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Abstract The Pacific islands and Island Southeast Asia have experienced multiple waves of human migrations, providing a case study for exploring the potential of ancient microbiomes to study human migration. We perform a metagenomic study of archaeological dental calculus from 102 individuals, originating from 10 Pacific islands and 1 island in Island Southeast Asia spanning ~3000 years. Oral microbiome DNA preservation in calculus is far higher than that of human DNA in archaeological bone, and comparable to that of calculus from temperate regions. Oral microbial community composition is minimally driven by time period and geography in Pacific and Island Southeast Asia calculus, but is found to be distinctive compared to calculus from Europe, Africa, and Asia. Phylogenies of individual bacterial species in Pacific and Island Southeast Asia calculus reflect geography. Archaeological dental calculus shows good preservation in tropical regions and the potential to yield information about past human migrations, complementing studies of the human genome.

Objective: The study objective was to determine if intraoperative peritoneal catheter placement is associated with improved outcomes in neonates undergoing high-risk cardiac surgery with cardiopulmonary bypass. Methods: This propensity score–matched retrospective study used data from 22 academic pediatric cardiac intensive care units. Consecutive neonates undergoing Society of Thoracic Surgeons–European Association for Cardio-Thoracic Surgery category 3 to 5 cardiac surgery with cardiopulmonary bypass at centers participating in the NEonatal and Pediatric Heart Renal Outcomes Network collaborative were studied to determine the association of the use of an intraoperative placed peritoneal catheter for dialysis or passive drainage with clinical outcomes, including the duration of mechanical ventilation. Results: Among 1490 eligible neonates in the NEonatal and Pediatric Heart Renal Outcomes Network dataset, a propensity-matched analysis was used to compare 395 patients with peritoneal catheter placement with 628 patients without peritoneal catheter placement. Time to extubation and most clinical outcomes were similar. Postoperative length of stay was 5 days longer in the peritoneal catheter placement cohort (17 vs 22 days, P = .001). There was a 50% higher incidence of moderate to severe acute kidney injury in the no-peritoneal catheter cohort (12% vs 18%, P = .02). Subgroup analyses between specific treatments and in highest risk patients yielded similar associations. Conclusions: This study does not demonstrate improved outcomes among neonates with placement of a peritoneal catheter during cardiac surgery. Outcomes were similar apart from longer hospital stay in the peritoneal catheter cohort. The no-peritoneal catheter cohort had a 50% higher incidence of moderate to severe acute kidney injury (12% vs 18%). This analysis does not support indiscriminate peritoneal catheter use, although it may support the utility for postoperative fluid removal among neonates at risk for acute kidney injury. A multicenter controlled trial may better elucidate peritoneal catheter effects.

Abstract Rationale & objective Glomerulonephritis (GN) is a leading cause of chronic kidney disease (CKD). Major adverse cardiovascular events (MACE) are prolific in CKD. The risk of MACE in GN cohorts is multifactorial. We investigated the prognostic significance of routine cardiac biomarkers, Troponin I and N-terminal pro-BNP (NT-proBNP) in predicting MACE within 5 years of GN diagnosis. Study Design Retrospective cohort study. Setting & participants Data were obtained from TriNetX, a global federated health research network of electronic health records (EHR). Exposure or predictor Biomarker thresholds: Troponin I: 18 ng/L, NT-proBNP: 400 pg/mL. Outcomes Primary outcome: Incidence of major adverse cardiovascular events (MACE). Secondary outcome: was the risk for each individual component of the composite outcome. Analytical Approach 1:1 propensity score matching using logistic regression. Cox proportional hazard models were used to assess the association of cardiac biomarkers with the primary and secondary outcomes, reported as Hazard Ratio (HR) and 95% confidence intervals (CI). Survival analysis was performed which estimates the probability of an outcome over a 5-year follow-up from the index event. Results Following PSM, 34,974 and 18,218 patients were analysed in the Troponin I and NTproBNP cohorts, respectively. In the Troponin I all cause GN cohort, 3,222 (9%) developed composite MACE outcome HR 1.79; (95% CI, 1.70, 1.88, p

Abstract Rewarewa (Knightia excelsa, Proteaceae) is a tree species endemic to Aotearoa New Zealand, with a natural distribution spanning Te Ika-a-Māui (North Island) and the top of Te Waipounamu (South Island). We used the pseudo-chromosome genome assembly of rewarewa as a reference and whole genome pooled sequencing from 35 populations sampled across Aotearoa New Zealand, including trees growing on Māori-owned land, to identify 1,443,255 single nucleotide polymorphisms (SNPs). Four genetic clusters located in the northern North Island (NNI), eastern North Island (NIE), western and southern North Island (NIWS), and the South Island (SI) were identified. Gene flow was revealed between the SI and NIE genetic clusters, plus bottleneck and contraction events within the genetic clusters since the mid-late Pleistocene, with divergence between North and South Island clusters estimated to have occurred ~115,000–230,000 years ago. Genotype environment analysis (GEA) was used to identify loci and genes linked with altitude, soil pH, soil carbon, slope, soil size, annual mean temperature, mean diurnal range, isothermality, annual precipitation, and precipitation seasonality. The location of the SNPs associated with these environmental variables was compared with the position of 52,192 gene-coding sequences that were predicted in the rewarewa genome using RNA sequencing. This new understanding of the genetic variation present in rewarewa and insights into the genetic control of adaptive traits will inform efforts to incorporate the species in restoration plantings and for marketing rewarewa honey based on provenance.

