bluuebunny/crossref_metadata_2025 huggingface dataset:
Strong postmating reproductive isolation inMimulussectionEunanus
Authors: Farnitano Matthew C. , Sweigart Andrea L.
Published: December 2022

Postmating reproductive isolation can help maintain species boundaries when premating barriers to reproduction are incomplete. The strength and identity of postmating reproductive barriers are highly variable among diverging species, leading to questions about their genetic basis and evolutionary drivers. These questions have been tackled in model systems but are less often addressed with broader phylogenetic resolution. In this study we analyze patterns of genetic divergence alongside direct measures of postmating reproductive barriers in an overlooked group of sympatric species within the model monkeyflower genus,Mimulus. Within thisMimulus brevipesspecies group, we find substantial divergence among species, including a cryptic genetic lineage. However, rampant gene discordance and ancient signals of introgression suggest a complex history of divergence. In addition, we find multiple strong postmating barriers, including postmating prezygotic isolation, hybrid seed inviability, and hybrid male sterility, leading to complete or substantial postmating isolation in all species pairs. Hybrid seed inviability appears linked to differences in seed size, providing a window into possible developmental mechanisms underlying this reproductive barrier. While geographic proximity and incomplete mating isolation may have allowed gene flow within this group in the distant past, strong postmating reproductive barriers today are likely to prevent any ongoing hybridization. By producing foundational information about reproductive isolation and genomic divergence in this understudied group, we add new diversity and phylogenetic resolution to our understanding of the mechanisms of plant speciation.
Seasonal and daily patterns in known dissolved metabolites in the northwestern Sargasso Sea
Authors: Longnecker Krista , Kido Soule Melissa C. , Swarr Gretchen J. , Parsons Rachel , Liu Shuting , Johnson Winifred M. , Widner Brittany , Curry Ruth , Carlson Craig A. , Kujawinski Elizabeth B.
Published: December 2022

Organic carbon in seawater plays a significant role in the global carbon cycle. The concentration and composition of dissolved organic carbon, operationally defined in this project as organic carbon that passes through a 0.2 µm filter, reflect the activity of the biological community and chemical reactions that occur in seawater. From 2016 to 2019, we repeatedly sampled the oligotrophic northwest Sargasso Sea in the vicinity of the Bermuda Atlantic Time-series Study site (BATS) to quantitatively follow known compounds within the pool of dissolved organic matter in the upper 1000 meters of the water column. Dissolved metabolite concentrations revealed patterns with depth and time with most metabolites showing surface enrichment and lower concentrations with increasing depth. Select metabolites displayed seasonal patterns throughout the year, and this seasonality was repeated in each of the years sampled. Concentrations of vitamins, including pantothenic acid (vitamin B5) and riboflavin (vitamin B2), increased annually during winter periods when mixed layer depths were deepest. During diel sampling, light-sensitive riboflavin decreased significantly during daylight hours. Metabolite concentrations over time at BATS showed less variability compared to a previous sample set collected over a broad latitudinal range in the western Atlantic Ocean. The metabolites examined in this study are all components of central carbon metabolism. By examining these metabolites at finer resolution and in a relatively long time series, we have insights into microbial biogeochemical activity, data which are fundamental to understanding the chemical response of marine systems to future changes in climate.
Prenatal methadone exposure selectively alters protein expression in primary motor cortex: implications for synaptic function
Authors: Haggerty David L. , Grecco Gregory G. , Huang Jui-Yen , Doud Emma H. , Mosley Amber L. , Lu Hui-Chen , Atwood Brady K.
Published: December 2022

As problematic opioid use has reached epidemic levels over the past two decades, the annual prevalence of opioid use disorder (OUD) in pregnant women has also increased 333%. Yet, how opioids affect the developing brain of offspring from mothers experiencing OUD remains understudied and not fully understood. Animal models of prenatal opioid exposure have discovered many deficits in the offspring of prenatal opioid exposed mothers, such as delays in the development of sensorimotor function and long-term locomotive hyperactivity. In attempt to further understand these deficits and link them with protein changes driven by prenatal opioid exposure, we used a mouse model of prenatal methadone exposure (PME) and preformed an unbiased multi-omic analysis across many sensoriomotor brain regions known to interact with opioid exposure. The effects of PME exposure on the primary motor cortex (M1), primary somatosensory cortex (S1), the dorsomedial striatum (DMS), and dorsolateral striatum (DLS) were assessed using quantitative proteomics and phosphoproteomics. PME drove many changes in protein and phosphopeptide abundance across all brain regions sampled. Gene and gene ontology enrichments were used to assess how protein and phosphopeptide changes in each brain region were altered. Our findings showed that M1 was uniquely affected by PME in comparison to other brain regions. PME uniquely drove changes in M1 glutamatergic synapses and synaptic function. Immunohistochemical analysis also identified anatomical differences in M1 for upregulating the density of glutamatergic and downregulating the density of GABAergic synapses due to PME. Lastly, comparisons between M1 and non-M1 multi-omics revealed conserved brain wide changes in phosphopeptides associated with synaptic activity and assembly, but only specific protein changes in synapse activity and assembly were represented in M1. Together, our studies show that lasting changes in synaptic function driven by PME are largely represented by protein and anatomical changes in M1, which may serve as a starting point for future experimental and translational interventions that aim to reverse the adverse effects of PME on offspring.
Dynamic readout of the Hh gradient in the Drosophila wing disc reveals pattern-specific tradeoffs between robustness and precision
Authors: Reyes Rosalío , Lander Arthur D. , Nahmad Marcos
Published: December 2022

