes. Here we describe spectroscopic studies of model ss-dsDNA fork constructs that contain dimers of ‘internally labeled’ cyanine (iCy3) chromophore probes that have been rigidly inserted within the sugar-phosphate backbones of the DNA strands. Our combined analyses of absorbance, circular dichroism (CD) and two-dimensional fluorescence spectroscopy (2DFS) permit us to characterize the local conformational parameters and conformational distributions. We find that the DNA sugar-phosphate backbones undergo abrupt successive changes in their local conformations – initially from a right-handed and ordered DNA state to a disordered splayed-open structure and then to a disordered left-handed conformation – as the dimer probes are moved across the ss-dsDNA junction. Our results suggest that the sugar-phosphate backbones at and near ss-dsDNA junctions adopt specific position-dependent local conformations and exhibit varying extents of conformational disorder that deviate widely from the Watson-Crick structure. We suggest that some of these conformations are likely to function as secondary-structure motifs for interaction with protein complexes that bind to and assemble at these sites.
BRCA1 and ELK-1 regulate Neural Progenitor Cell Fate in the Optic Tectum in response to Visual Experience in Xenopus laevis tadpoles
Authors: Huang Lin-Chien , He Haiyan , Ta Aaron C. , McKeown Caroline R. , Cline Hollis T.
Published: October 2021

In developing Xenopus tadpoles, the optic tectum begins to receive patterned visual input while visuomotor circuits are still undergoing neurogenesis and circuit assembly. This visual input regulates neural progenitor cell fate decisions such that maintaining tadpoles in the dark increases proliferation, expanding the progenitor pool, while visual stimulation promotes neuronal differentiation. To identify regulators of activity-dependent neural progenitor cell fate, we used RNA-Seq to profile the transcriptomes of proliferating neural progenitor cells and newly-differentiated immature neurons. Out of 1,130 differentially expressed (DE) transcripts, we identified six DE transcription factors which are predicted to regulate the majority of the other DE transcripts. Here we focused on Breast cancer 1 (BRCA1) and the ETS-family transcription factor, ELK-1. BRCA1 is known for its role in cancers, but relatively little is known about its potential role in regulating neural progenitor cell fate. ELK-1 is a multifunctional transcription factor which regulates immediate early gene expression. We investigated the effect of BRCA1 and ELK-1 on activity-regulated neurogenesis in the tadpole visual system using in vivo time-lapse imaging to monitor the fate of turbo-GFP-expressing SOX2+ neural progenitor cells in the optic tectum. Our longitudinal in vivo imaging analysis shows that knockdown of either BRCA1 or ELK-1 altered the fates of neural progenitor cells, and furthermore that the effects of visual experience on neurogenesis depend on BRCA1 expression, while the effects of visual experience on neuronal differentiation depend on ELK-1 expression. These studies provide insight into the potential mechanisms by which neural activity affects neural progenitor cell fate.