Abstract Well-motivated models of dark matter often result in a population of electrons and positrons within galaxies produced through dark matter annihilation — usually in association with gamma rays. As they diffuse through galactic magnetic fields, these e ± produce synchrotron radio emission. The intensity and morphology of this signal depends on the properties of the interstellar medium through which the e ± propagate. Using observations of the Andromeda Galaxy (M31) to construct a model of the gas, magnetic fields, and starlight, we set constraints on dark matter annihilation to b b ¯ $$ b\overline{b} $$ using the morphology of 3.6 cm radio emission. As the emission signal at the center of M31 is very sensitive to the diffusion coefficient and dark matter profile, we base our limits on the differential flux in the region between 0.9 – 6.9 kpc from the center. We exclude annihilation cross sections ≳ 3 × 10−25 cm3/s in the mass range 10 – 500 GeV, with a maximum sensitivity of 7 × 10−26 cm3/s at 20 – 40 GeV. Though these limits are weaker than those found in previous studies of M31, they are robust to variations of the diffusion coefficient.

Background: Repeat partial nephrectomy (PN) for tumors recurring in the ipsilateral kidney is associated with surgical complexity and a higher rate of complications. Objective: To evaluate the local oncologic efficacy of thermal ablation (TA) for renal cell carcinoma (RCC) in the ipsilateral kidney following PN. Design, setting, participation: We included patients who underwent ablation for renal tumors in the ipsilateral kidney after PN between January 2005 and December 2019. Demographics, tumor size, procedural details, complications, pathology, local oncologic outcomes, and survival outcomes are described. Outcome measurements and statistical analysis: The procedural, pathologic, and oncologic outcomes are described. Survival rates were estimated using the Kaplan-Meier method. Results and limitations: A total of 66 patients (46 male and 20 female) with a median age of 62 yr (interquartile range [IQR] 52–69) met our inclusion criteria. In these patients, 74 TA procedures were performed for 86 lesions (median tumor size 1.9 cm, IQR 1.6–2.5). Radiofrequency ablation and cryoablation accounted for 60 (81%) and 14 (19%) procedures, respectively. Three patients (3.7%) had Clavien-Dindo grade III complications. Of 65 lesion biopsies, 62 (95.5%) were diagnostic. The most common subtype was clear cell RCC (n = 37). The median imaging follow-up duration was 60 mo (IQR 43–88). Recurrence in the ablation zone occurred for four lesions (4.6%) at a median of 6.9 mo (IQR 6.4–10.7). The rates of overall, recurrence-free, and disease-free survival were 93.1%, 94.4%, and 65.6% at 5 yr, and 71.6%, 94.4%, and 60.1% at 10 yr, respectively. Limitations include the retrospective design and the lack of a control group. Conclusions: TA is effective for the treatment of RCC in the ipsilateral kidney following PN. Patient summary: Heat treatment to remove tumor tissue is an effective option for small kidney masses recurring after partial kidney removal for cancer. Long-term follow-up data revealed that this treatment resulted in low recurrence and complication rates.

Abstract In semi-arid environments, resources necessary for survival may be unevenly distributed across the landscape. Gould’s wild turkeys (Meleagris gallopavo mexicana) are spatially restricted to mountainous semi-arid areas of southwestern United States and Mexico, and information on their distribution and habitat use is limited. We described how landcover type and topographical features influenced space use and habitat selection by Gould’s wild turkeys in southeastern Arizona. We used GPS data from 51 Gould’s wild turkeys to describe resource selection during 2016–2017 in southeastern Arizona, USA. We estimated home ranges and calculated resource selection functions using distance from landcover types, slope, aspect, and elevation at used locations and random locations within individual home ranges. Gould’s wild turkeys selected areas closer to pine forest and water. Likewise, Gould’s wild turkeys selected locations with moderate elevations of 1641 ± 235 m (range = 1223–2971 m), and on north and west facing slopes with a 10° ± 8.5 (range = 0.0–67.4°) incline. Our findings suggest that conserving portions of the landscape with appropriate topography and landcover types as described above will promote habitat availability for Gould’s wild turkeys.

We present 2 cases of cancer of unknown origin in which RNA-based cancer classification testing provided vital insight and directed treatment management. The tissue of origin could not be determined in both of these patients utilizing morphology and immunohistochemical analysis of the tissue samples. Next-generation sequencing and tumor-of-origin testing using an RNA-based molecular cancer classifier were performed to elucidate the possible tissue of origin. A 61-year-old male with a history of localized basal cell carcinoma presented with a 4.4-cm axillary lymph node in addition to upper extremity edema and supraclavicular lymphadenopathy. RNA-based tumor origin testing revealed skin basal or squamous cell carcinoma as the likely tissue of origin, with a probability of 97%. He received vismodegib, a hedgehog inhibitor, after progression on cemiplimab and experienced a partial response by RECIST criteria, which is currently ongoing for over a year. A 74-year-old female patient with a remote history of ovarian cancer for which she underwent resection and adjuvant chemotherapy presented 15 years later with abdominal pain. The diagnostic workup revealed a 2-cm pancreatic mass and enlarged peritoneal lymph nodes. RNA sequencing revealed a 99% likelihood of the tissue of origin being serous ovarian carcinoma. Subsequently, she underwent surgery and adjuvant chemotherapy and is currently in remission with letrozole maintenance. Genomic data already plays a crucial role in therapeutic decision-making for individuals with cancer. These cases highlight the complementary role of genomic data in the diagnostic workup of cancer, leading to favorable patient outcomes.

