PNPLA3 risk allele is associated with risk of hepatocellular carcinoma but not decompensation in compensated cirrhosis.

BACKGROUND: The PNPLA3-rs738409-G, TM6SF2-rs58542926-T, and HSD17B13-rs6834314-A polymorphisms have been associated with cirrhosis, hepatic decompensation, and HCC. However, whether they remain associated with HCC and decompensation in people who already have cirrhosis remains unclear, which limits the clinical utility of genetics in risk stratification as HCC is uncommon in the absence of cirrhosis. We aimed to characterize the effects of PNPLA3, TM6SF2, and HSD17B13 genotype on hepatic decompensation, HCC, and liver-related mortality or liver transplant in patients with baseline compensated cirrhosis. METHODS: We conducted a single-center retrospective study of patients in the Michigan Genomics Initiative who underwent genotyping. The primary predictors were PNPLA3, TM6SF2, and HSD17B13 genotypes. Primary outcomes were either hepatic decompensation, HCC, or liver-related mortality/transplant. We conducted competing risk Fine-Gray analyses on our cohort. RESULTS: We identified 732 patients with baseline compensated cirrhosis. During follow-up, 50% of patients developed decompensation, 13% developed HCC, 24% underwent liver transplant, and 27% died. PNPLA3-rs738409-G genotype was associated with risk of incident HCC: adjusted subhazard hazard ratio 2.42 (1.40-4.17), p=0.0015 for PNPLA3-rs738409-GG vs. PNPLA3-rs738409-CC genotype. The 5-year cumulative incidence of HCC was higher in PNPLA3-rs738409-GG carriers than PNPLA3-rs738409-CC/-CG carriers: 15.6% (9.0%-24.0%) vs. 7.4% (5.2%-10.0%), p<0.001. PNPLA3 genotype was not associated with decompensation or the combined outcome of liver-related mortality or liver transplant. TM6SF2 and HSD17B13 genotypes were not associated with decompensation or HCC. CONCLUSIONS: The PNPLA3-rs738409-G allele is associated with an increased risk of HCC among patients with baseline compensated cirrhosis. People with cirrhosis and PNPLA3-rs738409-GG genotype may warrant more intensive HCC surveillance.

Patient characteristics and telehealth are associated with attendance rates in an outpatient rehabilitation infant bridge program.

OBJECTIVE: To describe the characteristics of patients who received outpatient therapy services through an infant bridge program using telehealth mode of service delivery and to identify if attendance rates vary by mode of service delivery. We hypothesized that telehealth visits will increase attendance rates. DESIGN: Retrospective, cross-sectional study. SETTING: UCSF Benioff Children's Hospital outpatient infant bridge program. PARTICIPANTS: Eighty infants with a history of NICU admission and scheduled for a therapy appointment between June 1, 2019 and December 31, 2020 were included in the study. Participants had an average(SD) gestational age of 34.63(4.41) weeks and length of stay was 43.55(56.03) weeks. The majority were English-speaking (96.3%), White (37.5%), and had commercial insurance (72.5%). MAIN OUTCOME MEASURE: Descriptive analyses were conducted across the entire group along with service delivery model subgroup analysis. Logistic regression was performed to assess patient characteristics associated with attendance and if service delivery model influences attendance. RESULTS: In the analysis of 596 scheduled visits, there were more completed telehealth sessions than for in-person sessions (90.0% versus 84.1%, p = .011). For in-person sessions, infants (N = 40) with lower birth gestational ages (p = .009), longer length of stay (p = .041), and Medi-Cal insurance (p = .006) were more likely to have ≥2 missed appointments. For the telehealth sessions, infants (N = 40) who had longer length of stay (p = .040) were more likely to have ≥2 missed appointments. There is a higher likelihood of ≥2 missed appointments for patients with a longer length of stay (OR = 1.02, 95% CI [1.01, 1.03]) and for in-person service delivery when compared to telehealth (OR = 6.25, 95% CI [1.37, 28.57]). CONCLUSIONS: Telehealth was associated with higher likelihood of attendance, revealing that telehealth has the potential to increase access to early therapy services for certain populations. Future studies with larger sample sizes to determine which populations benefit from telehealth is recommended.

