Distribution Of Phenotypes Research Articles

Population-aware permutation-based significance thresholds for genome-wide association studies

Abstract Motivation Permutation-based significance thresholds have been shown to be a robust alternative to classical Bonferroni significance thresholds in genome-wide association studies for skewed phenotype distributions. The recently published method permGWAS introduced a batch-wise approach to efficiently compute permutation-based genome-wide association studies. However, running multiple univariate tests in parallel leads to many repetitive computations and increased computational resources. More importantly, traditional permutation methods that permute only the phenotype break the underlying population structure. Results We propose permGWAS2, an improved method that does not break the population structure during permutations and uses an elegant block matrix decomposition to optimize computations, thereby reducing redundancies. We show on synthetic data that this improved approach yields a lower false discovery rate for skewed phenotype distributions compared to the previous version and the commonly used Bonferroni correction. In addition, we re-analyze a dataset covering phenotypic variation in 86 traits in a population of 615 wild sunflowers (Helianthus annuus L.). This led to the identification of dozens of novel associations with putatively adaptive traits, and removed several likely false-positive associations with limited biological support. Availability permGWAS2 is open-source and publicly available on GitHub for download: https://github.com/grimmlab/permGWAS. Supplementary information Supplementary data are available at Bioinformatics Advances online.

Screening of Klebsiella pneumoniae isolates reveals the spread of strong biofilm formers and class 1 integrons.

Klebsiella pneumoniae is a Gram-negative bacterium that can colonize, penetrate, and cause infections at several human anatomical locations. The emergence of hypervirulent K. pneumoniae and its ability to evade the immune system and develop antibiotic resistance has made it a key concern in the healthcare industry. The hypervirulent variants are increasingly involved in community-acquired infections. Therefore, it is pertinent to understand the biofilm formation potential among the clinical isolates. We acquired 225 isolates of K. pneumoniae from the Department of Microbiology, Symbiosis University Hospital and Research Centre (SUHRC), Pune, India over 1 year from March 2022- March 2023, and evaluated antimicrobial susceptibility, hypermucoviscous phenotype, virulence, and antimicrobial-resistant gene distribution in K. pneumoniae isolates and established a correlation between antimicrobial resistance and integrons. Most isolates were strong biofilm formers (76%). The isolates harbored one or more carbapenemase/ beta-lactamase encoding gene combinations. Hypermucoviscous (HMKP) isolates had considerably greater positive rates for iutA, magA, K2 serotype, rmpA, and rmpA2 than non-HMKP isolates. Isolates carrying integrons (43%) showed significantly more antibiotic resistance. The study reveals spread of strong biofilm formers with extensive virulence and antimicrobial-resistant genes, and integrons responsible for multi-drug resistance among the clinical isolates of K. pneumoniae in Pune, India, posing a threat to the public health and necessitating close surveillance, accurate diagnosis, control, and therapeutic management of infections.

Association of Angiotensin Converting Enzyme Phenotypes and Polymorphisms with Clinical Outcomes in SARS-CoV2 Patients with Hypertension in an Urban Emergency Department.

The role of Angiotensin-converting enzyme (ACE and ACE2) phenotypes and polymorphisms in modulating severe acute respiratory syndrome coronavirus (SARS-- CoV2) infection in hypertensive patients remains unclear. Our objective was to determine the distribution of ACE and ACE2 receptor phenotypes by patient demographics and correlate ACE and ACE2 levels of activity with SARS-CoV-2 outcomes. Hypertensive patients treated for SARS-CoV-2 at an urban emergency department (ED) were prospectively enrolled in a cohort study between August 2020 and April 2021. Blood samples were collected during ED visits or hospitalization. Outcome measures including hospitalization, intensive care unit (ICU) admission, and 30-day mortality were obtained from electronic health records. Multivariable logistic regression was used. Of the 150 patients enrolled, 60% were Black, 32% Hispanic/Latinx, 4% Non-Hispanic Whites, and 4% others. The mean age was 59 (+/-14) years. The rate of hospitalization was high (86%) and Hispanic/Latinx had a higher likelihood of ICU admission. Patients harboring the rs2285666 genotype TT, AA, and GC alleles were more likely to be admitted to ICU, and those with TT and AA had higher mortality. The ACE level was a significant predictor of hospitalization with a protective effect in both unadjusted and adjusted results. Hispanics/Latinx had a four times higher likelihood of ICU admission compared to all others, and age was significantly associated with 30-day mortality. Our results show that even after adjusting for age, race, and sex, ACE levels remained a predictor of hospitalization. ACE/ACE2 phenotypes and genotypes potentially play an important role in disease progression in SARS-CoV-2 patients.