Abstract Background Telemonitoring for the remote patient self-management of chronic conditions can be a cost-effective method for delivering care in chronic disease; nonetheless, its implementation in clinical practice remains low. The aim of this meta-synthesis is to explore barriers and facilitators associated with the use of remote patient monitoring of chronic disease, drawing on qualitative research, and assessing participant interactions with this technology. Method A meta-synthesis of qualitative studies was performed. MEDLINE, SCOPUS and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from database date of inception to 5 February 2021. The Critical Appraisal Skills Programme (CASP) was used to critically appraise each study. Thematic synthesis was performed to identify user (patients, carers and healthcare professionals) perspectives and experiences of patient remote monitoring of chronic disease (Type 2 diabetes mellitus, chronic obstructive pulmonary disease, and cardiovascular disease). Results Searches returned 10,401 studies and following independent screening by two reviewers, nine studies were included in this meta-synthesis. Data were synthesised and categorised into four key themes: (1) Improved care; (2) Communication; (3) Technology feasibility & acceptability; and (4) Intervention concerns. Most patients using patient remote devices felt motivated in managing their own lifestyles and felt reassured by the close monitoring and increased communication. Barriers identified involved generational differences and difficulties with the technology used. Conclusion Most studies showed a positive attitude to telemonitoring, with patients preferring the convenience of telemonitoring in comparison to attending regular clinics. Further research is required to assess the most effective technology for chronic disease management, how to maintain long-term patient adherence, and identify effective approaches to address generational variation in telemonitoring up-take.

Abstract Background T-cells play a crucial role in the adaptive immune system by triggering responses against cancer cells and pathogens, while maintaining tolerance against self-antigens, which has sparked interest in the development of various T-cell-focused immunotherapies. However, the identification of antigens recognised by T-cells is low-throughput and laborious. To overcome some of these limitations, computational methods for predicting CD8 + T-cell epitopes have emerged. Despite recent developments, most immunogenicity algorithms struggle to learn features of peptide immunogenicity from small datasets, suffer from HLA bias and are unable to reliably predict pathology-specific CD8 + T-cell epitopes. Methods We developed TRAP (T-cell recognition potential of HLA-I presented peptides), a robust deep learning workflow for predicting CD8 + T-cell epitopes from MHC-I presented pathogenic and self-peptides. TRAP uses transfer learning, deep learning architecture and MHC binding information to make context-specific predictions of CD8 + T-cell epitopes. TRAP also detects low-confidence predictions for peptides that differ significantly from those in the training datasets to abstain from making incorrect predictions. To estimate the immunogenicity of pathogenic peptides with low-confidence predictions, we further developed a novel metric, RSAT (relative similarity to autoantigens and tumour-associated antigens), as a complementary to ‘dissimilarity to self’ from cancer studies. Results TRAP was used to identify epitopes from glioblastoma patients as well as SARS-CoV-2 peptides, and it outperformed other algorithms in both cancer and pathogenic settings. TRAP was especially effective at extracting immunogenicity-associated properties from restricted data of emerging pathogens and translating them onto related species, as well as minimising the loss of likely epitopes in imbalanced datasets. We also demonstrated that the novel metric termed RSAT was able to estimate immunogenic of pathogenic peptides of various lengths and species. TRAP implementation is available at: https://github.com/ChloeHJ/TRAP . Conclusions This study presents a novel computational workflow for accurately predicting CD8 + T-cell epitopes to foster a better understanding of antigen-specific T-cell response and the development of effective clinical therapeutics.

BackgroundDespite pharmacological therapies to improve outcomes of pulmonary hypertension (PH), poor long-term survival remains. Exercised-based cardiac rehabilitation (ExCR) may be an alternative strategy to improve prognosis. Therefore, using an electronic medical record (EMR) database, the objective of this study was to compare mortality between patients with primary PH with ExCR vs. propensity-matched PH patients without ExCR.MethodsThe retrospective analysis was conducted on February 15, 2023 using anonymized data within TriNetX, a global federated health research network. All patients were aged ≥18 years with primary PH recorded in EMRs with at least 1-year follow-up from ExCR. Using logistic regression models, patients with PH with an EMR of ExCR were 1:1 propensity score-matched with PH patients without ExCR for age, sex, race, and comorbidities, and cardiovascular care.ResultsIn total, 109,736 patients with primary PH met the inclusion criteria for the control group and 784 patients with primary PH met the inclusion criteria for the ExCR cohort. Using the propensity score-matched cohorts, 1-year mortality from ExCR was proportionally lower with 13.6% (n = 101 of 744 patients) in the ExCR cohort compared to 23.3% (n = 174 of 747 patients) in the controls (OR 0.52, 95% CI 0.40–0.68).ConclusionThe present study of 1,514 patients with primary PH suggests that ExCR is associated with 48% lower odds of 1-year mortality, when compared to propensity score-matched patients without ExCR.

Abstract Remodelling is a fundamental biological process involved in the maintenance of bone physiology and function. We know that a range of health and lifestyle factors can impact this process in living and past societies, but there is a notable gap in bone remodelling data for populations from the Pacific Islands. We conducted the first examination of femoral cortical histology in 69 individuals from ca. 440–150 BP Taumako in Solomon Islands, a remote ‘Polynesian Outlier’ island in Melanesia. We tested whether bone remodelling indicators differed between age groups, and biological sex validated using ancient DNA. Bone vascular canal and osteon size, vascular porosity, and localised osteon densities, corrected by femoral robusticity indices were examined. Females had statistically significantly higher vascular porosities when compared to males, but osteon densities and ratios of canal-osteon (~ 8%) did not differ between the sexes. Our results indicate that, compared to males, localised femoral bone tissue of the Taumako females did not drastically decline with age, contrary to what is often observed in modern populations. However, our results match findings in other archaeological samples—a testament to past female bone physiology resilience, also now observed in the Pacific region.

