Allele frequency dynamics under sex-biased demography and sex-specific inheritance in a pedigreed jay population.

Sex-biased demography, including sex-biased survival or migration, can alter allele frequency changes across the genome. In particular, we can expect different patterns of genetic variation on autosomes and sex chromosomes due to sex-specific differences in life histories, as well as differences in effective population size, transmission modes, and the strength and mode of selection. Here, we demonstrate the role that sex differences in life history played in shaping short-term evolutionary dynamics across the genome. We used a 25-year pedigree and genomic dataset from a long-studied population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of sex-biased demography and inheritance in shaping genome-wide allele frequency trajectories. We used gene dropping simulations to estimate individual genetic contributions to future generations and to model drift and immigration on the known pedigree. We quantified differential expected genetic contributions of males and females over time, showing the impact of sex-biased dispersal in a monogamous system. Due to female-biased dispersal, more autosomal variation is introduced by female immigrants. However, due to male-biased transmission, more Z variation is introduced by male immigrants. Finally, we partitioned the proportion of variance in allele frequency change through time due to male and female contributions. Overall, most allele frequency change is due to variance in survival and births. Males and females make similar contributions to autosomal allele frequency change, but males make higher contributions to allele frequency change on the Z chromosome. Our work shows the importance of understanding sex-specific demographic processes in characterizing genome-wide allele frequency change in wild populations.

Impacts of increasing isolation and environmental variation on Florida Scrub-Jay demography.

Isolation caused by anthropogenic habitat fragmentation and degradation can destabilize populations. Population demography is shaped by complex interactions among local vital rates, environmental fluctuations, and changing immigration rates. Empirical studies of these interactions are critical for testing theoretical expectations of how populations respond to isolation. We used a 34-year demographic and environmental dataset from a population of Florida Scrub-Jays ( Aphelocoma coerulescens ) that has experienced declining immigration to create mechanistic models linking environmental factors and variation in vital rates to population growth rates over time. We found that the population has remained stable despite declining immigration and increasing inbreeding, owing to a coinciding increase in breeder survival. We find evidence of density-dependent responses of immigration, breeder survival, and fecundity, indicating that interactions between vital rates and local density likely play a role in buffering the population against change. Our study elucidates the interactions between environment and demography that underlie population stability.

Sitravatinib combined with PD-1 blockade enhances cytotoxic T-cell infiltration by M2 to M1 tumor macrophage repolarization in esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a leading cause of cancer-related mortality. Sitravatinib is a novel multi-gene tyrosine kinase inhibitor (TKI) that targets tumor-associated macrophage (TAM) receptors, VEGF, PDGF and c-Kit. Currently, sitravatinib is actively being studied in clinical trials across solid tumors and other TKIs have shown efficacy in combination with immune checkpoint inhibitors (ICI) in cancer models. In this study, we investigated the anti-tumor activity of sitravatinib alone and in combination with PD-1 blockade in an EAC rat model. Treatment response was evaluated by mortality, pre- and post-treatment MRI, gene expression, immunofluorescence and immunohistochemistry. Our results demonstrated adequate safety and significant tumor shrinkage in animals treated with sitravatinib, and more profoundly, sitravatinib and PD-1 inhibitor, AUNP-12 (P < 0.01). Suppression of TAM receptors resulted in increased gene expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines, enhanced infiltration of CD8+ T cells, and M2 to M1 macrophage phenotype repolarization in the tumor microenvironment of treated animals (P < 0.01). Moreover, endpoint immunohistochemistry staining corroborated the anti-tumor activity by downregulation of Ki67 and upregulation of Caspase-3 in the treated animals. Additionally, pretreatment gene expression of TAM receptors and PD-L1 were significantly higher in major responders compared with the non-responders, in animals that received sitravatinib and AUNP-12 (P < 0.02), confirming that TAM suppression enhances the efficacy of PD-1 blockade. In conclusion, this study proposes a promising immunomodulatory strategy using a multi-gene TKI to overcome developed resistance to an ICI in EAC, establishing rationale for future clinical development.