Demystifying the Digital Divide: Disparities in Telerehabilitation Readiness Among Older Adults in the United States.

OBJECTIVE: To estimate readiness of older rehabilitation users in the United States to participate in video-based telerehabilitation and assess disparities in readiness among racial and ethnic minoritized populations, socioeconomically disadvantaged populations, and rural-dwelling older adults. DESIGN: Retrospective cohort study using nationally representative survey data from the National Health and Aging Trends Study from 2015 and 2020. Survey-weighted regression models, accounting for complex survey design, were used to generate estimates of readiness and evaluate disparities across racial and ethnic, socioeconomic, and geographic subgroups. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated for each comparison. SETTING: Home or community rehabilitation environments. PARTICIPANTS: A cohort of 5274 home or community-based rehabilitation users aged 70 years or older (N=5274), representing a weighted 33,576,313 older adults in the United States. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Video-based telerehabilitation readiness was defined consistent with prior work; unreadiness was defined as lacking ownership of internet-enabled devices, limited proficiency of use, or living with severe cognitive, visual, or hearing impairment. Telerehabilitation readiness was categorized as "Ready" or "Unready". RESULTS: Approximately 2 in 3 older rehabilitation users were categorized as ready to participate in video-based rehabilitation. Significantly lower rates of readiness were observed among those living in rural areas (OR=0.75, 95% CI: 0.60-0.94), financially strained individuals (OR=0.37, 95% CI: 0.26-0.53), and among individuals identifying as Black or Hispanic (as compared with non-Hispanic White older adults: Non-Hispanic Black [OR=0.23, 95% CI: 0.18-0.30]; Hispanic [OR=0.17, 95% CI: 0.11, 0.27]). CONCLUSIONS: Our findings highlight significant disparities in the readiness to uptake video-based telerehabilitation. Policy and practice interventions to address telerehabilitation readiness should focus not only on improving broadband access but also on technology ownership and training to ensure equitable adoption in populations with lower baseline readiness.

Human myofiber-enriched aging-induced lncRNA FRAIL1 promotes loss of skeletal muscle function.

The loss of skeletal muscle mass during aging is a significant health concern linked to adverse outcomes in older individuals. Understanding the molecular basis of age-related muscle loss is crucial for developing strategies to combat this debilitating condition. Long noncoding RNAs (lncRNAs) are a largely uncharacterized class of biomolecules that have been implicated in cellular homeostasis and dysfunction across a many tissues and cell types. To identify lncRNAs that might contribute to skeletal muscle aging, we screened for lncRNAs whose expression was altered in vastus lateralis muscle from older compared to young adults. We identified FRAIL1 as an aging-induced lncRNA with high abundance in human skeletal muscle. In healthy young and older adults, skeletal muscle FRAIL1 was increased with age in conjunction with lower muscle function. Forced expression of FRAIL1 in mouse tibialis anterior muscle elicits a dose-dependent reduction in skeletal muscle fiber size that is independent of changes in muscle fiber type. Furthermore, this reduction in muscle size is dependent on an intact region of FRAIL1 that is highly conserved across non-human primates. Unbiased transcriptional and proteomic profiling of the effects of FRAIL1 expression in mouse skeletal muscle revealed widespread changes in mRNA and protein abundance that recapitulate age-related changes in pathways and processes that are known to be altered in aging skeletal muscle. Taken together, these findings shed light on the intricate molecular mechanisms underlying skeletal muscle aging and implicate FRAIL1 in age-related skeletal muscle phenotypes.

Inaugural editorial for Journal of Counseling Psychology.

The Journal of Counseling Psychology serves as the premier journal for critical and rigorous research within the field and beyond. In their inaugural editorial for Journa, Liu is joined by their associated editors and inaugural JCP fellows who have agreed to share authorship and their positionalities. In considering the Journal of Counseling Psychology for research, the editors encourage authors to reflect on these positionalities and how they might integrate their own into their publications. The editorial provides direction and some suggestions on submitted articles and research directions for JCP in the following areas: positionality and critical reflexivity; theoretical and conceptual advancement and clarity; body ideas, frameworks, and conceptualization; data clarity; and cultural validity of research instruments. The editors look forward to working with their communities as they transform their scholarship. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The Prevalence of Cognitive Impairment Among Medicare Beneficiaries Who Use Outpatient Physical Therapy.