We report the discovery of two ultrafaint dwarf galaxies, Leo M and Leo K, that lie outside the halo of the Milky Way (MW). Using Hubble Space Telescope imaging of the resolved stars, we create color–magnitude diagrams reaching the oldest main-sequence turnoff of each system and (i) fit for structural parameters of the galaxies; (ii) measure their distances using the luminosity of the horizontal branch stars; (iii) estimate integrated magnitudes and stellar masses; and (iv) reconstruct the star formation histories. Based on their location in the Local Group, neither galaxy is currently within the halo of the MW although Leo K is located ∼26 kpc from the low-mass galaxy Leo T and these two systems may have had a past interaction. Leo M and Leo K have stellar masses of ${1.8}_{-0.2}^{+0.3}\times {10}^{4}$ M _⊙ and 1.2 ± 0.2 × 10 ^4 M _⊙ , and were quenched ${10.6}_{-1.1}^{+2.2}$ Gyr and ${12.8}_{-4.2}^{+0.1}$ Gyr ago, respectively. Given that the galaxies are at farther distances from the MW, it is unlikely that they were quenched by environmental processing. Instead, given their low stellar masses, their early quenching timescales are consistent with the scenario that a combination of reionization and stellar feedback shut down star formation at early cosmic times.

Abstract To better understand the molecular mechanisms of tendon healing, we investigated the Murphy Roth’s Large (MRL) mouse, which is considered a model of mammalian tissue regeneration. We show that compared to C57Bl/6J (C57) mice, injured MRL tendons have reduced fibrotic adhesions and cellular proliferation, with accelerated improvements in biomechanical properties. RNA-seq analysis revealed that differentially expressed genes in the C57 healing tendon at 7 days post injury were functionally linked to fibrosis, immune system signaling and extracellular matrix (ECM) organization, while the differentially expressed genes in the MRL injured tendon were dominated by cell cycle pathways. These gene expression changes were associated with increased α-SMA+ myofibroblast and F4/80+ macrophage activation and abundant BCL-2 expression in the C57 injured tendons. Transcriptional analysis of upstream regulators using Ingenuity Pathway Analysis showed positive enrichment of TGFB1 in both C57 and MRL healing tendons, but with different downstream transcriptional effects. MRL tendons exhibited of cell cycle regulatory genes, with negative enrichment of the cell senescence-related regulators, compared to the positively-enriched inflammatory and fibrotic (ECM organization) pathways in the C57 tendons. Serum cytokine analysis revealed decreased levels of circulating senescence-associated circulatory proteins in response to injury in the MRL mice compared to the C57 mice. These data collectively demonstrate altered TGFB1 regulated inflammatory, fibrosis, and cell cycle pathways in flexor tendon repair in MRL mice, and could give cues to improved tendon healing.

Aged tendons have disrupted homeostasis, increased injury risk, and impaired healing capacity. Understanding mechanisms of homeostatic disruption is crucial for developing therapeutics to retain tendon health through the lifespan. Here, we developed a novel model of accelerated tendon extracellular matrix (ECM) aging via depletion of Scleraxis-lineage cells in young mice (Scx-DTR). Scx-DTR recapitulates many aspects of tendon aging including comparable declines in cellularity, alterations in ECM structure, organization, and composition. Single-cell RNA sequencing demonstrated a conserved decline in tenocytes associated with ECM biosynthesis in aged and Scx-DTR tendons, identifying the requirement for Scleraxis-lineage cells during homeostasis. However, the remaining cells in aged and Scx-DTR tendons demonstrate functional divergence. Aged tenocytes become pro-inflammatory and lose proteostasis. In contrast, tenocytes from Scx-DTR tendons demonstrate enhanced remodeling capacity. Collectively, this study defines Scx-DTR as a novel model of accelerated tendon ECM aging and identifies novel biological intervention points to maintain tendon function through the lifespan.

Abstract Background It remains uncertain if prior use of oral anticoagulants (OACs) in COVID-19 outpatients with multimorbidity impacts prognosis, especially if cardiometabolic diseases are present. Clinical outcomes 30-days after COVID-19 diagnosis were compared between outpatients with cardiometabolic disease receiving vitamin K antagonist (VKA) or direct-acting OAC (DOAC) therapy at time of COVID-19 diagnosis. Methods A study was conducted using TriNetX, a global federated health research network. Adult outpatients with cardiometabolic disease (i.e. diabetes mellitus and any disease of the circulatory system) treated with VKAs or DOACs at time of COVID-19 diagnosis between 20-Jan-2020 and 15-Feb-2021 were included. Propensity score matching (PSM) was used to balance cohorts receiving VKAs and DOACs. The primary outcomes were all-cause mortality, intensive care unit (ICU) admission/mechanical ventilation (MV) necessity, intracranial haemorrhage (ICH)/gastrointestinal bleeding, and the composite of any arterial or venous thrombotic event(s) at 30-days after COVID-19 diagnosis. Results 2275 patients were included. After PSM, 1270 patients remained in the study (635 on VKAs; 635 on DOACs). VKA-treated patients had similar risks and 30-day event-free survival than patients on DOACs regarding all-cause mortality, ICU admission/MV necessity, and ICH/gastrointestinal bleeding. The risk of any arterial or venous thrombotic event was 43% higher in the VKA cohort (hazard ratio 1.43, 95% confidence interval 1.03–1.98; Log-Rank test p = 0.029). Conclusion In COVID-19 outpatients with cardiometabolic diseases, prior use of DOAC therapy compared to VKA therapy at the time of COVID-19 diagnosis demonstrated lower risk of arterial or venous thrombotic outcomes, without increasing the risk of bleeding.