How patterning by morphogen gradients determine tradeoffs between robustness and precision is unclear. Gradients that exhibit self-enhanced ligand degradation provide robustness to perturbations in morphogen production rates. However, increased robustness achieved through this mechanism is traded off for lower precision to noise. Here we use a hypotheses-driven theoretical approach to show that Hedge-hog (Hh) signaling would confer the same robustness to all target genes established by the steady-state gradient, but when a dynamical interpretation of patterning is used, robustness is maintained for steady-state outputs, but is traded off for higher precision in outputs set prior to steady-state. As predicted by our model, the widths ofdecapentaplegic (dpp), andcollier (col), two target genes established by the Hh gradient in theDrosophilawing disc, exhibit differential robustness to Hh dosage. Particularly, higher robustness in thecolpattern is ensured by Hh-dependent upregulation of its receptor Patched, an evolutionary-conserved property of Hh signaling that results in self-promoted Hh degradation. In contrast,dppexpression that is determined by the transient overshoot gradient, is insensitive to self-enhanced ligand degradation and exhibits less robustness, in exchange for a more precise boundary. Our work reveals of how morphogen gradients can establish tunable patterning properties in a target-specific manner.
VCP acts downstream of tTAFs to downregulate mono-ubiquitinated H2A and promote spermatocyte differentiation inDrosophila
Authors: Butsch Tyler J. , Dubuisson Olga , Johnson Alyssa E. , Bohnert K. Adam
Published: December 2022

Valosin-containing protein (VCP) binds and extracts ubiquitinated cargo to regulate protein homeostasis. While VCP has been studied primarily in aging and disease contexts, it also affects germline development. However, the precise molecular functions of VCP in the germline, particularly in males, are poorly understood. Using theDrosophilamale germline as a model system, we find that VCP translocates from the cytosol to the nucleus as germ cells transition into the meiotic spermatocyte stage. Importantly, nuclear translocation of VCP appears to be one critical event stimulated by testis-specific TBP-associated factors (tTAFs) to drive spermatocyte differentiation. LiketTAFmutants, spermatocyte gene expression fails to properly activate inVCP-RNAi testes, and germ cells arrest in early meiosis. At a molecular level, VCP activity supports spermatocyte gene expression by downregulating a repressive histone modification, mono-ubiquitinated H2A (H2Aub), at this developmental transition. Remarkably, experimentally blocking H2Aub inVCP-RNAi testes is sufficient to overcome the meiotic-arrest phenotype and to promote development through meiosis. Collectively, our data highlight VCP as a novel downstream effector of tTAFs that downregulates H2Aub to facilitate meiotic progression.

SUMMARY STATEMENT

VCP promotes the downregulation of mono-ubiquitinated H2A (H2Aub), potentially by driving H2A turnover. VCP-dependent downregulation of H2Aub occurs downstream of testis-specific TBP-associated factors and supports spermatocyte gene expression and differentiation.
Tumor cell intrinsic RIG-I activation co-opts the host microenvironment to drive immune mediated tumor rejection
Authors: Fraile-Bethencourt Eugenia , Khou Sokchea , Baris Adrian , Ruhl Rebecca , Anand Sudarshan
Published: December 2022

Targeting cytosolic nucleic acid sensors is a potent approach to drive type I interferon responses and anti-tumor immunity. Recent evidence suggests that activation of retinoic acid inducible gene-I (RIG-I) using synthetic hairpin RNA agonists decreases tumor progression in multiple preclinical models. However, the role of tumor cell intrinsic RIG-I in shaping tumor cell fates and the host immune microenvironment remains unclear. Here, we show that RIG-I expression is correlated with better overall survival and a distinct immune gene signature in specific human cancers including colorectal cancer. Activation of RIG-I in breast and colorectal cancer cells is sufficient to drive tumor cell death in vitro and significantly delay tumor growth in vivo in multiple preclinical models. Importantly, the efficacy of tumor cell RIG-I activation is lost in immune deficient mice suggesting the requirement of immune responses for this effect. We observe that tumor cell intrinsic RIG-I activation elicits a robust cellular and molecular immune response. We show that tumor cell RIG-I activation also leads to induction of specific immune checkpoints including PD-L1. Using a publicly available database, we found that RIG-I expression serves as an excellent prognostic marker for responders to checkpoint immunotherapy, particularly PD-L1/PD-1 across cancers. Finally, combination of tumor cell intrinsic RIG-I activation with anti-PD-L1 led to a synergistic decrease in tumor growth in a colorectal tumor model. Our findings suggest that tumor cell intrinsic RIG-I can be targeted to enhance anti-tumor immune responses and highlights a potential strategy for anti-cancer vaccines that can invigorate the immune system.
Who removes seeds in a heavily urbanized area?
Authors: Hueso-Olaya Dayana , Rocha-Ortega Maya , Coronel-Arellano Helí , Palacino-Rodríguez Fredy , Córdoba-Aguilar Alex
Published: December 2022