Clinical Phenotyping for Prognosis and Immunotherapy Guidance in Bacterial Sepsis and COVID-19.

It is suggested that sepsis may be classified into four clinical phenotypes, using an algorithm employing 29 admission parameters. We applied a simplified phenotyping algorithm among patients with bacterial sepsis and severe COVID-19 and assessed characteristics and outcomes of the derived phenotypes. Retrospective analysis of data from prospective clinical studies. Greek ICUs and Internal Medicine departments. We analyzed 1498 patients, 620 with bacterial sepsis and 878 with severe COVID-19. We implemented a six-parameter algorithm (creatinine, lactate, aspartate transaminase, bilirubin, C-reactive protein, and international normalized ratio) to classify patients with bacterial sepsis intro previously defined phenotypes. Patients with severe COVID-19, included in two open-label immunotherapy trials were subsequently classified. Heterogeneity of treatment effect of anakinra was assessed. The primary outcome was 28-day mortality. The algorithm validated the presence of the four phenotypes across the cohort of bacterial sepsis and the individual studies included in this cohort. Phenotype α represented younger patients with low risk of death, β was associated with high comorbidity burden, and δ with the highest mortality. Phenotype assignment was independently associated with outcome, even after adjustment for Charlson Comorbidity Index. Phenotype distribution and outcomes in severe COVID-19 followed a similar pattern. A simplified algorithm successfully identified previously derived phenotypes of bacterial sepsis, which were predictive of outcome. This classification may apply to patients with severe COVID-19 with prognostic implications.

Calbindin and Girk2/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson’s disease model

The differential vulnerability of dopaminergic neurons of the substantia nigra pars compacta (SNc) is a critical and unresolved question in Parkinson´s disease. Studies in mice show diverse susceptibility of subpopulations of nigral dopaminergic neurons to various toxic agents. In the primate midbrain, the molecular phenotypes of dopaminergic neurons and their differential vulnerability are poorly characterized. We performed a detailed histological study to determine the anatomical distribution of different molecular phenotypes within identified midbrain neurons and their selective vulnerability in control and MPTP-treated monkeys. In the ventral tier of the SNc (nigrosome), neurons rich in Aldh1a1 and Girk2 are intermingled, whereas calbindin is the marker that best identifies the most resilient neurons located in the dorsal tier and ventral tegmental area, recapitulating the well-defined dorsoventral axis of susceptibility to degeneration of dopaminergic neurons. In particular, a loss of Aldh1a1+ neurons in the ventral SNc was observed in parallel to the progressive development of parkinsonism. Aldh1a1+ neurons were the main population of vulnerable dopaminergic nigrostriatal-projecting neurons, while Aldh1a1- neurons giving rise to nigropallidal projections remained relatively preserved. Moreover, bundles of entwined Aldh1a1+ dendrites with long trajectories extending towards the substantia nigra pars reticulata emerged from clusters of Aldh1a1+ neurons and colocalized with dense cannabinoid receptor 1 afferent fibers likely representing part of the striatonigral projection that is affected in human disorders, including Parkinson´s disease. In conclusion, vulnerable nigrostriatal-projecting neurons can be identified by using Aldh1a1 and Girk2. Further studies are needed to define the afferent/efferent projection patterns of these most vulnerable neurons.

Exogenous NT-3 Promotes Phenotype Switch of Resident Macrophages and Improves Sciatic Nerve Injury through AMPK/NF-κB Signaling Pathway.