BackgroundTelemedicine is an expanding and feasible approach to improve medical care for patients with long-term conditions. However, there is a poor understanding of patients’ acceptability of this technology and their rate of uptake. ObjectiveThe aim of this study was to systematically review the current evidence on telemonitoring in the management of patients with long-term conditions and evaluate the patients’ uptake and acceptability of this technology. MethodsMEDLINE, Scopus, and CENTRAL (the Cochrane Central Register of Controlled Trials) were searched from the date of inception to February 5, 2021, with no language restrictions. Studies were eligible for inclusion if they reported any of the following outcomes: intervention uptake and adherence; study retention; patient acceptability, satisfaction, and experience using the intervention; changes in physiological values; all-cause and cardiovascular-related hospitalization; all-cause and disease-specific mortality; patient-reported outcome measures; and quality of life. In total, 2 reviewers independently assessed the articles for eligibility. ResultsA total of 96 studies were included, and 58 (60%) were pooled for the meta-analyses. Meta-analyses showed a reduction in mortality (risk ratio=0.71, 95% CI 0.56-0.89; P=.003; I2=0%) and improvements in blood pressure (mean difference [MD]=−3.85 mm Hg, 95% CI −7.03 to −0.68; P=.02; I2=100%) and glycated hemoglobin (MD=−0.33, 95% CI −0.57 to −0.09; P=.008; I2=99%) but no significant improvements in quality of life (MD=1.45, 95% CI −0.10 to 3; P=.07; I2=80%) and an increased risk of hospitalization (risk ratio=1.02, 95% CI 0.85-1.23; P=.81; I2=79%) with telemonitoring compared with usual care. A total of 12% (12/96) of the studies reported adherence outcomes, and 9% (9/96) reported on satisfaction and acceptance outcomes; however, heterogeneity in the assessment methods meant that a meta-analysis could not be performed. ConclusionsTelemonitoring is a valid alternative to usual care, reducing mortality and improving self-management of the disease, with patients reporting good satisfaction and adherence. Further studies are required to address some potential concerns regarding higher hospitalization rates and a lack of positive impact on patients’ quality of life. Trial RegistrationPROSPERO CRD42021236291; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=236291

Understanding how livestock grazing strategies of native warm season grasses (NWSG) can impact facultative grassland bird nesting can provide insight for conservation efforts. We compared pre and post treatment effects of rotational grazing (ROT) and patch-burn grazing (PBG) for facultative grassland bird species nest success and nest-site selection on NWSG pastures at three Mid-South research sites. We established 14, 9.7 ha NWSG pastures and randomly assigned each to either ROT or PBG and monitored avian nest-site selection and nest success, 2014–2016. We collected nesting and vegetation data in 2014, before treatment implementation, as an experimental pre-treatment. We implemented treatments across all research sites in spring 2015. We used a step-wise model selection framework to estimate treatment effect for ROT or PBG on avian nest daily survival rate (DSR) and resource selection function (RSF) at the temporal scale and within-field variables. Daily survival rates were 0.93% (SE = 0.006) for field sparrow (Spizella pusilla), 0.96% (SE = 0.008) for red-winged blackbird (Agelaius phoeniceus), and 0.92% (SE = 0.01) for indigo bunting (Passerina cyanea). Model support for PBG treatment and vegetation height were indicated as negative and positive influences for field sparrow DSR, respectively. Red-winged blackbirds’ DSR were negatively influenced by ROT while vegetation height positively affected DSR, and DSR for indigo bunting did not differ among treatments. Combined RSF models indicated nest-site selection for all species was positively related to vegetation height and only weakly associated with other within-field variables. We provide evidence that ROT and/or PBG effects vary by species for DSR for these three facultative grassland birds, and vegetation characteristics affected their nest-site selection in the Mid-South USA. A lack of disturbance in Mid-South grasslands can lead to higher successional stages (i.e., mix shrub-grassland), but some combination of ROT, PBG, and unburned/ungrazed areas can provide adequate nesting habitat on small pasture lands (∼1.8 –7.8 ha) for various facultative grassland birds and potentially offer the opportunity to simultaneously maintain livestock production and grassland bird nesting habitat.

Abstract Thalassemias are inherited blood disorders that are found in high prevalences in the Mediterranean, Southeast Asia and the Pacific. These diseases provide varying levels of resistance to malaria and are proposed to have emerged as an adaptive response to malaria in these regions. The transition to agriculture in the Holocene has been suggested to have influenced the selection for thalassemia in the Mediterranean as land clearance for farming encouraged interaction between Anopheles mosquitos, the vectors for malaria, and human groups. Here we document macroscopic and microscopic skeletal evidence for the presence of thalassemia in both hunter-gatherer (Con Co Ngua) and early agricultural (Man Bac) populations in northern Vietnam. Firstly, our findings demonstrate that thalassemia emerged prior to the transition to agriculture in Mainland Southeast Asia, from at least the early seventh millennium BP, contradicting a long-held assumption that agriculture was the main driver for an increase in malaria in Southeast Asia. Secondly, we describe evidence for significant malarial burden in the region during early agriculture. We argue that the introduction of farming into the region was not the initial driver of the selection for thalassemia, as it may have been in other regions of the world.