Correction: Batch-produced, GIS-informed range maps for birds based on provenanced, crowd-sourced data inform conservation assessments.

[This corrects the article DOI: 10.1371/journal.pone.0259299.].

Factors Associated With Chronic Pain Intensity in U.S. Army Soldiers.

INTRODUCTION: Chronic pain is prevalent among U.S. military personnel and veterans. The effectiveness of evidence-based pain treatments can be boosted with knowledge of factors associated with chronic pain perception. This study examined the factors that influence soldiers' self-rating of their chronic pain intensity. MATERIALS AND METHODS: The study design was a retrospective review of the intake questionnaire from 203 soldiers seen at an Interdisciplinary Pain Management Center. The intake covered various aspects of soldiers' chronic pain experience, including pain intensity, interference in functioning, emotional sequelae, and pain-related catastrophic thinking. Pain intensity and impact were measured using the Defense and Veterans Pain Rating Scale. The mood was measured using the depression (Patient Health Questionnaire [PHQ]-9) and the anxiety (Generalized Anxiety Disorder-7) scales from the PHQ. Pain-related catastrophic thinking was measured using the Pain Catastrophizing Scale (PCS). Pain interference was assessed using a five-item scale that inquired about concentration, life and recreation enjoyment, task performance, and socializing. Data were analyzed using descriptive statistics and linear regression analyses. RESULTS: The mean duration of pain was 34.73 ± 38.66 months. Regression analysis using scores from the PHQ-9, Generalized Anxiety Disorder-7, three PCS subscales (rumination, magnification, and helplessness), and pain interference scale as predictors showed that pain interference and PCS helplessness factors were significant predictors of average pain rating (R2 = 24%, P < .001). CONCLUSIONS: Pain interference in functioning and pain-related thoughts of helplessness accounted for a significant degree of the variance in soldiers' self-rating of their chronic pain. The findings suggest that added attention should be directed at helping patients boost their self-efficacy in using pain-coping methods to improve their functioning and address the perception of helplessness about their pain.

Birmingham Royal Orthopaedic Hospital (BROH) Femoral Offset-An Ancillary Measure of Adult Dysplasia of the Hip.

Introduction Adult dysplasia of the hip (ADH) is a disorder of abnormal development of the hip joint resulting in a shallow acetabulum and uncovering of the femoral head. Several radiological measurements such as the Tönnis angle (acetabular index), lateral center edge angle of Wiberg, and cross-sectional imaging parameters exist to calculate hip dysplasia. Aims The aim of this article was to describe a new ancillary linear measure of ADH on cross-sectional imaging, the Birmingham Royal Orthopaedic Hospital (BROH) Femoral offset. Patients and Methods Anteroposterior radiographs of the pelvis and computed tomography imaging of 100 consecutive patients with suspected hip dysplasia were reviewed. Demographic details and clinical indications were recorded. Tönnis angle was utilized to measure hip slope on radiographs and the BROH femoral offset was calculated for each patient. Student's t -test and one-way analysis of variance (ANOVA) were performed. Intraclass correlation coefficient analysis was evaluated to assess the reliability between observers. Results There was a total of 100 patients (128 hips) included in the study (60 with normal Tönnis angle, 53 had dysplasia, and 15 had decreased Tönnis angle). The average BROH femoral offset in the dysplastic cohort was increased in comparison to the normal cohort with a statistically significant p -Value of 0.0001. The p -value was 0.00031 on ANOVA. The BROH femoral offset calculation revealed good intra- and interobserver reliability of 0.9 and 0.9, respectively. Conclusion The BROH femoral offset can be an additional index for measuring ADH that is easier to calculate, and reproducible with good intra- and inter-observer reliability on cross-sectional imaging.

Short-tailed shearwater (Ardenna tenuirostris) plastic loads and particle dimensions exhibit spatiotemporal similarity in the Pacific Ocean.