OBJECTIVE: The objective of this study was to estimate the prevalence of cognitive impairment (including cognitive impairment no dementia [CIND] and dementia) among Medicare fee-for-service beneficiaries who used outpatient physical therapy and to estimate the prevalence of cognitive impairment by measures that are relevant to rehabilitation practice. METHODS: This cross-sectional analysis included 730 Medicare fee-for-service beneficiaries in the 2016 wave of the Health and Retirement Study with claims for outpatient physical therapy. Cognitive status, our primary variable of interest, was categorized as normal, CIND, or dementia using a validated approach, and population prevalence of cognitive impairment (CIND and dementia) was estimated by sociodemographic variables and Charlson comorbidity index score. Age-, gender- (man/woman), race-/ethnicity-adjusted population prevalence of CIND and dementia were also calculated for walking difficulty severity, presence of significant pain, self-reported fall history, moderate-vigorous physical activity (MVPA) ≤1×/week, and sleep disturbance frequency using multinomial logistic regression. RESULTS: Among Medicare beneficiaries with outpatient physical therapist claims, the prevalence of any cognitive impairment was 20.3% (CIND:15.2%, dementia:5.1%). Cognitive impairment was more prevalent among those who were older, Black, had lower education attainment, or higher Charlson comorbidity index scores. The adjusted population prevalence of cognitive impairment among those who reported difficulty walking across the room was 29.8%, difficulty walking 1 block was 25.9%, difficulty walking several blocks was 20.8%, and no difficulty walking was 16.3%. Additionally, prevalence of cognitive impairment among those with MVPA ≤1×/week was 27.1% and MVPA >1×/week was 14.1%. Cognitive impairment prevalence did not vary by significant pain, self-reported fall history, or sleep disturbance. CONCLUSION: One in 5 older adults who use outpatient physical therapist services have cognitive impairment. Furthermore, cognitive impairment is more common in older physical therapist patients who report worse physical function and less physical activity. IMPACT: Physical therapists should consider cognitive screening for vulnerable older adults to inform tailoring of clinical practice toward a patient's ability to remember and process rehabilitation recommendations.

Associations between metabolic hyperferritinaemia, fibrosis-promoting alleles and clinical outcomes in steatotic liver disease.

BACKGROUND & AIMS: Ferritin has been investigated as a biomarker for liver fibrosis and iron in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, whether metabolic hyperferritinaemia predicts progression of liver disease remains unknown. In this study, we sought to understand associations between hyperferritinaemia and (1) adverse clinical outcomes and (2) common genetic variants related to iron metabolism and liver fibrosis. METHODS: This was a retrospective analysis of adults with MASLD seen at the University of Michigan Health System, where MASLD was defined by hepatic steatosis on imaging, biopsy or vibration-controlled transient elastography, plus metabolic risk factors in the absence of chronic liver diseases other than hemochromatosis. The primary predictor was serum ferritin level, which was dichotomized based on a cut-off of 300 or 450 mcg/L for women or men. Primary outcomes included (1) incident cirrhosis, liver-related events, congestive heart failure (CHF), and mortality and (2) distribution of common genetic variants associated with hepatic fibrosis and hereditary hemochromatosis. RESULTS: Of 7333 patients with MASLD, 1468 (20%) had elevated ferritin. In multivariate analysis, ferritinaemia was associated with increased mortality (HR 1.68 [1.35-2.09], p < .001) and incident liver-related events (HR 1.92 [1.11-3.32], p = .019). Furthermore, elevated ferritin was associated with carriage of cirrhosis-promoting alleles including PNPLA3-rs738409-G allele (p = .0068) and TM6SF2-rs58542926-T allele (p = 0.0083) but not with common HFE mutations. CONCLUSIONS: In MASLD patients, metabolic hyperferritinaemia was associated with increased mortality and higher incidence of liver-related events, and cirrhosis-promoting alleles but not with iron overload-promoting HFE mutations.