Arthropods have long been appreciated as useful and important ecological indicators of beneficial or detrimental changes occurring in their environment, especially those driven by anthropogenic activity. However, morphological identification, especially of key groups such as soil arthropods, is laborious and requires high-level expertise, limiting the spatiotemporal scales of such monitoring. Molecular methods based on environmental DNA (eDNA) sampling have potential for scaling up sampling of arthropod biodiversity for environmental monitoring, due to the high-throughput capabilities of such methods. However, we still do not have a clear understanding of how well molecular methods detect variation in arthropod biodiversity over space and time, particularly at fine grains. We therefore conducted a study employing a standard eDNA metabarcoding approach to monitor the composition of subterranean arthropod communities in a homogeneous forest (pine plantation) and a heterogeneous forest (regenerating native woody vegetation). We sampled the two habitats at a range of spatial scales (cm to m) and with temporal replicates over ten months to capture seasonal variation. Our analysis of almost 800 samples showed that arthropod community composition differed significantly between the two forest types and habitat explained 16.7% of the variation observed overall. However, we did not observe strong temporal or seasonal change in either richness or composition. We attribute the perceived lack of fine-grained spatiotemporal pattern to current limitations of eDNA metabarcoding, which captured inadequate biodiversity to detect changes at these fine grains. We show that increased sampling and replicate DNA extractions result in more biodiversity being captured and reveal amplification biases and a lack of taxonomic assignments. Identifying these weaknesses highlights where efforts to improve eDNA metabarcoding should be focused. The many benefits that eDNA metabarcoding can bring to biodiversity based ecological monitoring mean the efforts still required to improve the reliability and reproducibility of these methods are undoubtedly worthwhile priorities.

Background: Regular exercise is an effective non-pharmacological therapy for treatment and prevention of cardiovascular disease (CVD). The therapeutic benefits of exercise are mediated partly through improved vascular and increase in metabolic health. Release of exercise-responsive myokines, including irisin, is associated with beneficial effects of exercise in CVD patients.Observations: The present review provides an overview of the role of exercise in cardiac rehabilitation of patients with myocardial infarction (MI). Further, the role of irisin as a motion-responsive molecule in improving vascular and metabolic health is explored. Possible mechanism of cardioprotective effect of irisin-mediated exercise on myocardial infarction are also summarized in this review.Conclusion and significance of the review: Irisin is associated with reduced inflammation, antioxidant properties, and anti-apoptotic effect, implying that it is a potential key mediator of the beneficial effects of exercise on vascular and metabolic health. The findings show that irisin is a promising therapeutic target for treatment of patients with cardiovascular disease, particularly post-MI. Further research should be conducted to elucidate the potential mechanisms of cardioprotective effects of irisin and explored whether irisin induced by exercise exerts rehabilitation effects post-MI.

Abstract Background Involving peer volunteers in intervention delivery can provide social support and improve adherence. Whilst such interventions have the potential to reduce physical activity (PA) intervention costs, little is known about the process of delivering them in practice. This qualitative study explored the facilitators and challenges of delivering a peer-support PA intervention for older adults, with a view to making recommendations for the delivery of future interventions. Methods Data were collected via (7) semi-structured interviews and a focus group with stakeholders involved in a peer-support PA intervention for older adults in a large city in the North-West of England. Participants included local authority staff (n = 3), peer volunteers (n = 2) and service users (n = 7). Audio data were transcribed verbatim and thematically coded to identify perceived facilitators and challenges. Results Facilitators to delivery included social interaction, community referral pathways, suitable facilities, peer volunteers and high-quality instructors. Challenges surrounded inconsistent practice, staff capacity, safety and accountability, and awareness raising. Conclusions Peer volunteers can provide an additional support mechanism alongside qualified instructors for increasing social interaction within PA interventions. For optimal intervention delivery, consideration needs to be given to equipment and space, safety and accountability and consistency of practice.

The synthesis and characterisation of axially chiral atropisomeric 1,5-disubstituted 1,2,3-triazoles is reported. Molecules designed to display restricted rotation about 1,2,3-triazole N-1-aryl or 1,2,3-triazole C-5-aryl bonds were investigated by physical and computational techniques. The barrier to 1,2,3-triazole N-1-aryl rotation was found to be higher than that for 1,2,3-triazole C-5-aryl rotation, confirming axial chirality stemming from restricted rotation about an N-1-aryl bond in a 1,5-disubstituted 1,2,3-triazole to be the most suitable for the development of an axial chirality triazole-based platform.

As people, animals and materials are transported across increasingly large distances in a globalized world, threats to our biosecurity and food security are rising. Aotearoa New Zealand is an island nation with many endemic species, a strong local agricultural industry, and a need to protect these from pest threats, as well as the economy from fraudulent commodities. Mitigation of such threats is much more effective if their origins and pathways for entry are understood. We propose that this may be addressed in Aotearoa using strontium isotope analysis of both pests and products. Bioavailable radiogenic isotopes of strontium are ubiquitous markers of provenance that are increasingly used to trace the origin of animals and plants as well as products, but currently a baseline map across Aotearoa is lacking, preventing use of this technique. Here, we have improved an existing methodology to develop a regional bioavailable strontium isoscape using the best available geospatial datasets for Aotearoa. The isoscape explains 53% of the variation (R2 = 0.53 and RMSE = 0.00098) across the region, for which the primary drivers are the underlying geology, soil pH, and aerosol deposition (dust and sea salt). We tested the potential of this model to determine the origin of cow milk produced across Aotearoa. Predictions for cow milk (n = 33) highlighted all potential origin locations that share similar 87Sr/86Sr values, with the closest predictions averaging 7.05 km away from their true place of origin. These results demonstrate that this bioavailable strontium isoscape is effective for tracing locally produced agricultural products in Aotearoa. Accordingly, it could be used to certify the origin of Aotearoa's products, while also helping to determine if new pest detections were of locally breeding populations or not, or to raise awareness of imported illegal agricultural products.