In urban landscapes, granivores play a key ecosystem service: they contribute to the establishment of plants and thereby increase the probability of vegetal community recovery. It is therefore a priority to determine how and by whom seeds are removed, which seeds are removed and where they are removed. Our objective here was to determine the removal patterns in three core zones of an urban reserve, three urban parks, and three peri-urban parks, all in and around Mexico City. We performed a selective exclusion experiment with treatments for each type of seed consumer (ants, birds, and rodents) and seeds of nine plant species. Ants were the most important granivores in terms of seed removal (especially small seeds), followed by rodents and birds. Seeds of the native plantsPassiflora subpeltata, Pittocaulon praecoxandOpuntia joconostlehad higher removal rates than other exotic and cosmopolitan species. The urban reserve had higher rates of seed predation compared to the urban and peri-urban parks. Thus, ants are pivotal in keeping seed removal and vegetation communities. We propose a series of measures to promote the ecosystem function of seed removal and increase plant diversity in these different urban patches.
Formation and growth of co-culture tumour spheroids: new compartment-based mathematical models and experiments
Authors: Murphy Ryan J. , Gunasingh Gency , Haass Nikolas K. , Simpson Matthew J.
Published: December 2022

Co-culture tumour spheroid experiments are routinely performed to investigate cancer progression and test anti-cancer therapies. Therefore, methods to quantitatively characterise and interpret coculture spheroid growth are of great interest. However, co-culture spheroid growth is complex. Multiple biological processes occur on overlapping timescales and different cell types within the spheroid may have different characteristics, such as differing proliferation rates or responses to nutrient availability. At present there is no standard, widely-accepted mathematical model of such complex spatio-temporal growth processes. Typical approaches to analyse these experiments focus on the late-time temporal evolution of spheroid size and overlook early-time spheroid formation, spheroid structure and geometry. Here, using a range of ordinary differential equation-based mathematical models and parameter estimation, we interpret new co-culture experimental data. We provide new biological insights about spheroid formation, growth, and structure. As part of this analysis we connect Greenspan’s seminal mathematical model to co-culture data for the first time. Furthermore, we generalise a class of compartment-based spheroid mathematical models that have previously been restricted to one population so they can be applied to multiple populations. As special cases of the general model, we explore multiple natural two population extensions to Greenspan’s seminal model and reveal biological mechanisms that can describe the internal dynamics of growing co-culture spheroids and those that cannot. This mathematical and statistical modelling-based framework is well-suited to analyse spheroids grown with multiple different cell types and the new class of mathematical models provide opportunities for further mathematical and biological insights.
Progressive spreading of DNA methylation in the GSTP1 promoter CpG island across transitions from precursors to invasive prostate cancer
Authors: Gupta Harshath , Inoue Hitoshi , Nakai Yasutomo , Nakayama Masashi , Jones Tracy , Hicks Jessica , Kumar Balasubramanian , Gurel Meltem , Nelson William G. , De Marzo Angelo M. , Yegnasubramanian Srinivasan
Published: December 2022

Glutathione S-transferase pi 1 (GSTP1) is lowly expressed in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy lesions (PIA). GSTP1 becomes silenced in prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma (CaP) via cytosine-phospho-guanine (CpG) island promoter hypermethylation. However,GSTP1methylation patterns in PIA and PIN, and their relationship to patterns in CaP are poorly understood. We used bisulfite genomic sequencing to examine patterns ofGSTP1promoter CpG island methylation in laser capture microdissected benign, PIA, PIN, and CaP regions from 32 subjects that underwent radical prostatectomy. We analyzed 908 sequence clones across 24 normal epithelium, 37 PIA, 18 PIN, and 23 CaP regions, allowing assessment of 34,863 CpG sites with allelic phasing. Normal and PIA lesions were mostly unmethylated with 0.52 and 1.3% of total CpG sites methylated, respectively. PIN and CaP lesions had greater methylation with 24% and 51% of total CpG sites methylated, respectively. The degree ofGSTP1methylation showed progression from PIA ≪ PIN < CaP. PIN lesions showed more partial methylation compared to CaP lesions. Partially methylated lesions were enriched for methylation changes at AP1 and SP1 transcription factor binding sites. These results demonstrate that methylation density in theGSTP1CpG island in PIN was intermediate relative to that in normal prostate epithelium/PIA and CaP lesions. These results are consistent with gradual spreading of DNA methylation centered at the SP1/AP1 transcription factor binding sites in precursor lesions, with subsequent spreading of methylation across the entire CpG island in transition to CaP.
Comparative analysis of chloroplast genome between wild and cultivatedRehmannia glutinosa Libosch
Authors: Yang Hao , Sasaki Yohei , Lian Conglong , Zhang Liping , Wang Lili , Yang Jingfan , Xue Shujuan , Chen Suiqing
Published: December 2022