Short-tailed shearwater (Ardenna tenuirostris) stomach contents provide some of the earliest documentation of oceanic plastic pollution, one of the longer data series of seabird stomach samples, and the species' wide range in the North and South Pacific provides comparative data for the Pacific Ocean. A mortality event in the North Pacific in 2019 provided additional data for spatiotemporal comparisons. In the North Pacific the percent occurrence, mass, and number of pieces were similar since the first records in the 1970s. Particle size increased slightly reflecting a transition from uniform pre-manufactured pellets in initial reports to irregular user fragments in recent reports. Contemporary North and South Pacific plastic loads and particle dimensions were similar. A lack of temporal or spatial difference affirms previous conclusions that plastic retained in short-tailed shearwaters and other Procellariiformes is related to body size, gastrointestinal structure, and species' preferences rather than the availability of oceanic plastic.

Examining the potential for resource-dependent female reproductive fluid-sperm interactive effects in a livebearing fish.

Sexually selected traits can be costly to produce and maintain. The amount of resources available to an individual is therefore expected to influence investment in costly sexual traits. While resource-dependent expression of sexually selected traits has traditionally been examined in males, resource limitation can also influence how sexual selection operates in females. Female reproductive fluids are thought to be costly to produce and may play an important role in shaping the outcome of postcopulatory sexual selection by influencing sperm performance. However, we know surprisingly little about whether and how female reproductive fluids are influenced by resource limitation. Here, we examine if resource restriction influences female reproductive fluid-sperm interactive effects in the pygmy halfbeak (Dermogenys collettei), a small internally fertilizing freshwater fish where females store sperm. After experimentally altering female diets (high vs. restricted diets), we compared how female reproductive fluids influence two key metrics of sperm quality: sperm viability and velocity. While female reproductive fluids enhanced sperm viability and velocity, we found no evidence that female diet influenced the interactive effect between female reproductive fluids and sperm viability or velocity. Our findings build on the growing evidence that female reproductive fluids influence sperm performance and call for further attention to be devoted to understanding how resource quantity and quality influence how female reproductive fluids affect sperm performance.

The structure and organisation of an Amazonian bird community remains little changed after nearly four decades in Manu National Park.

Documenting patterns of spatiotemporal change in hyper-diverse communities remains a challenge for tropical ecology yet is increasingly urgent as some long-term studies have shown major declines in bird communities in undisturbed sites. In 1982, Terborgh et al. quantified the structure and organisation of the bird community in a 97-ha. plot in southeastern Peru. We revisited the same plot in 2018 using the same methodologies as the original study to evaluate community-wide changes. Contrary to longitudinal studies of other neotropical bird communities (Tiputini, Manaus, and Panama), we found little change in community structure and organisation, with increases in 5, decreases in 2 and no change in 7 foraging guilds. This apparent stability suggests that large forest reserves such as the Manu National Park, possibly due to regional topographical influences on precipitation, still provide the conditions for establishing refugia from at least some of the effects of global change on bird communities.

Infection after ureteroscopy for ureteric stones: analysis of 71 305 cases in the Hospital Episode Statistics database.

OBJECTIVES: To investigate the burden of infectious complications following ureteroscopy (URS) for ureteric stones on a national level in England using data from the Hospital Episodes Statistics (HES) data warehouse. MATERIALS AND METHODS: A retrospective cohort was identified and followed up in HES during the period April 2013 to March 2020 for all procedure codes relating to ureteroscopic stone treatment (M27.1, M27.2, M27.3). Treatment episodes relating to the first URS ('index ureteroscopy') for each patient were further analysed. All subsequent admissions within 30 days were also captured. The primary outcome was diagnosis of urinary tract infection (UTI; including all codes relating to a UTI/sepsis within the first 30 days of index URS). Secondary outcomes were critical care attendance, attendance at the accident and emergency department (A&E) within 30 days, and mortality. RESULTS: A total of 71 305 index ureteroscopies were eligible for analysis. The median age was 55 years, and 81% of procedures were elective and 45% were undertaken as day-cases. At the time of index URS, 16% of patients had diabetes, 0.5% had coexisting neurological disease and 40% had an existing stent/nephrostomy. Overall, 6.8% of the cohort (n = 4822) had a diagnosis of UTI within 30 days of index URS (3.9% immediately after surgery). A total of 339 patients (0.5%) required an unplanned stay in critical care during their index URS admission; 8833 patients (12%) attended A&E within 30 days. Overall mortality was 0.18% (60 in-hospital, 65 within 30 days); 40 deaths (0.056%) included infection as a contributing cause of death. CONCLUSION: We present the largest series evaluating infectious complications after ureteroscopic stone treatment. The procedure is safe, with low inpatient infective complication and critical care admission rates.