Tendons are composed of a heterogeneous cell environment, with Scleraxis-lineage (ScxLin) cells being the predominant population. Although ScxLin cells are required for maintenance of tendon homeostasis, their functions during tendon healing are unknown. To this end, we first characterized the spatiotemporal dynamics of ScxLin cells during tendon healing, and identified that the overall ScxLin pool continuously expands up to early remodeling healing phase. To better define the function of ScxLin cells during the late proliferative phase of healing, we inducibly depleted ScxLin cells from day 14–18 post-surgery using the Scx-Cre; Rosa-DTR mouse model, with local administration of diphtheria toxin inducing apoptosis of ScxLin cells in the healing tendon. At D28 post-surgery, ScxLin cell depleted tendons (DTRScxLin) had substantial impairments in structure and function, relative to WT, demonstrating the importance of ScxLin cells during tendon healing. Next, bulk RNAseq was utilized to identify the underlying mechanisms that were impaired with depletion and revealed that ScxLin depletion induced molecular and morphological stagnation of the healing process at D28. However, this stagnation was transient, such that by D56 tendon mechanics in DTRScxLin were not significantly different than wildtype repairs. Collectively, these data offer fundamental knowledge on the dynamics and roles of ScxLin cells during tendon healing.

Background Cardiomyopathy is a common cause of atrial fibrillation (AF) and may also present as a complication of AF. However, there is a scarcity of evidence of clinical outcomes for people with cardiomyopathy and concomittant AF. The aim of the present study was therefore to characterize the prevalence of AF in major subtypes of cardiomyopathy and investigate the impact on important clinical outcomes. Methods and Results A retrospective cohort study was conducted using electronic medical records from a global federated health research network, with data primarily from the United States. The TriNetX network was searched on January 17, 2021, including records from 2002 to 2020, which included at least 1 year of follow‐up data. Patients were included based on a diagnosis of hypertrophic, dilated, or restrictive cardiomyopathy and concomitant AF. Patients with cardiomyopathy and AF were propensity‐score matched for age, sex, race, and comorbidities with patients who had a cardiomyopathy only. The outcomes were 1‐year mortality, hospitalization, incident heart failure, and incident stroke. Of 634 885 patients with cardiomyopathy, there were 14 675 (2.3%) patients with hypertrophic, 90 117 (7.0%) with restrictive, and 37 685 (5.9%) with dilated cardiomyopathy with concomitant AF. AF was associated with significantly higher odds of all‐cause mortality (odds ratio [95% CI]) for patients with hypertrophic (1.26 [1.13–1.40]) and dilated (1.36 [1.27–1.46]), but not restrictive (0.98 [0.94–1.02]), cardiomyopathy. Odds of hospitalization, incident heart failure, and incident stroke were significantly higher in all cardiomyopathy subtypes with concomitant AF. Among patients with AF, catheter ablation was associated with significantly lower odds of all‐cause mortality at 12 months across all cardiomyopathy subtypes. Conclusions Findings of the present study suggest AF may be highly prevalent in patients with cardiomyopathy and associated with worsened prognosis. Subsequent research is needed to determine the usefulness of screening and multisdisciplinary treatment of AF in this population.

We report the discovery of an ultrafaint dwarf (UFD) galaxy, Pegasus W, located on the far side of the Milky Way–M31 system and outside the virial radius of M31. The distance to the galaxy is ${915}_{-91}^{+60}$ kpc, measured using the luminosity of horizontal branch stars identified in Hubble Space Telescope optical imaging. The galaxy has a half-light radius ( r _h ) ${100}_{-13}^{+11}$ pc, ${M}_{V}=-{7.20}_{-0.16}^{+0.17}$ mag, and a present-day stellar mass ${6.5}_{-1.4}^{+1.1}\times {10}^{4}$ M _⊙ . We identify sources in the color–magnitude diagram (CMD) that may be younger than ∼500 Myr, suggesting late-time star formation in the UFD galaxy, although further study is needed to confirm these are bona fide young stars in the galaxy. Based on fitting the CMD with stellar evolution libraries, Pegasus W shows an extended star formation history. Using the τ _90 metric (defined as the timescale by which the galaxy formed 90% of its stellar mass), the galaxy was quenched only ${7.4}_{-2.6}^{+2.2}$ Gyr ago, which is similar to the quenching timescale of a number of UFD satellites of M31 but significantly more recent than the UFD satellites of the Milky Way. Such late-time quenching is inconsistent with the more rapid timescale expected by reionization and suggests that, while not currently a satellite of M31, Pegasus W was nonetheless slowly quenched by environmental processes.