Rehmanniaeradix, as a tonic Chinese medicine, has a good therapeutic effect on cardiovascular and cerebrovascular diseases and central nervous system diseases, and has a good development prospect in the international market.R.glutinosaLibosch has a large number of source varieties, and the wild and cultivated varieties are different types ofR.glutinosaLibosch. There has been a lot of controversy in the formulation of scientific names for wild and cultivated types ofR.glutinosaLibosch. In order to learn more about the genetic information of wildR.glutinosaLibosch and explore the phylogenetic relationship between wildR.glutinosaLibosch and cultivatedR.glutinosaLibosch. In the current study, we constructed and annotated a complete circular chloroplast genome of wildR.glutinosaLibosch. The chloroplast genome of wildR.glutinosa Libosch. is 153,678 bp in length, including two inverted repeat (IR) regions of 25,759 bp, separated by a large single copy (LSC) region of 84,544 bp and a small single copy (SSC) region of 17,616 bp. The GC content of whole chloroplast genome is 37.9%. The genome contains 133 different genes, including 88 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Among them, 23 genes contained introns, 50 SSR loci and 49 long repeats were found by Microsatellite scan, and codon use showed obvious A, T base preference. Nine variation regions were screened by mVISTA analysis and combined with DnaSP analysis, and psaJ-rpl33 was finally identified as a region with high variation, which could be used as a candidate DNA barcode for later interspecific identification ofR.glutinosaLibosch.. Neighbor-joining method phylogenomic analysis showed that wildR.glutinosa Libosch. formed a monophyletic group, and was sister to other groups ofR.glutinosa Libosch.The results of this study revealed the chloroplast genome information of wildR.glutinosa Liboschin detail, and found the genetic information difference between wild and cultivatedR.glutinosa Libosch. which laid the foundation for the variety identification, genetic engineering, biosynthesis and other studies.
The structural basis of itch receptor MRGPRX1 activation
Authors: Gan Bing , Yu Leiye , Yang Haifeng , Jiao Haizhan , Pang Bin , Chen Yian , Wang Chen , Lv Rui , Hu Hongli , Cao Zhijian , Ren Ruobing
Published: December 2022

Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are four primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 angstrom via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over opioid receptor. According to the structure analysis, we revealed that MRGPRX1 shares common features of the Gq-mediated receptor activation mechanism of MRGPRX family members. However, the variable residues in orthosteric pocket of MRGPRX1 exhibits the unique agonist recognition pattern, which may facilitate to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.
Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease susceptibility and age-of-onset
Authors: Williams Alexander T , Chen Jing , Coley Kayesha , Batini Chiara , Izquierdo Abril , Packer Richard , Abner Erik , Shepherd David J , Free Robert C , Hollox Edward J , Brunskill Nigel J , Ntalla Ioanna , Reeve Nicola , Brightling Christopher E , Venn Laura , Adams Emma , Bee Catherine , Wallace Susan , Pareek Manish , Hansell Anna L , Esko Tõnu ,   Estonian Biobank Research Team, Hennah William , Rao Balasubramanya S , Dudbridge Frank , Wain Louise V , Shrine Nick , Tobin Martin D , John Catherine
Published: December 2022

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Electronic health records were used to undertake the largest genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identified 158 novel signals, more than doubling the number of known associations with TSH, and implicating 112 putative causal genes, of which 78 were not previously implicated. For the first time, we demonstrate that a polygenic score for TSH was associated with TSH levels in all ancestries in UK Biobank, and strongly predicted age of onset of hypothyroidism and hyperthyroidism in European ancestry participants. We developed pathway-specific genetic risk scores for TSH levels and used these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.
To test or not to test? A new behavioral epidemiology framework for COVID-19
Authors: Sarkar Jayanta
Published: December 2022

Recent clinical research finds that rapid transmission of SARS-CoV-2 is facilitated by substantial undocumented asymptomatic infections. Asymptomatic infections have implications for behavioral response to voluntary testing. The paper argues that a substantial proportion of SARS-CoV-2 infections are hidden due to rational test avoidance behavior, especially among those without perceptible disease symptoms. However, if perception of disease threat is prevalence dependent, testing compliance increases in response to reported infection prevalence rate in the population. This behavior, in turn, affects infection and mortality dynamics. This paper proposes an analytical framework that explicitly incorporates prevalence-dependent testing behavior in a standard epidemiological model, generating distinctive equilibrium epidemiological outcomes with significant policy implications. Numerical simulations show that failure to consider endogenous testing behavior among asymptomatic individuals leads to over- and underestimation of infection rates at the peaks and troughs, respectively, thereby distorting the disease containment policies. The results underscore the importance of augmenting testing capacity as an effective mitigation policy for COVID-19 and similar infectious diseases.