Telehealth Walking Self-Management for Individuals With Amputation: A Qualitative Study of Therapist Perspectives on Adoption.

OBJECTIVE: The aim of this study was to understand therapist-identified factors influencing clinical adoption of a telehealth walking self-management intervention for individuals with lower limb amputation. METHODS: Semi-structured focus groups were completed with actively practicing physical and occupational therapists treating populations that are medically complex. A qualitative explorative design was employed with conventional content analysis and iterative independent parallel coding using 2 analysts. Themes and subthemes were generated with a consensus building process identifying patterns and collapsing codes to represent participant perspectives. RESULTS: Thematic saturation was met after 5 focus groups (24 therapists). Therapists were on average 34 years old and predominantly female (n = 19; 79%) physical therapists (n = 17; 71%). Three primary facilitator and barrier themes were identified for intervention adoption: system, therapist, and person. System considerations included telehealth support and interprofessional care coordination. Therapist facilitators included self-management programming that overlapped with standard of care and personalization methods. However, limited behavioral theory training was a therapist level barrier. Finally, person factors such as patient activation could influence both positively and negatively. Person facilitators included social support and barriers included the complex health condition. CONCLUSION: System, therapist, and person facilitators and barriers must be considered to maximize the adoption of similar telehealth walking self-management interventions and prior to larger scale implementation of the current intervention for individuals with lower limb amputation. IMPACT: A telehealth walking self-management intervention has potential impact for individuals with lower limb amputation and must be considered in terms of optimizing system, therapist, and person level facilitators and barriers to implementation.

Prevalence of cognitive impairment in home health physical therapy.

BACKGROUND: The prevalence of cognitive impairment in home health physical therapy (HHPT) is unknown. We sought to identify the prevalence of cognitive impairment, including cognitive impairment no dementia (CIND) and dementia, among older adults who used HHPT, and if cognitive impairment prevalence was higher among those with HHPT-relevant characteristics. METHODS: For our cross-sectional analysis, we identified 963 fee-for-service Medicare beneficiaries with HHPT claims (>85 years old: 28.8%, women: 63.7%, non-Hispanic White: 82.1%) in the 2014 and 2016 waves of the Health and Retirement Study (HRS) and used a validated algorithm to categorize cognitive status as normal, CIND, or dementia. We estimated the population prevalence and calculated age, gender, race/ethnicity adjusted odds ratio (aOR) of CIND and dementia for characteristics relevant to HHPT service delivery including depression, walking difficulty, fall history, incontinence, moderate-vigorous physical activity (MVPA) ≤1x/week, and community-initiated HHPT using multinomial logistic regression. RESULTS: The population prevalence of cognitive impairment was 46.4% (CIND: 27.3%, dementia: 19.1%). The prevalence of cognitive impairment was greater among those with depression (46.7% vs. 39.5%), difficulty walking across the room (58.9% vs. 41.8%), fall history (49.1% vs. 42.9%), MVPA ≤1x/week (50.0% vs. 38.0%), and community-initiated HHPT (55.2% vs. 40.2%). Compared to normal cognitive status, the odds of cognitive impairment were greater for those with MVPA≤1x/week (CIND: aOR = 1.57 [95% CI: 1.05-2.33], dementia: aOR = 2.55 [95% CI: 1.54-4.22]), depression (dementia: aOR = 1.99 [95% CI: 1.19-3.30]), difficulty walking across the room (dementia: aOR = 2.54 [95% CI: 1.40-4.60]), fall history (dementia: aOR = 1.85 [95% CI: 1.20-2.83]), and community-initiated HHPT (dementia: aOR = 1.72 (95% CI: 1.13-2.61]). CONCLUSION: There is a high prevalence of CIND and dementia in HHPT, and no characteristics had a low prevalence of cognitive impairment. Physical therapists should be ready to identify cognitive impairment and adapt home health service delivery for this vulnerable population of older adults.

GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle.

Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of growth arrest and DNA damage inducible α (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MAP kinase kinase kinase 4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.

An enhancer RNA recruits MLL1 to regulate transcription of Myb.