Neurotrophin-3 (NT-3) is an important family of neurotrophic factors with extensive neurotrophic activity, which can maintain the survival and regeneration of nerve cells. However, the mechanism of NT-3 on macrophage phenotype transformation after sciatic nerve injury is not clear. In this study, we constructed a scientific nerve compression injury animal model and administered different doses of NT-3 treatment through osmotic minipump. 7 days after surgery, we collected sciatic nerve tissue and observed the distribution of macrophage phenotype through iNOS and CD206 immunofluorescence. During the experiment, regular postoperative observations were conducted on rats. After the experiment, sciatic nerve tissue was collected for HE staining, myelin staining, immunofluorescence staining, and Western blot analysis. To verify the role of the AMPK/NF-κB pathway, we applied the AMPK inhibitor Compound C and the NF-κB inhibitor BAY11-7082 to repeat the above experiment. Our experimental results reveal that NT-3 promotes sciatic nerve injury repair and polarization of M2 macrophage phenotype, promotes AMPK activation, and inhibits NF-κB activation. The repair effect of high concentration NT-3 on sciatic nerve injury is significantly enhanced compared to low concentration. Compound C administration can weaken the effect of NT-3, while BAY 11-7082 can enhance the effect of NT-3. In short, NT-3 significantly improves sciatic nerve injury in rats, promotes sciatic nerve function repair, accelerates M2 macrophage phenotype polarization, and improves neuroinflammatory response. The protective effects of NT-3 mentioned above are partially related to the AMPK/NF-κB signal axis.

Distribution of endometriosis phenotypes according to patients' age in adult women with surgical evaluation.

What is the distribution of endometriosis phenotypes according to age in adult women undergoing surgery? The phenotype of endometriosis did not significantly vary after 24 years old. The phenotypic evolution of endometriosis over time remains unclear. While adolescents can exhibit any type of endometriosis lesions, ovarian endometriosis (OMA) and/or deep-infiltrating endometriosis (DIE) tend to increase with age in young adults. In adulthood, understanding the evolution of lesions is crucial for disease management, but the literature on this subject is limited. This study aims to examine the distribution of endometriosis phenotypes in relation to age among adult patients requiring surgical treatment. This observational cohort study included patients aged between ≥18 and ≤42 years, who underwent surgery for benign gynecological conditions at our institution between January 2004 and December 2022. A standardized questionnaire was completed for each patient during a face-to-face interview conducted by the surgeon in the month preceding surgery. Women with histologically proven endometriosis were included. The distribution of endometriosis phenotypes (isolated superficial (SUP) endometriosis, OMA ± SUP, DIE ± SUP/OMA) was compared between young adults (≤24 years) and adults (>24 years) and among adults (25-28 years, 29-33 years, 34-38 years, 39 to ≤42 years) using univariate and multivariate analysis. The distribution of different subtypes of DIE (uterosacral ligament(s), vagina, bladder, intestine, and ureter), OMA size, and intensity of pain symptoms were also examined. A total of 1311 adult women with histologically proven endometriosis were included. In women aged 24 years or younger (n = 116), the distribution of endometriosis phenotypes differed significantly from women older than 24 years (n = 1195): The frequency of the DIE ± SUP/OMA phenotype was lower (41.4% versus 56.1%, respectively), while the rate of isolated superficial lesions was higher (from 32.0% versus 25.9%) (P = 0.001). In the group of women aged >24 years, a significantly higher proportion of vaginal DIE lesions (P = 0.012) and a lower proportion of uterosacral ligament DIE lesions (P = 0.004) were found compared to women aged ≤24years. No significant differences were observed in terms of endometrioma size. Between the ages of 25 and 42years, there were no significant changes in the distribution of endometriosis phenotypes after univariate and multivariate analysis. The distribution of subtype of DIE lesions did not significantly change with age between 25 and 42 years. Concerning pain symptom scores, there was a significant decrease with age for dysmenorrhea and dyspareunia. Inclusion of only surgical patients may have introduced a selection bias. Women referred to our center may have suffered from particularly severe clinical forms of endometriosis. This study highlights that endometriosis presentation did not change with age in adult women. Further research on endometriosis phenotype evolution is necessary to assist practitioners in clinical decisions and treatment strategies. None declared. N/A.