JEL Codes

I12, I18
Long working and commuting times as risk factors for depressive symptoms. Cross-sectional and longitudinal analyses
Authors: Dragano Nico , Burr Hermann , Formazin Maren , Schulz Anika , Rose Uwe
Published: December 2022

Background

Regular long working and commuting hours are thought to have negative consequences for mental health. However, the study results are not clear and vary by country. The present analysis examines associations between working or commuting hours and depressive symptoms for Germany.

Method

The S-MGA study (German Study on Mental Health at Work) is a longitudinal cohort of a random sample of employees subject to social insurance contributions. We analysed data from 3 413 participants of the baseline survey (cross-sectional analysis) and from 2 019 people who participated at baseline and at a follow-up survey five years later (longitudinal analysis). Weekly working and commuting hours as well as covariates (age, gender, occupational position, psychosocial working conditions) were collected at baseline. Depressive symptoms were recorded with thePatient Health Questionnaireat both waves. Multivariate logistic regression models were used to control for covariates.

Results

At baseline survey, 7 % of the employees had overlong working hours of ≥ 55 hours per week, and another 8 % worked > 48-54 hours. Long working hours were cross-sectionally associated with moderately elevated depressive symptoms compared to normal working hours (35-< 40 h/week). When new depressive symptoms after five years were considered, the correlation was significant for > 55 weekly working hours (odds ratio [OR] 2.14; 95 % confidence interval [CI] 1.11;4.12), but not for > 48-54 h (OR 1.26, CI 0.65;2.43). Employees who commuted ten hours or more per week had more depressive symptoms cross-sectionally (OR 1.83; CI 1.13;2.94) compared to the reference group who commuted < 2.5 hours. This correlation was not observed longitudinally.

Conclusions

The results suggest that excessive working and commuting time is associated with depressive symptoms in employees, although the effects of commuting time were only found cross-sectionally. The results underline the importance of adhering to working time regulations and avoiding excessive working hours. Further research is needed on the role of commuting.
Cardiorespiratory fitness interventions for individuals with lower limb amputation: a scoping review
Authors: van Kammen K , Seves B.L. , Vrieling A.H. , Dekker R. , van Dijk A. , Dijkstra P.U. , Geertzen J.H.B.
Published: December 2022

Purpose

This scoping review aimed to provide an overview of different cardiorespiratory training methods and their effects on cardiorespiratory fitness in persons with a lower limb amputation (LLA).

Methods

Studies were searched in PubMed, EMBASE, CINAHL, Cochrane Library and Web of Science. The search strategy comprised four search strings with terms related to ‘amputation’ or ‘limb loss’, ‘lower extremity’, ‘training’ or ‘exercise’, and ‘endurance’ or ‘aerobic’. Studies were included if they reported on persons with a LLA who followed a cardiorespiratory training. The Effective Public Health Practice Project tool was used for quality assessment.

Results

Nine studies (88 participants) were included, with weak (7 studies) to moderate (2 studies) quality. Duration of the programmes ranged from 1.5 to 26 weeks, with a frequency of 3-5 sessions per week. The intensity of the workload increased during the programmes in two studies. After training, maximal oxygen uptake (VO2max) had increased in all studies, in three studies significantly. The training effects were inconclusive for resting heart rate, peak heart rate, and blood pressure

Conclusions

Cardiorespiratory training methods – with tailored duration and intensity – tended to increase VO2max and are feasible in persons with a LLA but quality of the studies was weak.

Implications for rehabilitation

VO2max of persons with a lower limb amputation can improve after cardiorespiratory training.

Training methods to improve cardiorespiratory fitness in persons with a lower limb amputation, in which training intensity is tailored to the patient (based on heart rate) are feasible.

Due to the low methodological quality of the included studies, this scoping review cannot provide an evidence-based overview of training methods to improve cardiorespiratory fitness in persons with a lower limb amputation.
Adiposity and Mortality among Patients Severely Ill with COVID-19 and non-COVID-19 Respiratory Conditions: A Cross-Context Comparison Study in the UK
Authors: Bell Joshua A. , Carslake David , Hughes Amanda , Tilling Kate , Dodd James W. , Doidge James C. , Harrison David A. , Rowan Kathryn M. , Smith George Davey
Published: December 2022

Objective

To assess the causality of adiposity for mortality among patients severely ill with COVID-19 and non-COVID-19 respiratory conditions by examining the consistency of associations across temporal and geographical contexts where biases vary

Design

Prospective cohort study

Setting

297 intensive care units (ICUs) in England, Wales, and Northern Ireland monitored by the Intensive Care National Audit and Research Centre Case Mix Programme