Resource-dependent investment in male sexual traits in a viviparous fish.

Exaggerated and conspicuous sexually selected traits are often costly to produce and maintain. Costly traits are expected to show resource-dependent expression, since limited resources prevent animals from investing maximally in multiple traits simultaneously. However, there may be critical periods during an individual's life where the expression of traits is altered if resources are limited. Moreover, costly sexual traits may arise from sexual selection acting both before (pre-copulatory) and after mating (post-copulatory). Gaining a robust understanding of resource-dependent trait expression therefore requires an approach that examines both episodes of sexual selection after resource limitation during different times in an individual's life. Yet few studies have taken such an approach. Here, we examine how resource restriction influences a set of pre- and post-copulatory traits in male pygmy halfbeaks (Dermogenys collettei), which invest in sexual ornaments and routinely engage in male-male contests and sperm competition. Critically, we examined responses in males when resources were restricted during development and after reaching sexual maturity. Both pre- and post-copulatory traits are resource-dependent in male halfbeaks. Body size, beak size, courtship behavior, and testes size were reduced by diet restriction, while, unexpectedly, the restricted-diet group had a larger area of red color on the beak and fins after diet treatment. These patterns were generally consistent when resources were restricted during development and after reaching sexual maturity. The study reinforces the role of resource acquisition in maintaining variation among sexual traits.

Fertilization mode differentially impacts the evolution of vertebrate sperm components.

Environmental change frequently drives morphological diversification, including at the cellular level. Transitions in the environment where fertilization occurs (i.e., fertilization mode) are hypothesized to be a driver of the extreme diversity in sperm morphology observed in animals. Yet how fertilization mode impacts the evolution of sperm components-head, midpiece, and flagellum-each with different functional roles that must act as an integrated unit remains unclear. Here, we test this hypothesis by examining the evolution of sperm component lengths across 1103 species of vertebrates varying in fertilization mode (external vs. internal fertilization). Sperm component length is explained in part by fertilization mode across vertebrates, but how fertilization mode influences sperm evolution varies among sperm components and vertebrate clades. We also identify evolutionary responses not influenced by fertilization mode: midpieces evolve rapidly in both external and internal fertilizers. Fertilization mode thus influences vertebrate sperm evolution through complex component- and clade-specific evolutionary responses.

Investigation of breakage behavior and its effects on spray-dried agglomerated whey protein-lactose powders: Effect of protein and lactose contents.

Particle breakage of dairy powders occurs easily during many processes, reducing the powder functionality. The characteristics of particles and the applied stress from processing conditions on the particles are 2 main factors that can be manipulated to reduce breakage. In this study, we explored the effect of whey protein and lactose contents on dynamic breakage in agglomerated whey protein-lactose powders to provide useful information, in terms of particle characteristics, for controlling unwanted dairy powder breakage. A series of model agglomerates with different whey protein:lactose ratios were produced under the same spray-drying conditions, through a pilot plant trial. We evaluated physical characteristics, composition, and structure of samples; analyzed dynamic breakage under different mechanical stresses; and investigated the rehydration and water adsorption properties of model powders before and after breakage. The particle size and irregularity of agglomerates with more lactose was significantly higher than of samples that contained more protein. This resulted in higher particle breakage during dynamic breakage for samples with more lactose. The breakage of agglomerates was affected by the moisture content of powders and fatigue, where particle breakage happens when mechanical loads, lower than the strength of particles, occur multiple times. Breakage changed the morphology and surface composition of particles and decreased particle size. It also decreased the dispersibility of powders and increased the wetting time of wettable samples but decreased the wetting time of powders with poor wettability. Breakage accelerated time-dependent crystallization and decreased the crystallization temperature but did not affect the glass transition temperature of samples. Thus, under the same drying conditions, composition of powders significantly affected breakage, mainly by altering the physical properties of their particles, which resulted in deteriorated functionality.

