Increased genetic diversity and immigration after West Nile virus emergence in American crows: No evidence for a genetic bottleneck.

Infectious diseases can cause steep declines in wildlife populations, leading to changes in genetic diversity that may affect the susceptibility of individuals to infection and the overall resilience of populations to pathogen outbreaks. Here, we examine evidence for a genetic bottleneck in a population of American crows (Corvus brachyrhynchos) before and after the emergence of West Nile virus (WNV). More than 50% of marked birds in this population were lost over the 2-year period of the epizootic, representing a 10-fold increase in adult mortality. Using analyses of single-nucleotide polymorphisms (SNPs) and microsatellite markers, we tested for evidence of a genetic bottleneck and compared levels of inbreeding and immigration in the pre- and post-WNV populations. Counter to expectations, genetic diversity (allelic diversity and the number of new alleles) increased after WNV emergence. This was likely due to increases in immigration, as the estimated membership coefficients were lower in the post-WNV population. Simultaneously, however, the frequency of inbreeding appeared to increase: Mean inbreeding coefficients were higher among SNP markers, and heterozygosity-heterozygosity correlations were stronger among microsatellite markers, in the post-WNV population. These results indicate that loss of genetic diversity at the population level is not an inevitable consequence of a population decline, particularly in the presence of gene flow. The changes observed in post-WNV crows could have very different implications for their response to future pathogen risks, potentially making the population as a whole more resilient to a changing pathogen community, while increasing the frequency of inbred individuals with elevated susceptibility to disease.

Combining Species Delimitation, Species Trees, and Tests for Gene Flow Clarifies Complex Speciation in Scrub-Jays.

Complex speciation, involving rapid divergence and multiple bouts of post-divergence gene flow, can obfuscate phylogenetic relationships and species limits. In North America, cases of complex speciation are common, due at least in part to the cyclical Pleistocene glacial history of the continent. Scrub-Jays in the genus Aphelocoma provide a useful case study in complex speciation because their range throughout North America is structured by phylogeographic barriers with multiple cases of secondary contact between divergent lineages. Here, we show that a comprehensive approach to genomic reconstruction of evolutionary history, i.e., synthesizing results from species delimitation, species tree reconstruction, demographic model testing, and tests for gene flow, is capable of clarifying evolutionary history despite complex speciation. We find concordant evidence across all statistical approaches for the distinctiveness of an endemic southern Mexico lineage (A. w. sumichrasti), culminating in support for the species status of this lineage under any commonly applied species concept. We also find novel genomic evidence for the species status of a Texas endemic lineage A. w. texana, for which equivocal species delimitation results were clarified by demographic modeling and spatially explicit models of gene flow. Finally, we find that complex signatures of both ancient and modern gene flow between the non-sister California Scrub-Jay (Aphelocoma californica) and Woodhouse's Scrub-Jay (Aphelocoma woodhouseii) result in discordant gene trees throughout the species' genomes despite clear support for their overall isolation and species status. In sum, we find that a multi-faceted approach to genomic analysis can increase our understanding of complex speciation histories, even in well-studied groups. Given the emerging recognition that complex speciation is relatively commonplace, the comprehensive framework that we demonstrate for interrogation of species limits and evolutionary history using genomic data can provide a necessary roadmap for disentangling the impacts of gene flow and incomplete lineage sorting (ILS) to better understand the systematics of other groups with similarly complex evolutionary histories. [Gene flow; genomics; introgression; phylogenomics; population genetics; species delimitation; species trees; systematics.].

The Pain Clinic for Older People.