Participants

Patients aged ≥16 years admitted to ICU with COVID-19 (N=33,352; Feb 2020-Aug 2021) and non-COVID-19 respiratory conditions (N=24,739; Feb 2018-Aug 2019)

Main outcome measure

30-day mortality post ICU admission

Results

Compared with non-COVID-19 respiratory patients, COVID-19 patients were younger, less often of a white ethnic group, and more often with extreme obesity (body mass index (BMI) ≥ 40kg/m2). COVID-19 patients had fewer comorbidities but higher mortality (35% vs. 23% mortality in non-COVID-19). Socio-demographic and comorbidity factors and their associations with BMI and mortality varied more by date than geographical region of ICU admission, particularly among COVID-19 patients. Among COVID-19 patients, higher BMI was associated with a small excess mortality (hazard ratio (HR) per standard deviation (SD)=1.05; 95% CI=1.03, 1.08), driven by extreme obesity (HR per SD=1.21; 95% CI=1.13, 1.31 vs. normal-weight). Extreme obesity was strongly associated with higher mortality only during Feb-April 2020 (HR=1.49, 95% CI=1.27, 1.73 vs. normal-weight); this association weakened thereafter (BMI-date interaction P=0.03). Among non-COVID-19 respiratory patients, higher BMI was associated with lower mortality (HR per SD=0.84; 95% CI=0.82, 0.87), seen across all overweight/obesity groups. These negative obesity-mortality associations were similar across most admission dates and regions.

Conclusions

Obesity is associated with higher mortality among COVID-19 patients, but lower mortality among non-COVID respiratory patients. These associations appear vulnerable to confounding/selection bias in both patient groups, questioning the existence or stability of causal effects. Among COVID-19 patients, unfavourable obesity-mortality associations differ by admission date. Among non-COVID-19 respiratory patients, favourable obesity-mortality associations may reflect comorbidity-induced weight loss.
A predictive model of a growing fetus
Authors: Kumari Chandrani , Menon Gautam I , Narlikar Leelavati , Ram Uma , Siddharthan Rahul
Published: December 2022

Fetal growth is monitored periodically during pregnancy via ultrasound measurements of fetal dimensions such as femur length (FL), head circumference (HC), abdominal circumference (AC), and biparietal diameter (BPD). Multiple growth standards have been published for each of these, which are clinically used to place a fetus on a “growth chart”. These consist of percentile tables varying by weeks of gestation, computed from cohorts of “low-risk” women with healthy lifestyles, living conditions, and clinical parameters. Such charts are prescriptive of ideal growth, but not necessarily descriptive of diverse real-world populations where they may be used. Moreover, they are constructed by pooling all fetal measurements across the cohort, not based on a growth model, and therefore not necessarily predictive of growth of an individual fetus.

We show that the Gompertz model, a standard model for constrained growth, with just three intuitive parameters, convincingly fits the growth of fetal ultrasound biometries. Two of these parameters—t0(the inflection time) andc(the rate of decrease of growth rate)—can be treated as universal to all fetuses, while the third parameterAcan be modeled as an overall scale parameter specific to each fetus, which captures the individual variation in growth. On our cohort of 817 pregnant women (“Seethapathy cohort”), we show that not only can the value ofAfor each fetus be inferred from ultrasound data available by the second or the third trimester, but the weight of the baby at delivery can also be predicted with remarkable accuracy using these inferred Gompertz parameters. A model trained on the Seethapathy cohort performs well in estimating the birth weight in an independent validation cohort of 365 women, demonstrating the predictive power of the model. Moreover, we find that deviation from Gompertz-like growth is linked to neonatal complications. Finally, we show that the Gompertz growth curve is a close fit to the standards from WHO, NICHD and INTERGROWTH, with the optimalt0andcclose to that in the Seethapathy cohort. We propose that the Gompertz formula be a basis for future growth standards, with almost all variation described by a single scale parameterA, which can serve either as a descriptor of mean or variance in population, or as a descriptor for growth of an individual fetus. Indeed, the formula is descriptive of typical growth, predictive of future growth, and may be used in prescriptive standards.
Aberrant brain criticality as a neural basis of preclinical Alzheimer’s disease
Authors: Javed Ehtasham , Suárez-Méndez Isabel , Susi Gianluca , Verdejo Román Juan , Palva J Matias , Maestú Fernando , Palva Satu
Published: December 2022

Alzheimer’s disease (AD) is a chronic, nonlinearly progressive neurodegenerative disease that affects multiple domains of behaviour and is the most common form of dementia. However, there is scarce understanding of its biological basis nor there are reliable markers for the earliest disease stages preceding AD. Here we investigated whether AD progression is predicted by increasingly aberrant critical brain dynamics driven by underlying E/I imbalance using magnetoencephalography (MEG) data from cross-sectional (N=343) and longitudinal (N=45) cohorts. As a hallmark of brain criticality, we quantified long-range temporal correlations (LRTCs) in neuronal oscillations and tracked changes in neuronal excitability. We demonstrate that attenuation and progressive changes of LRTCs characterize the earliest stages of disease progression and yield accurate classification to individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Our data indicate that pathological brain critical dynamics in AD progression provide a clinical marker for targeting specific treatments to individuals at increased risk.
Diversification of the recombinant anti-kinesin monoclonal antibody H2
Authors: Niwa Shinsuke , Chiba Kyoko
Published: December 2022