Serum Paraoxonase Activity and Phenotype Distribution in Covid-19 Patients

Objective: For the phenotype classification, it is important to determine the relationship between enzyme activity and the severity of the COVID-19 disease. Reaching significant differences between healthy and infected individuals in terms of genotype and allele distributions may be a guide in the fight against the COVID-19 pandemic. This study, it was aimed to investigate the relationship between serum arylesterase PON1 enzyme activity and disease severity in COVID-19 patients. Methods: Patients over the age of 18 who applied to the Emergency Service between 01-30 April 2020 and were examined with a preliminary diagnosis of COVID-19 were included in the study. In the study, serum PON1 activity was measured in the venous blood of 56 patients diagnosed with Covid-19 disease by either CT or RT-PCR and who have not received any systemic treatment yet. Results: The Arylesterase (AREase) and Paraoxonase (POase) activity levels of the study and control groups were 131.49 ± 52.75 kU/L 142.29 ± 38.82 kU/L, 276.48 ± 220.4 U/L 505.30 ± 301.4 U/L, respectively. It was found that 64.3 % of those infected with Covid-19 had the low-activity PON1 phenotype (p= 0.007) Conclusion: Genetic variability in PON1 may be associated with exposure to or risk of developing the disease. As a result, vaccination of individuals with low activity phenotype can be given priority at the vaccination stage in order to reduce the mortality rate in the fight against the pandemic. Awareness and protection measures of societies with low activity phenotypes can be increased.

Emergence and expansion of carbapenem resistant enterobacterales in the Western Cape Province, South Africa.

Carbapenem resistant Enterobacterales (CRE) have become established as leading pathogens in South African healthcare facilities. The aim of this study is to describe the epidemiology of CRE carriage and clinical infection episodes at healthcare facilities in the Western Cape Province of South Africa (2016-2020), and identify factors associated with mortality in CRE infected patients. We used routine data from the Provincial Health Data Centre to track the emergence of CRE in healthcare facilities in the Western Cape Province of South Africa. We included all CRE episodes (clinical and carriage) at Western Cape hospitals (including day and inpatients) from 2016 to 2020 to determine the distribution of CRE, patient demographics and antibiotic resistance phenotypes. Logistic regression was performed to identify factors associated with mortality from clinical CRE episodes. 2242 CRE episodes (1580 [70.5%] clinical and 662 [29.5%] carriage) were identified. From these, 2281 CRE isolates were identified, with Klebsiella species predominating (1644, 72.1%). Affected patients had a median age of 31 (IQR 0-52) years, and 1167 (52.0%) were male. Most CRE episodes were recorded in central hospitals (70.0%, p < 0.001). Where outcome data was available, crude in-hospital mortality rates were 26.9% (371/1379) for CRE clinical episodes versus 6.4% (41/640) for CRE carriage episodes (p < 0.001). Factors that showed a statistically significant association with in-hospital mortality were female sex [adjusted odd ratio (aOR) 1.40 (95% confidence interval (CI) 1.09-1.560)], adult patients [aOR 1.76 (95% CI 1.20-2.57)], CRE isolation from a sterile specimen [aOR 0.41 (95% CI 0.32-0.53)], and >3 days between hospital admission and specimen collection [aOR 1.56 (95% CI 1.11-2.18)]. CRE episodes at Western Cape healthcare facilities are concentrated at tertiary hospitals, with high case fatality rates in patients with clinical CRE episodes. Infection control interventions must be strengthened to reduce transmission of CRE, and to reduce infection risks.

Mesenchymal stem cells from adipose tissue prone to lose their stemness associated markers in obesity related stress conditions