OBJECTIVE: Multidisciplinary pain clinics have an established role in the management of persistent pain, but there is little evidence to support this approach in an older population. This study describes the characteristics and pain outcomes of patients attending a pain clinic designed exclusively for older people. METHODS: A retrospective audit was performed of outcomes of the Pain Clinic for Older People (PCOP) in 2015-2019. Response to treatment was determined by change in Brief Pain Inventory (BPI) scores at initial attendance and after a treatment program. Clinically meaningful improvement was defined by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus criteria of ≥30% improvement in average pain and one-point improvement in pain interference. Results were compared with the national benchmark collated by the electronic Persistent Pain Outcomes Collaboration (ePPOC), which reports the combined results from 67 participating Australian and New Zealand pain services. RESULTS: Patients attending the PCOP had a mean age of 80.5 years and had high rates of frailty (84%), cognitive impairment (30%), and multimorbidity. Significant reductions in BPI average pain and BPI pain interference scores were achieved. Clinically meaningful improvement in BPI average pain was achieved in 63% of patients attending the PCOP who were 65-74 years of age and in 46% of patients who were ≥75 years of age, which met the national benchmark set by ePPOC of 40% for both age groups. Clinically meaningful improvement in BPI pain interference was achieved in 69% of those attending the PCOP who were 65-74 years of age and in 66% of those who were ≥75 years of age, comparable to the ePPOC benchmark of 71% and 65% for the respective age groups. CONCLUSION: PCOP clients achieved significant and meaningful improvements in their pain outcomes that satisfied the national benchmark. Advanced age, cognitive impairment, frailty and multimorbidity should not be regarded as barriers to benefit from a pain clinic specifically designed for older people.

Impact of oral/dental disease burden on postoperative infective complications: a prospective cohort study.

OBJECTIVES: This prospective cohort study aimed to assess the association between dental disease burden and postoperative infective complications (POICs) in patients undergoing major surgical procedures under general anaesthesia. METHODS: Pre-surgical dental assessment was undertaken on patients planned for major surgery. Demographic and surgical variables including putative risk factors for POICs and POIC status were documented. The univariable association between POIC status and each factor was examined. Those variables associated at P value ≤ 0.2 were candidates for inclusion in multiple logistic regression models. Backward stepwise variable selection was used to identify the independent predictors for POIC in the best fitting logistic regression model. The area under the receiver operating curve (AUC) was used to quantify the model's global classification performance. RESULTS: Among the 285 patients, 49 patients (17.2%) had POICs. The independent predictors for POIC were expected length of hospital stay (4-6 days; odds ratio [OR] = 4.80, 95% confidence internal [CI]: 1.30-17.70, P = 0.018, 7-9 days; OR = 5.42, 95% CI: 1.51-19.41, P = 0.009, ≥ 10 days; OR = 28.80, 95% CI: 4.12-201.18, P < 0.001), four or more decayed teeth (OR = 6.03, 95% CI: 2.28-15.94, P < 0.001) and visible tongue plaque (OR = 3.21, 95% CI: 1.54-6.70, P = 0.002). The AUC was 0.78 (95% CI: 0.71-0.85) indicating good discrimination. A simple screening tool for POIC was developed. CONCLUSIONS/CLINICAL RELEVANCE: In addition to systemic/surgical factors, this study identified clinically detected decayed teeth and visible tongue plaque as independent predictors for POICs. Preoperative dental assessment/care might be beneficial to assess risk for POICs and improve postoperative outcomes.

Nature, Data, and Power: How Hegemonies Shaped This Special Section.

AbstractSystems of oppression-racism, colonialism, misogyny, cissexism, ableism, heteronormativity, and more-have long shaped the content and practice of science. But opportunities to reckon with these influences are rarely found within academic science, even though such critiques are well developed in the social sciences and humanities. In this special section, we attempt to bring cross-disciplinary conversations among ecology, evolution, behavior, and genetics on the one hand and critical perspectives from the social sciences and humanities on the other into the pages-and in front of the readers-of a scientific journal. In this introduction to the special section, we recount and reflect on the process of running this cross-disciplinary experiment to confront harms done in the name of science and envision alternatives.

Taking quantitative genomics into the wild.

We organized this special issue to highlight new work and review recent advances at the cutting edge of 'wild quantitative genomics'. In this editorial, we will present some history of wild quantitative genetic and genomic studies, before discussing the main themes in the papers published in this special issue and highlighting the future outlook of this dynamic field.

Habitat-linked genetic variation supports microgeographic adaptive divergence in an island-endemic bird species.