Kinesin-1, a motor protein composed of the kinesin heavy chain (KHC) and the kinesin light chain (KLC), is fundamental to cellular morphogenesis and function. A monoclonal antibody (mAb) called H2 recognizes the KHC in a broad range of species and is one of the most widely used mAbs in cytoskeletal motor research. Here, we generated vectors that expressed recombinant H2 in mammalian cells. We demonstrated that the recombinant H2 performed as well as the hybridoma-derived H2 in western blotting and immunofluorescence assays. The recombinant H2 could detect all three human KHC isotypes (KIF5A, KIF5B, and KIF5C) and amyotrophic lateral sclerosis (ALS)-associated KIF5A aggregates in the cell. Immunofluorescence microscopy showed that the single chain variable fragment (scFv) derived from the H2 mAb could specifically recognize KHCs in cells. In addition, we developed a chickenized anti-KHC scFv(H2), which broadens the application of H2 in immunofluorescence microscopy. Collectively, our findings validate recombinant H2 as useful for studying the function of KHCs.
Directed Biosynthesis of Mitragynine Stereoisomers
Authors: Schotte Carsten , Jiang Yindi , Grzech Dagny , Dang Thu-Thuy T. , Laforest Larissa , León Francisco , Mottinelli Marco , Nadakuduti Satya S. , McCurdy Christopher R. , O’Connor Sarah E.
Published: December 2022

Mitragyna speciosa(“Kratom”) is used as a natural remedy for pain and management of opioid dependence. The pharmacological properties of Kratom have been linked to a complex mixture of monoterpene indole alkaloids, most notably mitragynine. Here, we report the central biosynthetic steps responsible for the scaffold formation of mitragynine and related corynanthe-type alkaloids. We illuminate the mechanistic basis by which the key stereogenic centre of this scaffold is formed. These discoveries were leveraged for the enzymatic production of mitragynine, the C-20 epimer speciogynine, and a series of fluorinated analogues.
Migration strategy varies with novel environment response in common noctule bats
Authors: Schabacker Theresa , Rizzi Sofia , Teige Tobias , Hoffmeister Uwe , Voigt Christian C. , Snijders Lysanne
Published: December 2022

Global ecosystems are changing dramatically due to land transformation and climate change. Global change is a particular challenge for migratory animals that rely on multiple stepping stones on their journeys. Migratory animals have a range of strategies to accomplish this, but not all of these strategies may be appropriate for the challenges ahead. Understanding the variation in migratory strategies and their behavioural correlates is therefore critical to understand how vulnerable species will be in the future, especially in endangered and elusive taxa such as bats. Here, we combined isotopic geolocation with an in-situ behavioural assay to investigate whether behavioural responses to a roost-like novel environment correlated with variation in migration strategies (local or distant origin based on isotopic geographic assignments), in the partially migratory bat,Nyctalus noctula. We quantified emergence behaviour, spatial activity, and echolocation call activity. Local bats were more likely to emerge into the novel environment than bats from more distant origins. However, local and distant bats did not differ in spatial activity and acoustic exploration (relative call activity per space unit). Our findings indicate that local bats may more pro-actively cope with novelty, but that acoustic exploration is equally important for local and migratory bats during explorations.
Differential ripple propagation along the hippocampal longitudinal axis
Authors: De Filippo Roberto , Schmitz Dietmar
Published: December 2022

Hippocampal ripples are highly synchronous neural events critical for memory consolidation and retrieval. A minority of strong ripples has been shown to be of particular importance in situations of increased memory demands. The propagation dynamics of strong ripples inside the hippocampal formation are, however, still opaque. We analyzed ripple propagation within the hippocampal formation in a large open access dataset comprising 267 Neuropixel recordings in 49 awake, head-fixed mice. Surprisingly, strong ripples (top 10% in ripple strength) propagate differentially depending on their generation point along the hippocampal longitudinal axis. The septal hippocampal pole is able to generate longer ripples that engage more neurons and elicit spiking activity for an extended time even at considerable distances. Accordingly, a substantial portion of the variance in strong ripple duration (R² = 0.463) is explained by the ripple generation location on the longitudinal axis. Our results are consistent with a possible distinctive role of the hippocampal septal pole in conditions of high memory demand.
Balanced mitochondrial function at low temperature is linked to cold adaptation inDrosophilaspecies
Authors: Jørgensen Lisa Bjerregaard , Hansen Andrea Milena , Willot Quentin , Overgaard Johannes
Published: December 2022