The Myb proto-oncogene encodes the transcription factor c-MYB, which is critical for hematopoiesis. Distant enhancers of Myb form a hub of interactions with the Myb promoter. We identified a long non-coding RNA (Myrlin) originating from the -81 kb murine Myb enhancer. Myrlin and Myb are coordinately regulated during erythroid differentiation. Myrlin TSS deletion using CRISPR/Cas9 reduced Myrlin and Myb expression and LDB1 complex occupancy at the Myb enhancers, compromising enhancer contacts and reducing RNA Pol II occupancy in the locus. In contrast, CRISPRi silencing of Myrlin left LDB1 and the Myb enhancer hub unperturbed, although Myrlin and Myb expression were downregulated, decoupling transcription and chromatin looping. Myrlin interacts with the MLL1 complex. Myrlin CRISPRi compromised MLL1 occupancy in the Myb locus, decreasing CDK9 and RNA Pol II binding and resulting in Pol II pausing in the Myb first exon/intron. Thus, Myrlin directly participates in activating Myb transcription by recruiting MLL1.

Applying i-PARIHS to Identify Emerging Innovations in Hospital Discharge Decision Making in Response to System Stress: A Qualitative Study.

Background: The purpose of this qualitative study was to use a Learning Health System approach to identify factors influencing the emergence of innovation in rehabilitation hospital discharge decision-making during the Coronavirus 2019 (COVID-19) pandemic. Methods: Rehabilitation clinicians were recruited from the Veterans Affairs Health Care System and participated in individual semi-structured interviews guided by the integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework. Data were analyzed using a rapid qualitative, deductive team-based approach informed by directed content analysis. Results: Twenty-three rehabilitation clinicians representing physical (N = 11) and occupational therapy (N = 12) participated in the study. Three primary themes were generated: (1) Recipients: innovations emerged as approaches to communicating discharge recommendations changed (in-person to virtual) and strong patient/family preferences to discharge to the home challenged collaborative goal setting; (2) Context: the ability of rehabilitation clinicians to innovate and the form of innovations were influenced by the broader hospital system, interdisciplinary team dynamics, and policy fluctuations; (3) Innovation: emerging innovations in discharge processes included perceived increases in team collaboration, shifts in caseload prioritization, and alternative options for post-acute care. Conclusions: Our findings reinforce that rehabilitation clinicians developed innovative strategies to quickly adapt to multiple systems-level factors that were changing in the face of the COVID-19 pandemic. Future research is needed to assess the impact of innovations, remediate unintended consequences, and evaluate the implementation of promising innovations to respond to emerging healthcare delivery needs more rapidly.

Progression to cirrhosis is similar among all ages in nonalcoholic fatty liver disease, but liver-related events increase with age.

BACKGROUND: NAFLD is increasingly common among young people. Whether NAFLD carries a more benign course in younger adults is not known. We aimed to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression across age groups. METHODS: We conducted a retrospective study of adults with NAFLD seen within Michigan Medicine, a tertiary care center, between 2010 and 2021. NAFLD was defined by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases. Cirrhosis was determined by validated International Classification of Diseases-9/10 codes or imaging. Fine-Gray competing risk models were generated, with incident cirrhosis and liver-related events (LREs) as the primary outcomes and death without cirrhosis or LREs as a competing risk. The primary predictor was the age category. RESULTS: We included 31,505 patients with NAFLD, with 8,252 aged 18 to younger than 40, 15,035 aged 40 to younger than 60, and 8,218 aged 60 years or older years at diagnosis. Compared with older patients, young adults more often had obesity, higher ALT, and high-risk PNPLA3 alleles, and fewer had prevalent cirrhosis, hypertension, hyperlipidemia, and diabetes. The 10-year risk of incident cirrhosis was similar between ages (3.4% in age 18 to <40 vs 3.7% in age 40 to <60 vs 4.7% in age ≥60; p = 0.058). Predictors of LREs were advancing age and diabetes, with a significantly higher 10-year risk of LREs in the oldest age group (0.2% in age 18 to <40 vs 0.7% in age 40 to <60 vs 1.1% in age ≥60; p = 0.008). CONCLUSIONS: While the baseline prevalence of cirrhosis was higher among older adults, the rate of NAFLD progression to cirrhosis was similar in young and older adults. Older patients were more likely to have LREs.