Dynamics of reduced genetic diversity in increasingly fragmented populations of Florida scrub jays,Aphelocoma coerulescens.

Understanding the genomic consequences of population decline is important for predicting species' vulnerability to intensifying global change. Empirical information about genomic changes in populations in the early stages of decline, especially for those still experiencing immigration, remains scarce. We used 7834 autosomal SNPs and demographic data for 288 Florida scrub jays (Aphelocoma coerulescens; FSJ) sampled in 2000 and 2008 to compare levels of genetic diversity, inbreeding, relatedness, and lengths of runs of homozygosity (ROH) between two subpopulations within dispersal distance of one another but have experienced contrasting demographic trajectories. At Archbold Biological Station (ABS), the FSJ population has been stable because of consistent habitat protection and management, while at nearby Placid Lakes Estates (PLE), the population declined precipitously due to suburban development. By the onset of our sampling in 2000, birds in PLE were already less heterozygous, more inbred, and on average more related than birds in ABS. No significant changes occurred in heterozygosity or inbreeding across the 8-year sampling interval, but average relatedness among individuals decreased in PLE, thus by 2008 average relatedness did not differ between sites. PLE harbored a similar proportion of short ROH but a greater proportion of long ROH than ABS, suggesting one continuous population of shared demographic history in the past, which is now experiencing more recent inbreeding. These results broadly uphold the predictions of simple population genetic models based on inferred effective population sizes and rates of immigration. Our study highlights how, in just a few generations, formerly continuous populations can diverge in heterozygosity and levels of inbreeding with severe local population decline despite ongoing gene flow.

Are behavioral responses to eyespots in sticklebacks influenced by the visual environment? An experimental examination.

Eyespots are taxonomically widespread color patterns consisting of large concentric rings that are commonly assumed to protect prey by influencing the behaviors of predators. Although there is ample experimental evidence supporting an anti-predator function of eyespots in terrestrial animals, whether eyespots have a similar deterring function in aquatic animals remains unclear. Furthermore, studies in terrestrial systems suggest that the protective function of eyespots depends on ambient light conditions where predators encounter them, but this effect has never been tested in aquatic environments. Here, we examine how eyespots influence behavioral responses in an aquatic environment under different visual environments, using laboratory-reared three-spined sticklebacks (Gasterosteus aculeatus) as model predators. Specifically, we experimentally examined behavioral responses of sticklebacks toward artificial prey patterns (control vs. eyespots) under two different light environment treatments (low vs. high). We found that eyespots did not postpone attacks from sticklebacks. However, sticklebacks approaching eyespots stopped more frequently than sticklebacks approaching prey items with a control pattern. Sticklebacks were (marginally) slower to attack prey in the low-light treatment, but the light level did not influence stickleback behavioral responses toward eyespots. We conclude that eyespots can modulate some behaviors of an aquatic predator, albeit with a different functional role from that previously demonstrated in terrestrial species.

Breakage behaviour and functionality of spray-dried agglomerated model infant milk formula: Effect of proteins and carbohydrates content.

This study explored the effect of protein content (whey protein and casein) and carbohydrate content (lactose, sucrose, and maltodextrin) on the breakage behaviour and its influence on spray-dried agglomerated model infant milk formula. Whey protein powders were bigger in particle size, weaker in structural strength, and marginally more irregular in shape, which resulted in better rehydration properties but more breakage than pure casein powders. Similarly, sucrose samples had better rehydration properties and higher glass transition temperatures but suffered more breakage than maltodextrin and pure lactose powders because of their bigger particle size. The influence of proteins on breakage was greater than that of carbohydrates. Breakage changed the physical and structural properties of powders, especially for whey protein and sucrose samples, which caused the deterioration of rehydration properties and the decrease in crystallization temperatures. From the perspective of particle breakage, unwanted dairy powder breakage could be controlled by changing powder formulations.

The Linear Hallux Valgus Offset- A novel way to measure Hallux Valgus.