We investigated the potential mechanisms driving habitat-linked genetic divergence within a bird species endemic to a single 250-km2 island. The island scrub-jay (Aphelocoma insularis) exhibits microgeographic divergence in bill morphology across pine-oak ecotones on Santa Cruz Island, California (USA), similar to adaptive differences described in mainland congeners over much larger geographic scales. To test whether individuals exhibit genetic differentiation related to habitat type and divergence in bill length, we genotyped over 3000 single nucleotide polymorphisms in 123 adult island scrub-jay males from across Santa Cruz Island using restriction site-associated DNA sequencing. Neutral landscape genomic analyses revealed that genome-wide genetic differentiation was primarily related to geographic distance and differences in habitat composition. We also found 168 putatively adaptive loci associated with habitat type using multivariate redundancy analysis while controlling for spatial effects. Finally, two genome-wide association analyses revealed a polygenic basis to variation in bill length with multiple loci detected in or near genes known to affect bill morphology in other birds. Our findings support the hypothesis that divergent selection at microgeographic scales can cause adaptive divergence in the presence of ongoing gene flow.

Indirect Genetic Effects: A Cross-disciplinary Perspective on Empirical Studies.

Indirect genetic effects (IGE) occur when an individual's phenotype is influenced by genetic variation in conspecifics. Opportunities for IGE are ubiquitous, and, when present, IGE have profound implications for behavioral, evolutionary, agricultural, and biomedical genetics. Despite their importance, the empirical study of IGE lags behind the development of theory. In large part, this lag can be attributed to the fact that measuring IGE, and deconvoluting them from the direct genetic effects of an individual's own genotype, is subject to many potential pitfalls. In this Perspective, we describe current challenges that empiricists across all disciplines will encounter in measuring and understanding IGE. Using ideas and examples spanning evolutionary, agricultural, and biomedical genetics, we also describe potential solutions to these challenges, focusing on opportunities provided by recent advances in genomic, monitoring, and phenotyping technologies. We hope that this cross-disciplinary assessment will advance the goal of understanding the pervasive effects of conspecific interactions in biology.

Allele frequency dynamics in a pedigreed natural population.

A central goal of population genetics is to understand how genetic drift, natural selection, and gene flow shape allele frequencies through time. However, the actual processes underlying these changes-variation in individual survival, reproductive success, and movement-are often difficult to quantify. Fully understanding these processes requires the population pedigree, the set of relationships among all individuals in the population through time. Here, we use extensive pedigree and genomic information from a long-studied natural population of Florida Scrub-Jays (Aphelocoma coerulescens) to directly characterize the relative roles of different evolutionary processes in shaping patterns of genetic variation through time. We performed gene dropping simulations to estimate individual genetic contributions to the population and model drift on the known pedigree. We found that observed allele frequency changes are generally well predicted by accounting for the different genetic contributions of founders. Our results show that the genetic contribution of recent immigrants is substantial, with some large allele frequency shifts that otherwise may have been attributed to selection actually due to gene flow. We identified a few SNPs under directional short-term selection after appropriately accounting for gene flow. Using models that account for changes in population size, we partitioned the proportion of variance in allele frequency change through time. Observed allele frequency changes are primarily due to variation in survival and reproductive success, with gene flow making a smaller contribution. This study provides one of the most complete descriptions of short-term evolutionary change in allele frequencies in a natural population to date.

Apocrine Hidrocystoma with IgG4 Plasma Cell Infiltration Presenting as Recurrent Chalazion: A Case Report.

Apocrine hidrocystomas are benign cystic tumors resulting from apocrine sweat glands' proliferation. They typically present as solitary, slow-growing nodules at the head and neck, especially in the periorbital cutaneous region. We present a case of periorbital apocrine hidrocystoma in a 22-year-old woman that was treated as chalazion previously. Besides the hallmark histopathological findings of apocrine hidrocystoma, IgG4 plasma cell infiltration of the cystic wall was also found. The ratio of IgG4-to-IgG-positive plasma cells was high, whereas serum IgG4 was within the standard limit. This is, to date, the only probable IgG4-related ophthalmic disease associated with apocrine hidrocystoma.