The ability of ectothermic animals to live in different thermal environments is closely associated with their capacity to maintain physiological homeostasis across diurnal and seasonal temperature fluctuations. For chill-susceptible insects, such asDrosophila, cold tolerance is tightly linked to ion and water homeostasis obtained through a regulated balance of active and passive transport. Active transport at low temperature requires a constant delivery of ATP and we therefore hypothesize that cold-adaptedDrosophilaare characterized by superior mitochondrial capacity at low temperature relative cold-sensitive species. To address this, we investigated how experimental temperatures 19-1 °C affected mitochondrial substrate oxidation in flight muscle of seven tropical and temperateDrosophilaspecies that represent a broad spectrum of cold tolerance. Mitochondrial oxygen consumption rates measured using a substrate-uncoupler-inhibitor-titration protocol showed that cooling generally reduced oxygen consumption of all steps of the electron transport system across species. Complex I is the primary consumer of oxygen at benign temperatures, but low temperature decreases complex I respiration to a much greater extent in cold-sensitive species than in cold-adapted species. Accordingly, cold-induced reduction of complex I correlates strongly with CTmin(the temperature inducing cold coma). The relative contribution of alternative substrates, proline, succinate and glycerol-3-phosphate increased as temperature decreased, particularly in the cold-sensitive species. At present it is unclear whether the oxidation of alternative substrates can be used to offset the effects of the temperature-sensitive complex I, and the potential functional consequences of such a substrate switch are discussed.

Summary statement

Mitochondrial oxygen consumption decreases at low temperature, particularly in cold-sensitiveDrosophilaspecies, which turn to oxidation of alternative substrates as complex I-supported respiration is impaired.
The link between construction apps’ acceptance and digital attributes of construction professionals: perspectives from digital competence model
Authors: Olugboyega Oluseye , Ilesanmi Kayode Emmanuel , Oseghale Godwin Ehis , Aigbavboa Clinton
Published: December 2022

Purpose

The advancement of digital technological breakthroughs in the construction industry is dependent on connecting the attributes of the intended consumers to the technologies. Thus, this study aims to look at the relationship between construction app acceptance and the digital qualities of construction professionals (CPs) to determine whether understanding the connection can assist predict construction app user behaviour.

Design/methodology/approach

This study’s theoretical approach was derived from the European Union digital competence model, which supports the hypothesis that the traits associated with digital competence enable digitally competent CPs to embrace construction apps. Six hypotheses were developed to investigate the theories, and multiple linear regression analysis was used to predict the acceptance of construction apps based on the CP’s attributes.

Findings

The investigation’s findings revealed that the CP’s attributes can explain at least 50% of the proportion of variance in 34 construction apps. The use of a smartphone (Mean Score = 3.30; Factor Loading = 0.609), technological orientation (Mean Score = 3.55; Factor Loading = 0.663), information technology skills (Mean Score = 3.48; Factor Loading = 0.649), information on construction innovation (Mean Score = 3.73; Factor Loading = 0.528) and interest in R&D (Mean Score = 3.48; Factor Loading = 0.531) are the digital characteristics that can essentially forecast the acceptance of construction apps. The data backs up the notion that CPs would gain digital competency before accepting construction apps. This is because a digitally savvy CP will most likely embrace construction apps.

Research limitations/implications

Frameworks for accelerating digital technologies and innovations in the construction industry have been unveiled in this study. The research also gives recommendations for the evaluation, design and implementation of a more attractive construction app. This study also has implications for investigating the impacts of risk aversion, personal connection, social influence, technological curiosity and digital nativity as predictors of construction app uptake.

Practical implications

The findings of this study serve as an index for prioritising digital traits for CPs and characterising a digitally proficient construction professional. The findings provide recommendations for organising, training and supporting construction personnel’ digital competencies. The research is useful for developing and implementing instructional digital training programmes.

Originality/value

This study is unusual in that it provides clear insights on construction apps as well as variables for building great user-experience apps for CPs, which are both limited in the literature.
Post pandemic “revenge travel”: developing organizations to address staff shortage
Authors: Jeffrey Heather Louise , Sposato Martin
Published: December 2022

Purpose

The purpose of this viewpoint is to discuss and provide solutions for the current staffing crisis facing tourism-related industries. Considering that staff shortages are prominent in most industries this article suggests organizational changes that are needed to address these problems

Design/methodology/approach

This viewpoint unpacks the reason behind the shortage in staff and suggests potential solutions, based on organizational development

Findings

The strategies offered here as potential solutions for human resources center on changing the image of the roles that are suffering shortages. This includes developing organizational practices to provide changes in the areas of recruitment, reward, and work-life balance. These strategies are contextualized with the transformation of other jobs due to the global pandemic and the feminized nature of the tourism-related industries.

Originality/value

This viewpoint is particularly topical as it speaks to the current well-publicized crises in the staffing of airports and wider shortages of hospitality staff in developed nations. It is well positioned to spark discussion and future research on areas such as dignity at work in tourism-related industries, gendered work, and post-pandemic employment practices in services.