The transcription regulator ATF4 is a mediator of skeletal muscle aging.

Aging slowly erodes skeletal muscle strength and mass, eventually leading to profound functional deficits and muscle atrophy. The molecular mechanisms of skeletal muscle aging are not well understood. To better understand mechanisms of muscle aging, we investigated the potential role of ATF4, a transcription regulatory protein that can rapidly promote skeletal muscle atrophy in young animals deprived of adequate nutrition or activity. To test the hypothesis that ATF4 may be involved in skeletal muscle aging, we studied fed and active muscle-specific ATF4 knockout mice (ATF4 mKO mice) at 6 months of age, when wild-type mice have achieved peak muscle mass and function, and at 22 months of age, when wild-type mice have begun to manifest age-related muscle atrophy and weakness. We found that 6-month-old ATF4 mKO mice develop normally and are phenotypically indistinguishable from 6-month-old littermate control mice. However, as ATF4 mKO mice become older, they exhibit significant protection from age-related declines in strength, muscle quality, exercise capacity, and muscle mass. Furthermore, ATF4 mKO muscles are protected from some of the transcriptional changes characteristic of normal muscle aging (repression of certain anabolic mRNAs and induction of certain senescence-associated mRNAs), and ATF4 mKO muscles exhibit altered turnover of several proteins with important roles in skeletal muscle structure and metabolism. Collectively, these data suggest ATF4 as an essential mediator of skeletal muscle aging and provide new insight into a degenerative process that impairs the health and quality of life of many older adults.

Dismantling and eradicating anti-Blackness and systemic racism.

Anti-Blackness and systemic racism are long-standing pressing social issues that have received increasing attention in the counseling psychology literature. However, the past few years have demonstrated what can only be described as an emboldening of anti-Blackness-the brutal individual and systemic threats of emotional and physical violence and loss of life that Black individuals and communities face on a daily basis-and a harsh reminder of the systemic racism that continues to threaten the well-being of Black, Indigenous, and People of Color. In this introduction for the special section on Dismantling and Eradicating Anti-Blackness and Systemic Racism, we provide readers an opportunity to pause and reflect on the ways in which those of us in the field can more intentionally seek to disrupt anti-Blackness and systemic racism. We believe that counseling psychology has an opportunity to increase its real-world relevance as an applied specialty area of psychology to the degree to which it evolves its ways of disrupting anti-Blackness and systemic racism in every content area and domain of the field. In this introduction, we review exemplars of work that helps the field re-envision its approaches to anti-Blackness and systemic racism. We also offer our perspectives on additional ways in which the field of counseling psychology can increase its relevance and real-world impact in 2023 and beyond. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Unraveling the genomic complexity of sylvatic mosquitoes in changing Neotropical environments.

Sylvatic New World mosquitoes (e.g. Old-growth Forest species) can transmit viruses among non-human primates. This could be a continuous source of viral cycling and spillover events from animals to humans, particularly in changing environments. However, most species of Neotropical sylvatic mosquitoes (genera Aedes, Haemagogus, and Sabethes), which include vector and non-vector species, currently lack genomic resources because there is no reliable and accurate approach for creating de novo reference genomes for these insects. This is a major knowledge gap in the biology of these mosquitoes, restricting our ability to predict and mitigate the emergence and spread of novel arboviruses in Neotropical regions. We discuss recent advances and potential solutions for generating hybrid de novo assemblies from vector and non-vector species using pools of consanguineous offspring. We also discussed research opportunities likely to emerge from these genomic resources.

Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV).