Periocular Infection of Mycobacterium avium Complex in a Patient with Interferon-γ Autoantibodies: A Case Report.

The neutralizing anti-interferon-γ autoantibody (nAIGA)-associated immunodeficiency is an emerging entity frequently associated with the nontuberculosis mycobacterium (NTM) infection and other opportunistic infections. We present a female patient with a mysterious periocular Mycobacterium avium complex (MAC) infection, accompanied by sequential opportunistic infections including Salmollelosis and herpes zoster infection. Her condition stabilized after long-term antimycobacterial treatment. Nevertheless, neutralizing anti-interferon-γ autoantibody was found in her serum, which was compatible with the scenario of adult-onset immunodeficiency.

Comparison of adult census size and effective population size support the need for continued protection of two Solomon Island endemics.

Because a population's ability to respond to rapid change is dictated by standing genetic variation, we can better predict a population's long-term viability by estimating and then comparing adult census size (N) and effective population size (N e ). However, most studies only measure N or N e , which can be misleading. Using a combination of field and genomic sequence data, we here estimate and compare N and N e in two range-restricted endemics of the Solomon Islands. Two Zosterops White-eye species inhabit the small island of Kolombangara, with a high elevation species endemic to the island (Z. murphyi) and a low elevation species endemic to the Solomon Islands (Z. kulambangrae). Field observations reveal large values of N for both species with Z. kulambangrae numbering at 114,781 ± 32,233 adults, and Z. murphyi numbering at 64,412 ± 15,324 adults. In contrast, genomic analyses reveal that N e was much lower than N, with Z. kulambangrae estimated at 694.5 and Z. murphyi at 796.1 individuals. Further, positive Tajima's D values for both species suggest that they have experienced a demographic contraction, providing a mechanism for low values of N e . Comparison of N and N e suggests that Z. kulambangrae and Z. murphyi are not at immediate threat of extinction but may be at genetic risk. Our results provide important baseline data for long-term monitoring of these island endemics, and argue for measuring both population size estimates to better gauge long-term population viability.

Identification of Optimal Measures of Human Abuse Potential: A Post Hoc Assessment of 19 Studies.

BACKGROUND: Human abuse potential studies include multiple measures to assess the subjective effects of central nervous system-active drugs. In this retrospective analysis, measurement properties of commonly used measures were assessed, and factor analysis was conducted to identify a core battery of measures. METHODS: Measures of positive, negative and other effects, for example, bipolar "at-the-moment" Drug Liking visual analog scale (VAS), were derived for active controls and placebo from 19 studies in recreational drug users (N = 570). Distribution, placebo response, variability, convergent/discriminant validity, parameter effect sizes (eg, maximum effect [Emax], time-averaged area under the effect curve), and predictive validity were evaluated. A factor analysis was conducted with 9 studies. RESULTS: Most parameters were not normally distributed. Bipolar VAS exhibited the lowest variability. Drug Liking VAS Emax was very sensitive, showed large effect sizes (>1.0), and was moderately to strongly correlated with Emax of other positive effects measures (r > 0.5), but weaker with less specific scales (eg, high, Any Effects VAS); time-averaged area under the effect curve showed higher variability and lower effect sizes. Maximum effect at any dose (EmaxD) was significantly correlated with Emax across all selected measures and showed higher effect sizes. In the overall factor analysis, factors could be categorized into positive effects/euphoria (77% of variance), negative effects (17.9%), and pharmacologic effects (5%). For predictive validity, effect sizes for Drug Liking VAS Emax/EmaxD were moderately correlated with postmarket adverse events related to abuse (R = 0.52). CONCLUSIONS: A core battery of 7 subjective measures was proposed, with additional measures added based on pharmacologic effects.

Soluble guanylate cyclase stimulators for the treatment of hypertension: Discovery of MK-2947.

The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.

Deconstructing isolation-by-distance: The genomic consequences of limited dispersal.