Obesity is a health problem characterized by large expansion of adipose tissue. During this expansion, genotoxic stressors can be accumulated and negatively affect the mesenchymal stem cells (MSCs) of adipose tissue. Due to the oxidative stress generated by these genotoxic stressors, senescence phenotype might be observed in adipose tissue MSCs. Senescent MSCs lose their proliferations and differentiation properties and secrete senescence-associated molecules to their niche thus triggering senescence for the rest of the tissue. Accumulation of senescent cells in adipose tissue results in decreased tissue regeneration and functional impairment not only in the close vicinity but also in the other tissues. Here we hypothesized that declined tissue regeneration might be associated with loss of stemness markers in MSCs population. We analyzed the expression of several stemness-associated genes of in vitro cultured MSCs originated from adipose tissue of high-fat diet and normal diet mice models. Since the heterogenous MSCs population covers a small percentage of the pluripotent stem cells, which have roles in proliferation and tissue regeneration, we measured the percentage of these cells via TRA-1-60 pluripotent state antigen. Additionally, by conducting a shotgun proteomic approach using LC-MS/MS, whole cell proteome of the adipose tissue MSCs of high-fat diet and normal diet mice were analyzed and identified proteins were evaluated via gene ontology and PPI network analysis. MSCs of obese mice showed senescent phenotype and altered cell cycle distribution due to a hostile environment with oxidative stress in adipose tissue where they reside. Additionally, the number of pluripotent markers expressing cells declined in the MSC population of the high-fat diet mice. Gene expression analysis evidenced the loss of stemness with a decrease in the expression of stemness-associated genes. Of the proteomic comparison of the normal and the high-fat diet group, MSCs revealed that stemness-associated molecules were decreased while inflammation and senescence-associated phenotypes emerged in obese mice MSCs. Our results showed us that the MSCs of adipose tissue may lose their stemness properties due to obesity-associated stress conditions.

Identification of Individuals of Two Takin Subspecies Using Biological and Ecological Criteria in Eastern Himalayas of China.

Limited background data are available on the Mishmi takin (Budorcas taxicolor taxicolor) and Bhutan takin (Budorcas taxicolor whitei) subspecies in the Eastern Himalayas of China because of the lack of systematic field investigations and research. Therefore, mature-animal ecological methods were used to evaluate these takin subspecies' phenotypic characteristics, distribution range, activity rhythm, and population size. From 2013 to 2022, 214 camera traps were installed for wild ungulate monitoring and investigation in all human-accessible areas of the Eastern Himalayas, resulting in 4837 distinguishable takin photographs. The external morphological characteristics were described and compared using visual data. Artificial image correction and related technologies were used to establish physical image models based on the differences between subspecies. MaxEnt niche and random encounter models obtained distribution ranges and population densities. Mishmi takins have a distribution area of 17,314 km2, population density of 0.1729 ± 0.0134 takins/km2, and population size of 2995 ± 232. Bhutan takins have a distribution area of 25,006 km2, population density of 0.1359 ± 0.0264 takins/km2, and population size of 3398 ± 660. Long-term monitoring data confirmed that the vertical migration within the mountain ecosystems is influenced by climate. Mishmi takins are active at 500-4500 m, whereas Bhutan takins are active at 1500-4500 m. The two subspecies were active at >3500 m from May to October yearly (rainy season). In addition, surveying combined with model simulation shows that the Yarlung Zangbo River is not an obstacle to migration. This study provides basic data that contribute to animal diversity knowledge in biodiversity hotspots of the Eastern Himalayas and detailed information and references for species identification, distribution range, and population characteristics.

Analysis of The Results of The Rhesus System Blood Group Phenotyping Examination in Routine Type O Blood Donors

The Rhesus (Rh) system is the second most important blood group system after ABO, has the highest immunogenicity and tends to produce alloantibodies that cause most transfusion reactions. In the Rh blood group system, there are more than 55 antigens, but the main ones are D, C, E, c, and e. Currently, only the D antigen is carried out without examining four other important Rh antigens. Still scarce, studies on the proportion of Rh antigens, except D, in Indonesia; in this study we have determined Rh antigens and phenotypes among a population of routine blood donors. The purpose of this study was to determine the phenotypic variation and frequency distribution of the main antigens of the Rhesus blood group system in routine blood type O blood donors at UDD PMI Depok City. This study was descriptive and observational with a cross-sectional design. Primary data are obtained from the Rhesus system antigen examination results on donor blood samples. The sample was 140 blood samples from 140 routine donors. A rhesus phenotyping examination was carried out using the gel method. The study was conducted on 140 routine donor blood samples at UDD PMI Depok City. The characteristics of the subjects were male (69.29%) and female (30.71%), with an average age of 38 years. Samples are analyzed for five major Rhesus antigens. Rhesus antigen test shows D antigen (100%), e antigen (97.14%), C antigen (95.71%), c antigen (36.43%) and E antigen (27.86%). Rhesus phenotype results were R1R1 (DCe/Dce) (62.86%), R1R2 (DCe/DcE) (22.86%), R1r (DCe/dce) (9.29%), R2R2 (DcE/DcE) (2.86%), R2r (DcE/dce) (1.43%), and R1RZ (DCe/DCE) (0.71%). In conclusion, the frequency of phenotypic changes in the Rh blood group system of regular blood donors at UDD PMI Depok City is classified as the most common types: DCe/DCe, DCe/DcE, DCe/dce, DcE/DcE, DcE/dce and DCe/DCE.