The high morbidity and mortality associated with SARS-CoV-2 infection, the etiological agent of COVID-19, has had a major impact on global public health. Significant progress has been made in the development of an array of vaccines and biologics, however, the emergence of SARS-CoV-2 variants and breakthrough infections are an ongoing major concern. Furthermore, there is an existing paucity of small-molecule host and virus-directed therapeutics and prophylactics that can be used to counter the spread of SARS-CoV-2, and any emerging and re-emerging coronaviruses. We describe herein our efforts to address this urgent need by focusing on the structure-guided design of potent broad-spectrum inhibitors of SARS-CoV-2 3C-like protease (3CLpro or Main protease), an enzyme essential for viral replication. The inhibitors exploit the directional effects associated with the presence of a gem-dimethyl group that allow the inhibitors to optimally interact with the S4 subsite of the enzyme. Several compounds were found to potently inhibit SARS-CoV-2 and MERS-CoV 3CL proteases in biochemical and cell-based assays. Specifically, the EC50 values of aldehyde 1c and its corresponding bisulfite adduct 1d against SARS-CoV-2 were found to be 12 and 10 nM, respectively, and their CC50 values were >50 µM. Furthermore, deuteration of these compounds yielded compounds 2c/2d with EC50 values 11 and 12 nM, respectively. Replacement of the aldehyde warhead with a nitrile (CN) or an α-ketoamide warhead or its corresponding bisulfite adduct yielded compounds 1g, 1eand1f with EC50 values 60, 50 and 70 nM, respectively. High-resolution cocrystal structures have identified the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and, furthermore, have illuminated the mechanism of action of the inhibitors. Overall, the high Safety Index (SI) (SI=CC50/EC50) displayed by these compounds suggests that they are well-suited to conducting further preclinical studies.

Comparative phylogeography reveals widespread cryptic diversity driven by ecology in Panamanian birds.

Widespread species often harbor unrecognized genetic diversity, and investigating the factors associated with such cryptic variation can help us better understand the forces driving diversification. Here, we identify potential cryptic species based on a comprehensive dataset of COI mitochondrial DNA barcodes from 2,333 individual Panamanian birds across 429 species, representing 391 (59%) of the 659 resident landbird species of the country, as well as opportunistically sampled waterbirds. We complement this dataset with additional publicly available mitochondrial loci, such as ND2 and cytochrome b, obtained from whole mitochondrial genomes from 20 taxa. Using barcode identification numbers (BINs), we find putative cryptic species in 19% of landbird species, highlighting hidden diversity in the relatively well-described avifauna of Panama. Whereas some of these mitochondrial divergence events corresponded with recognized geographic features that likely isolated populations, such as the Cordillera Central highlands, the majority (74%) of lowland splits were between eastern and western populations. The timing of these splits are not temporally coincident across taxa, suggesting that historical events, such as the formation of the Isthmus of Panama and Pleistocene climatic cycles, were not the primary drivers of cryptic diversification. Rather, we observed that forest species, understory species, insectivores, and strongly territorial species-all traits associated with lower dispersal ability-were all more likely to have multiple BINs in Panama, suggesting strong ecological associations with cryptic divergence. Additionally, hand-wing index, a proxy for dispersal capability, was significantly lower in species with multiple BINs, indicating that dispersal ability plays an important role in generating diversity in Neotropical birds. Together, these results underscore the need for evolutionary studies of tropical bird communities to consider ecological factors along with geographic explanations, and that even in areas with well-known avifauna, avian diversity may be substantially underestimated.

Especies extendidas frecuentemente tiene diversidad genética no reconocida, y investigando los factores asociados con esta variación críptica puede ayudarnos a entender las fuerzas que impulsan la diversificación. Aquí, identificamos especies crípticas potenciales basadas en un conjunto de datos de códigos de barras de ADN mitocondrial de 2,333 individuos de aves de Panama en 429 especies, representando 391 (59%) de las 659 especies de aves terrestres residentes del país, además de algunas aves acuáticas muestreada de manera oportunista. Adicionalmente, complementamos estos datos con secuencias mitocondriales disponibles públicamente de otros loci, tal como ND2 o citocroma b, obtenidos de los genomas mitocondriales completos de 20 taxones. Utilizando los números de identificación de código de barras (en ingles: BINs), un sistema taxonómico numérico que proporcina una estimación imparcial de la diversidad potencial a nivel de especie, encontramos especies crípticas putativas en 19% de las especies de aves terrestres, lo que destaca la diversidad oculta en la avifauna bien descrita de Panamá. Aunque algunos de estos eventos de divergencia conciden con características geográficas que probablemente aislaron las poblaciones, la mayoría (74%) de la divergencia en las tierras bajas se encuentra entre las poblaciones orientales y occidentales. El tiempo de esta divergencia no coincidió entre los taxones, sugiriendo que eventos históricos tales como la formación del Istmo de Panamá y los ciclos climáticos del pleistoceno, no fueron los principales impulsores de la especiación. En cambio, observamos asociaciones fuertes entre las características ecológicas y la divergencia mitocondriale: las especies del bosque, sotobosque, con una dieta insectívora, y con territorialidad fuerte mostraton múltiple BINs probables. Adicionalmente, el índice mano-ala, que está asociado a la capacidad de dispersión, fue significativamente menor en las especies con BINs multiples, sugiriendo que la capacidad de dispersión tiene un rol importamente en la generación de la diversidad de las aves neotropicales. Estos resultos demonstran la necesidad de que estudios evolutivos de las comunidades de aves tropicales consideren los factores ecológicos en conjunto con las explicaciones geográficos.