Geographically limited dispersal can shape genetic population structure and result in a correlation between genetic and geographic distance, commonly called isolation-by-distance. Despite the prevalence of isolation-by-distance in nature, to date few studies have empirically demonstrated the processes that generate this pattern, largely because few populations have direct measures of individual dispersal and pedigree information. Intensive, long-term demographic studies and exhaustive genomic surveys in the Florida Scrub-Jay (Aphelocoma coerulescens) provide an excellent opportunity to investigate the influence of dispersal on genetic structure. Here, we used a panel of genome-wide SNPs and extensive pedigree information to explore the role of limited dispersal in shaping patterns of isolation-by-distance in both sexes, and at an exceedingly fine spatial scale (within ~10 km). Isolation-by-distance patterns were stronger in male-male and male-female comparisons than in female-female comparisons, consistent with observed differences in dispersal propensity between the sexes. Using the pedigree, we demonstrated how various genealogical relationships contribute to fine-scale isolation-by-distance. Simulations using field-observed distributions of male and female natal dispersal distances showed good agreement with the distribution of geographic distances between breeding individuals of different pedigree relationship classes. Furthermore, we built coalescent simulations parameterized by the observed dispersal curve, population density, and immigration rate, and showed how incorporating these extensions to Malécot's theory of isolation-by-distance allows us to accurately reconstruct observed sex-specific isolation-by-distance patterns in autosomal and Z-linked SNPs. Therefore, patterns of fine-scale isolation-by-distance in the Florida Scrub-Jay can be well understood as a result of limited dispersal over contemporary timescales.

Mechanical stretch upregulates connexin43 in human trabecular meshwork cells.

BACKGROUND: Primary open angle glaucoma (POAG) patients have hallmark increases in intraocular pressure (IOP) and noted dysfunction of the trabecular meshwork (TM). Connexin43 (Cx43) is a gap junction widely expressed on the TM that is important for intercellular communication. The human gene is known as gap junction alpha-1 (GJA1). Since the role of Cx43 in the TM is not fully understood, we set out to determine the effect of excess mechanical stretch on cultured human trabecular meshwork cells (hTMCs) and to specifically investigate the effect of stretch on Cx43 expression and function. METHODS: Primary hTMCs were cultured and subjected to 48 hours of 15% cyclic mechanical stretch at a frequency of 1 Hz. Levels of apoptosis and necrosis secondary to stretch were investigated using colorimetric assays. The effect of stretch on gap junction Cx43 and GJA1 was investigated by RT-PCR, immunoblotting and immunofluorescence. The migration of Lucifer Yellow dye was used to assess intercellular communication. RESULTS: Stretch significantly increased the rates of apoptosis and necrosis in hTMCs. The increased rate of injury in stretched hTMCs was further associated with significant upregulation of GJA1 mRNA and Cx43 protein. Upregulation of Cx43 protein was concomitant to increased intercellular communication. CONCLUSIONS: We have shown stretch to increase GJA1 gene and Cx43 protein expression, as well as intercellular communication. We have further shown stretch to be injurious to hTMCs. Upregulation of Cx43 in the hTM subsequent to stretch is a novel finding, which may be useful in elucidating the mechanism of TM injury in POAG patients.

In vitro drug-drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes.

1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P450 (CYP) 3A and the efflux transporter P-glycoprotein (P-gp). This study aimed to evaluate the potential of budesonide to act as a perpetrator or a victim of transporter- or CYP-mediated drug-drug interactions (DDIs). 2. In vitro studies were conducted for P-gp, breast cancer resistance protein and organic anion and cation transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2) in transporter-transfected cells. Changes in mRNA expression in human hepatocytes and enzyme activity in human liver microsomes by budesonide were determined for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A. 3. The data indicated that budesonide is a substrate of P-gp but is not a substrate or an inhibitor of the other transporters investigated. Budesonide is neither an inducer nor an inhibitor of major CYP enzymes. The effect of P-gp on budesonide disposition is anticipated to be low owing to CYP3A-mediated clearance. 4. Collectively, our data indicate there is a low risk of budesonide perpetrating clinical DDIs mediated by the transporters or CYPs studied.