Introduction: Hallux Valgus (HV) is a complex deformity involving the first ray of the forefoot and a common cause of forefoot pain. Several radiological measurements such as Hallux Valgus Angle (HVA), First Metatarsophalangeal Angle (IMA) and Distal metatarsal articular angle (DMAA) exist to calculate the severity of HV and direct patient management. However, these are angular measurements are prone to error with variable intra- and inter-observer reliability. Purpose: To describe a new radiological linear hallux valgus offset (LHVO) to measure HV deformity. Patient and methods: We performed a retrospective cohort study looking at Antero-posterior, weight-bearing foot radiographs of 100 consecutive patients with forefoot pain referred to our foot and ankle clinic. Demographic details, clinical indication, HVA (hallux valgus angle) and LHVO were measured for each patient and data were analyzed using the student t-test. Intraclass Correlation Coefficient (ICC) analysis was evaluated to assess the intra-class reliability between observers. Results: There was a female predominance of approximately 2:1, with 51.3 years (range 13-86 years). There was a statistically significant difference of LHVO between normal and hallux valgus cohorts with a p-value of 0.0001. The LHVO gave moderate intra-observer and inter-observer reliability on ICC analysis of 0.7. Conclusion: The LHVO can be an additional measure of assessing severity of hallux valgus. In contrary to the traditional angular measurements, this linear measure is easier to calculate and reproducible on plain, weight bearing radiographs. LHVO measurement has shown a moderate inter-observer reliability in the study to complement traditional radiological evaluation of hallux valgus alignment.

Botanically-Derived Δ9-Tetrahydrocannabinol and Cannabidiol, and Their 1:1 Combination, Modulate Toll-like Receptor 3 and 4 Signalling in Immune Cells from People with Multiple Sclerosis.

The innate immune response to bacterial and viral molecules involves the coordinated production of cytokines, chemokines, and type I interferons (IFNs), which is orchestrated by toll-like receptors (TLRs). TLRs, and their intracellular signalling intermediates, are closely associated with multiple sclerosis (MS) pathogenesis. Recent data from our laboratory reported that the plant-derived cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), regulate viral and bacterial inflammatory signalling pathways controlled by TLR3 and TLR4 in macrophages. The aim of this study was to assess the impact of THC and CBD, when delivered in isolation and in combination (1:1), on TLR3- and TLR4-dependent signalling in peripheral blood mononuclear cells (PBMCs) from people with MS (pwMS; n = 21) and healthy controls (HCs; n = 26). We employed the use of poly(I:C) and lipopolysaccharide (LPS) to induce viral TLR3 and bacterial TLR4 signalling, and PBMCs were pre-exposed to plant-derived highly purified THC (10 µM), CBD (10 µM), or a combination of both phytocannabinoids (1:1 ratio, 10:10 µM), prior to LPS/poly(I:C) exposure. TLR3 stimulation promoted the protein expression of the chemokine CXCL10 and the type I IFN-ß in PBMCs from both cohorts. THC and CBD (delivered in 1:1 combination at 10 µM) attenuated TLR3-induced CXCL10 and IFN-ß protein expression in PBMCs from pwMS and HCs, and this effect was not seen consistently when THC and CBD were delivered alone. In terms of LPS, TLR4 activation promoted TNF-α expression in PBMCs from both cohorts, and, interestingly, CBD when delivered alone at 10 µM, and in combination with THC (in 1:1 combination at 10 µM), exacerbated TLR4-induced TNF-α protein expression in PBMCs from pwMS and HCs. THC and CBD displayed no evidence of toxicity in primary PBMCs. No significant alteration in the relative expression of TLR3 and TLR4 mRNA, or components of the endocannabinoid system, including the cannabinoid receptor CB1 (encoded by CNR1 gene) and CB2 (encoded by CNR2 gene), and endocannabinoid metabolising enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGLL), was determined in PBMCs from pwMS versus HCs. Given their role in inflammation, TLRs are clinical targets, and data herein identify CBD and THC as TLR3 and TLR4 modulating drugs in primary immune cells in vitro. This offers insight on the cellular target(s) of phytocannabinoids in targeting inflammation in the context of MS.