Replicate contact zones suggest a limited role of plumage in reproductive isolation among subspecies of the variable seedeater (Sporophila corvina).

After establishing secondary contact, recently diverged populations may remain reproductively isolated or may hybridize to a varying extent depending on factors such as hybrid fitness and the strength of assortative mating. Here, we used genomic and phenotypic data from three independent contact zones between subspecies of the variable seedeater (Sporophila corvina) to examine how coloration and genetic divergence shape patterns of hybridization. We found that differences in plumage coloration are probably maintained by divergent selection across contact zones; however, the degree of plumage differentiation does not match overall patterns of hybridization. Across two parallel contact zones between populations with divergent phenotypes (entirely black vs. pied plumage), populations hybridized extensively across one contact zone but not the other, suggesting that plumage divergence is not sufficient to maintain reproductive isolation. Where subspecies hybridized, hybrid zones were wide and formed by later-generation hybrids, suggesting frequent reproduction and high survivorship for hybrid individuals. Moreover, contemporary gene flow has played an important role in shaping patterns of genetic structure between populations. Replicated contact zones between hybridizing taxa offer a unique opportunity to explore how different factors interact to shape patterns of hybridization. Overall, our results demonstrate that divergence in plumage coloration is important in reducing gene flow but insufficient in maintaining reproductive isolation in this clade, and that other factors such as divergence in song and time since secondary contact may also play an important role in driving patterns of reduced hybridization and gene flow.

Al establecer contacto secundario, las poblaciones que divergieron recientemente pueden permanecer reproductivamente aisladas o pueden hibridarse en distintos grados, dependiendo de factores como la aptitud (fitness) y la fuerza del apareamiento selectivo. Aquí, utilizamos datos genómicos y fenotípicos de tres zonas de contacto independientes entre subespecies del Semillero Variable (Sporophila corvina), para examinar cómo la coloración y la divergencia genética regulan los patrones de hibridación. A través de las zonas de contacto, encontramos que las diferencias en la coloración del plumaje posiblemente se mantienen por selección divergente, pero el grado de diferenciación no coincide con los patrones generales de hibridación. En dos zonas de contacto análogas entre poblaciones con fenotipos divergentes (totalmente negro vs plumaje de varios colores), las poblaciones hibridaron ampliamente en una zona de contacto, pero no en la otra, lo que sugiere que la divergencia del plumaje no es suficiente para mantener el aislamiento reproductivo. Donde las subespecies hibridaron, las zonas híbridas eran amplias y estaban formadas por híbridos de generaciones posteriores, lo que sugiere reproducción frecuente y alta sobrevivencia de los híbridos. Además, el flujo génico ha desempeñado un papel importante en la configuración de patrones de estructura genética entre poblaciones. Las réplicas de zonas de contacto entre taxones que hibridan ofrecen una oportunidad para explorar cómo interactúan diversos factores para dar forma a los patrones de hibridación. En general, nuestros resultados demuestran que la divergencia en la coloración del plumaje es importante para reducir el flujo génico, pero insuficiente para mantener el aislamiento reproductivo en este clado, y que otros factores, como la divergencia en el canto y el tiempo transcurrido desde el contacto secundario, también pueden desempeñar un papel importante en la reducción del flujo génico e hibridación.