MSPB: a longitudinal multi-sensor dataset with phenotypic trait measurements from honey bees

We present a one-year-long multi-sensor dataset collected from honey bee colonies (Apis mellifera) with rich phenotypic measurements. Data were collected non-stop from April 2020 to April 2021 from 53 hives located at two apiaries in Québec, Canada. The sensor data included audio features, temperature, and relative humidity. The phenotypic measurements contained beehive population, number of brood cells (eggs, larva and pupa), Varroa destructor infestation levels, defensive and hygienic behaviors, honey yield, and winter mortality. Our study is amongst the first to combine a wide variety of phenotypic trait measurements annotated by apicultural science experts with multi-sensor data, which facilitate a broader scope of analysis. We first summarize the data collection procedure, sensor data pre-processing steps, and data composition. We then provide an overview of the phenotypic data distribution as well as a visualization of the sensor data patterns. Lastly, we showcase several hive monitoring applications based on sensor data analysis and machine learning, such as winter mortality prediction, hive population estimation, and the presence of an active and laying queen.

Genetic diversity of a Silybum marianum (L.) Gaertn. germplasm collection revealed by DNA Diversity Array Technology (DArTseq).

Silybum marianum (L.) Gaertn. is a multipurpose crop native to the Mediterranean and middle east regions and mainly known for the hepatoprotective properties of fruit-derived silymarin. Despite growing interest in milk thistle as a versatile crop with medicinal value, its potential in agroindustry is hindered by incomplete domestication and limited genomic knowledge, impeding the development of competitive breeding programs. The present study aimed to evaluate genetic diversity in a panel of S. marianum accessions (n = 31), previously characterized for morphological and phytochemical traits, using 5,178 polymorphic DArTseq SNP markers. The genetic structure investigated using both parametric and non-parametric approaches (e.g. PCA, AWclust, Admixture), revealed three distinctive groups reflecting geographical origins. Indeed, Pop1 grouped accessions from Central Europe and UK, Pop3 consisted mainly of accessions of Italian origin, and Pop2 included accessions from different geographical areas. Interestingly, Italian genotypes showed a divergent phenotypic distribution, particularly in fruit oleic and linoleic acid content, compared to the other two groups. Genetic differentiation among the three groups, investigated by computing pairwise fixation index (FST), confirmed a greater differentiation of Pop3 compared to other subpopulations, also based on other diversity indices (e.g. private alleles, heterozygosity). Finally, 22 markers were declared as putatively under natural selection, of which seven significantly affected some important phenotypic traits such as oleic, arachidonic, behenic and linoleic acid content. These findings suggest that these markers, and overall, the seven SNP markers identified within Pop3, could be exploited in specific breeding programs, potentially aimed at diversifying the use of milk thistle. Indeed, incorporating genetic material from Pop3 haplotypes carrying the selected loci into milk thistle breeding populations might be the basis for developing milk thistle lines with higher levels of oleic, arachidonic, and behenic acids, and lower levels of linoleic acid, paving new avenues for enhancing the nutritional and agronomic characteristics of milk thistle.

How does climate change impact social bees and bee sociality?