Understanding Cervical Cancer Screening among Latinas through the Lens of Structure, Culture, Psychology and Communication.

This study explored how structural and cultural forces work together with psychological and communication factors in influencing Pap test compliance among Latinas in Los Angeles County, a group who face health disparities related to cervical cancer screening, incidence and mortality. By adopting a multilevel approach to obtain a grounded understanding of this issue, this work revealed that structural barriers, fatalism, religious service attendance, perceived susceptibility, perceived costs, and cues to action from health care providers are all associated with Pap test compliance. Financial barriers also influence compliance, with underinsurance having a stronger negative impact compared to no insurance at all. These findings provide insights into how communication efforts can be strategically designed to address both individual- and system-level barriers to promote health-seeking behaviors among Latinas, and potentially among other population groups experiencing health disparities due to similar reasons.

Acute Zonal Occult Outer Retinopathy (AZOOR): a case report of vision improvement after intravitreal injection of Ozurdex.

BACKGROUND: AZOOR was first described by Gass in 1993 as a syndrome with rapid loss of one or more extensive zones of the outer retinal segments. It is characterized by photopsia, minimal funduscopic changes, and electroretinographic abnormalities. The efficacy of systemic steroids in treating AZOOR has been previously described and advocated by the concept of autoimmune retinopathy. However, the use of intravitreal of sustained-released steroid had not been mentioned to date. CASE PRESENTATION: A 34-year-old man had sudden onset of central scotoma and photopsia in the left eye. His visual acuity continued deteriorating. The visual field defect demonstrated bilateral enlarged blind spots and altitudinal defects. Fluorescein angiography (FA) showed nonspecific retinal inflammation, and an electroretinogram (ERG) illustrated decreased amplitude of the b wave in both eyes. Optical coherence tomography (OCT) examinations revealed parafoveal loss of the photoreceptor inner/outer segment (IS/OS) junction. Therefore, acute zonal occult outer retinopathy (AZOOR) was diagnosed. Although his vision did not improve under the initial treatment of systemic corticosteroid and calcium channel blocker, remarkable improvement was noticed after the intravitreal injection(IVI) of Ozurdex, consistent with the recovered IS/OS junction disruption. CONCLUSIONS: We herein report a typical case of AZOOR, suggesting that the intravitreal injection of steroid may benefit in certain patients.

The genome of the pear (Pyrus bretschneideri Rehd.).

The draft genome of the pear (Pyrus bretschneideri) using a combination of BAC-by-BAC and next-generation sequencing is reported. A 512.0-Mb sequence corresponding to 97.1% of the estimated genome size of this highly heterozygous species is assembled with 194× coverage. High-density genetic maps comprising 2005 SNP markers anchored 75.5% of the sequence to all 17 chromosomes. The pear genome encodes 42,812 protein-coding genes, and of these, ~28.5% encode multiple isoforms. Repetitive sequences of 271.9 Mb in length, accounting for 53.1% of the pear genome, are identified. Simulation of eudicots to the ancestor of Rosaceae has reconstructed nine ancestral chromosomes. Pear and apple diverged from each other ~5.4-21.5 million years ago, and a recent whole-genome duplication (WGD) event must have occurred 30-45 MYA prior to their divergence, but following divergence from strawberry. When compared with the apple genome sequence, size differences between the apple and pear genomes are confirmed mainly due to the presence of repetitive sequences predominantly contributed by transposable elements (TEs), while genic regions are similar in both species. Genes critical for self-incompatibility, lignified stone cells (a unique feature of pear fruit), sorbitol metabolism, and volatile compounds of fruit have also been identified. Multiple candidate SFB genes appear as tandem repeats in the S-locus region of pear; while lignin synthesis-related gene family expansion and highly expressed gene families of HCT, C3'H, and CCOMT contribute to high accumulation of both G-lignin and S-lignin. Moreover, alpha-linolenic acid metabolism is a key pathway for aroma in pear fruit.