Climatic factors are known to shape the expression of social behaviours. Likewise, variation in social behaviour can dictate climate responses. Understanding interactions between climate and sociality is crucial for forecasting vulnerability and resilience to climate change across animal taxa. These interactions are particularly relevant for taxa like bees that exhibit a broad diversity of social states. An emerging body of literature aims to quantify bee responses to environmental change with respect to variation in key functional traits, including sociality. Additionally, decades of research on environmental drivers of social evolution may prove fruitful for predicting shifts in the costs and benefits of social strategies under climate change. In this review, we explore these findings to ask two interconnected questions: (a) how does sociality mediate vulnerability to climate change, and (b) how might climate change impact social organisation in bees? We highlight traits that intersect with bee sociality that may confer resilience to climate change (e.g. extended activity periods, diet breadth, behavioural thermoregulation) and we generate predictions about the impacts of climate change on the expression and distribution of social phenotypes in bees. The social evolutionary consequences of climate change will be complex and heterogeneous, depending on such factors as local climate and plasticity of social traits. Many contexts will see an increase in the frequency of eusocial nesting as warming temperatures accelerate development and expand the temporal window for rearing a worker brood. More broadly, climate-mediated shifts in the abiotic and biotic selective environments will alter the costs and benefits of social living in different contexts, with cascading impacts at the population, community and ecosystem levels.

Sexual color ornamentation, microhabitat choice, and thermal physiology in the common wall lizard (Podarcis muralis).

Common wall lizards (Podarcis muralis) in Italy show a striking variation in body coloration across the landscape, with highly exaggerated black and green colors in hot and dry climates and brown and white colors in cool and wet climates. Males are more intensely colored than females, and previous work has suggested that the maintenance of variation in coloration across the landscape reflects climatic effects on the strength of male-male competition, and through this sexual selection. However climatic effects on the intensity of male-male competition would need to be exceptionally strong to fully explain the geographic patterns of color variation. Thus, additional processes may contribute to the maintenance of color variation. Here we test the hypothesis that selection for green and black ornamentation in the context of male-male competition is opposed by selection against ornamentation because the genes involved in the regulation of coloration have pleiotropic effects on thermal physiology, such that ornamentation is selected against in cool climates. Field observations revealed no association between body coloration and microhabitat use or field active body temperatures. Consistent with these field data, lizards at the extreme ends of the phenotypic distribution for body coloration did not show any differences in critical minimum temperature, preferred body temperature, temperature-dependent metabolic rate, or evaporative water loss when tested in the laboratory. Combined, these results provide no evidence that genes that underlie sexual ornamentation are selected against in cool climate because of pleiotropic effects on thermal biology.

Blood Lipoproteins Shape the Phenotype and Lipid Content of Early Atherosclerotic Lesion Macrophages: A Dual-Structured Mathematical Model

Macrophages in atherosclerotic lesions exhibit a spectrum of behaviours or phenotypes. The phenotypic distribution of monocyte-derived macrophages (MDMs), its correlation with MDM lipid content, and relation to blood lipoprotein densities are not well understood. Of particular interest is the balance between low density lipoproteins (LDL) and high density lipoproteins (HDL), which carry bad and good cholesterol respectively. To address these issues, we have developed a mathematical model for early atherosclerosis in which the MDM population is structured by phenotype and lipid content. The model admits a simpler, closed subsystem whose analysis shows how lesion composition becomes more pathological as the blood density of LDL increases relative to the HDL capacity. We use asymptotic analysis to derive a power-law relationship between MDM phenotype and lipid content at steady-state. This relationship enables us to understand why, for example, lipid-laden MDMs have a more inflammatory phenotype than lipid-poor MDMs when blood LDL lipid density greatly exceeds HDL capacity. We show further that the MDM phenotype distribution always attains a local maximum, while the lipid content distribution may be unimodal, adopt a quasi-uniform profile or decrease monotonically. Pathological lesions exhibit a local maximum in both the phenotype and lipid content MDM distributions, with the maximum at an inflammatory phenotype and near the lipid content capacity respectively. These results illustrate how macrophage heterogeneity arises in early atherosclerosis and provide a framework for future model validation through comparison with single-cell RNA sequencing data.

Genome-wide discovery for biomarkers using quantile regression at biobank scale

Genome-wide association studies (GWAS) for biomarkers important for clinical phenotypes can lead to clinically relevant discoveries. Conventional GWAS for quantitative traits are based on simplified regression models modeling the conditional mean of a phenotype as a linear function of genotype. We draw attention here to an alternative, lesser known approach, namely quantile regression that naturally extends linear regression to the analysis of the entire conditional distribution of a phenotype of interest. Quantile regression can be applied efficiently at biobank scale, while having some unique advantages such as (1) identifying variants with heterogeneous effects across quantiles of the phenotype distribution; (2) accommodating a wide range of phenotype distributions including non-normal distributions, with invariance of results to trait transformations; and (3) providing more detailed information about genotype-phenotype associations even for those associations identified by conventional GWAS. We show in simulations that quantile regression is powerful across both homogeneous and various heterogeneous models. Applications to 39 quantitative traits in the UK Biobank demonstrate that quantile regression can be a helpful complement to linear regression in GWAS and can identify variants with larger effects on high-risk subgroups of individuals but with lower or no contribution overall.

Transmission of Norwegian reindeer CWD to sheep by intracerebral inoculation results in an unusual phenotype and prion distribution

Chronic wasting disease (CWD), a prion disease affecting cervids, has been known in North America (NA) since the 1960s and emerged in Norway in 2016. Surveillance and studies have revealed that there are different forms of CWD in Fennoscandia: contagious CWD in Norwegian reindeer and sporadic CWD in moose and red deer. Experimental studies have demonstrated that NA CWD prions can infect various species, but thus far, there have been no reports of natural transmission to non-cervid species. In vitro and laboratory animal studies of the Norwegian CWD strains suggest that these strains are different from the NA strains. In this work, we describe the intracerebral transmission of reindeer CWD to six scrapie-susceptible sheep. Detection methods included immunohistochemistry (IHC), western blot (WB), enzyme-linked immunosorbent assay (ELISA), real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA). In the brain, grey matter vacuolation was limited, while all sheep exhibited vacuolation of the white matter. IHC and WB conventional detection techniques failed to detect prions; however, positive seeding activity with the RT-QuIC and PMCA amplification techniques was observed in the central nervous system of all but one sheep. Prions were robustly amplified in the lymph nodes of all animals, mainly by RT-QuIC. Additionally, two lymph nodes were positive by WB, and one was positive by ELISA. These findings suggest that sheep can propagate reindeer CWD prions after intracerebral inoculation, resulting in an unusual disease phenotype and prion distribution with a low amount of detectable prions.

Diversity, virulence and antibiotic resistance of Vibrio Harveyi clade species associated with bivalve aquaculture within marine protected areas

The aim of the present study was to investigate the diversity, distribution of virulence factor genes and antimicrobial resistance phenotypes of Vibrio Harveyi clade species from two distinct and spatially distant near-shore bivalve farming environments located in protected marine reserves of the eastern Adriatic. Tissues of farmed Mediterranean mussel Mytilus galloprovincialis and European flat oyster Ostrea edulis, seawater and sediment samples were collected during six bi-monthly sampling events conducted over one year from farming locations in Lim Bay and Mali Ston Bay, Croatia. Eight distinctive Harveyi subclades, namely, V. harveyi, V. alginolyticus, V. diabolicus, V. jasicida, V. parahaemolyticus, V. rotiferianus, V. campbellii and V. communis, were detected by Phylogenetic Multilocus Sequence Analysis (MLSA) based on rpoD, toxR and rctB concatenated genes sequences. Genomic fingerprinting of MLSA-classified samples revealed substantial diversity of environmental isolates. The virulence-related genes considered typical for the Harveyi clade and their homologues were represented in all subclades with varying frequencies. Of twelve antibiotics commonly used in human and veterinary medicine, the most frequent resistance phenotypes were resistance to ampicillin (90%), erythromycin (39%), imipenem (29%) and streptomycin (22%). >60% of isolates were resistant to at least two classes of antibiotics. Seasonal or site-specific differences were found in the proportion of isolates carrying virulence genes and displaying specific antibiotic resistance phenotype.This study is the first to provide a broader perspective on the properties of Vibrio Harveyi clade species associated with ecosystems under presumably low anthropogenic pressures, such as marine protected areas. New data on virulence and antibiotic resistance are presented of Harveyi clade species coexisting in different environmental compartments, including those that have been largely overlooked or understudied in the context of bivalve aquaculture. Taken together, these results highlight the importance of monitoring the presence of potentially pathogenic strains in the natural Vibrio population of bivalve farming areas to reduce the risk to seafood consumers.