Background: Several anthropometric measurements are used to assess cardiovascular risk and progress during clinical treatment. Most commonly used anthropometric measurements include total body weight and body mass index (BMI), with several other simple anthropometric measures typically underused in clinical practice. Herein, we review the evidence on the relationship between different anthropometric measurements and cardiovascular risk in patients with and without cardiovascular disease (CVD). Methods: Data for this review were identified by searches in PubMed, the Web of Science, Google Scholar, and references from relevant articles by using appropriate and related terms. The last search was performed on June 22, 2022. Articles published in English and Spanish were reviewed and included, if appropriate. We included studies detailing the relationship between skinfolds thickness, waist-to-hip ratio (WHR) and Conicity index with cardiovascular risk in adults with/without CVD. Results: In patients from the general population, elevated subscapular and triceps skinfolds showed a positive relationship with the development of hypertension, diabetes mellitus, hypercholesterolemia, cardiovascular mortality, and all-cause mortality. A higher subscapular skinfold was also associated with increased risk of coronary artery disease and stroke. A higher WHR, as well as other less common anthropometric measurements such as the Conicity index, was associated with an increased risk of myocardial infarction, incident CVD, major adverse cardiovascular events, and mortality in both patients with and without previous CVD. Conclusions: Non-traditional anthropometric measurements including skinfolds and WHR seem to improve the prediction of cardiovascular risk in the general population, and recurrent events in patients with previous CVD. Use of additional anthropometric techniques according to an objective and standardized method, may aid cardiovascular risk stratification in patients from the general population and the evaluation of therapeutic interventions for patients with CVD.

Sabulopteryx botanica Hoare & Patrick, sp. nov. (Lepidoptera, Gracillariidae, Gracillariinae) is described as a new species from New Zealand. It is regarded as endemic, and represents the first record of its genus from the southern hemisphere. Though diverging in some morphological features from previously described species, it is placed in genus Sabulopteryx Triberti, based on wing venation, abdominal characters, male and female genitalia and hostplant choice; this placement is supported by phylogenetic analysis based on the COI mitochondrial gene. The life history is described: the larva is an underside leaf-miner on the endemic divaricating shrub Teucrium parvifolium (Lamiaceae), and exits the mine to pupate in a cocoon in a folded leaf of the host plant. The remarkable history of the discovery and rediscovery of this moth is discussed: for many years it was only known from a single sap-feeding larva found in a leaf-mine in a pressed herbarium specimen of the host. The adult was discovered by BHP in Christchurch Botanic Gardens in 2013. Most distribution records of the moth come from a recent search for mines and cocoons on herbarium specimens of T. parvifolium. Sabulopteryx botanica has high conservation status, and is regarded as ‘Nationally Vulnerable’ according to the New Zealand Department of Conservation threat classification system, based on the rarity and declining status of its host plant. However, the presence of apparently thriving populations of S. botanica on cultivated plants of T. parvifolium, especially at the type locality, Christchurch Botanic Gardens, suggests that encouraging cultivation of the plant could greatly improve the conservation status of the moth. A revised checklist of New Zealand Gracillariidae is presented, assigning all species to the currently recognised subfamilies. The Australian Macarostola ida (Meyrick, 1880) is newly recorded from New Zealand (Auckland), where it is established on Eucalyptus.

Abstract Background In standard high throughput sequencing analysis, genetic variants are not assigned to a homologous chromosome of origin. This process, called haplotype phasing, can reveal information important for understanding the relationship between genetic variants and biological phenotypes. For example, in genes that carry multiple heterozygous missense variants, phasing resolves whether one or both gene copies are altered. Here, we present a novel approach to phasing variants that takes advantage of unique properties of paired tumor:normal sequencing data from cancer studies. Results VAF phasing uses changes in variant allele frequency (VAF) between tumor and normal samples in regions of somatic chromosomal gain or loss to phase germline variants. We apply VAF phasing to 6180 samples from the Cancer Genome Atlas (TCGA) and demonstrate that our method is highly concordant with other standard phasing methods, and can phase an average of 33% more variants than other read-backed phasing methods. Using variant annotation tools designed to score gene haplotypes, we find a suggestive association between carrying multiple missense variants in a single copy of a cancer predisposition gene and earlier age of cancer diagnosis. Conclusions VAF phasing exploits unique properties of tumor genomes to increase the number of germline variants that can be phased over standard read-backed methods in paired tumor:normal samples. Our phase-informed association testing results call attention to the need to develop more tools for assessing the joint effect of multiple genetic variants.

Background There is limited evidence of long‐term impact of exercise‐based cardiac rehabilitation (CR) on clinical end points for patients with atrial fibrillation (AF). We therefore compared 18‐month all‐cause mortality, hospitalization, stroke, and heart failure in patients with AF and an electronic medical record of exercise‐based CR to matched controls. Methods and Results This retrospective cohort study included patient data obtained on February 3, 2021 from a global federated health research network. Patients with AF undergoing exercise‐based CR were propensity‐score matched to patients with AF without exercise‐based CR by age, sex, race, comorbidities, cardiovascular procedures, and cardiovascular medication. We ascertained 18‐month incidence of all‐cause mortality, hospitalization, stroke, and heart failure. Of 1 366 422 patients with AF, 11 947 patients had an electronic medical record of exercise‐based CR within 6‐months of incident AF who were propensity‐score matched with 11 947 patients with AF without CR. Exercise‐based CR was associated with 68% lower odds of all‐cause mortality (odds ratio, 0.32; 95% CI, 0.29–0.35), 44% lower odds of rehospitalization (0.56; 95% CI, 0.53–0.59), and 16% lower odds of incident stroke (0.84; 95% CI, 0.72–0.99) compared with propensity‐score matched controls. No significant associations were shown for incident heart failure (0.93; 95% CI, 0.84–1.04). The beneficial association of exercise‐based CR on all‐cause mortality was independent of sex, older age, comorbidities, and AF subtype. Conclusions Exercise‐based CR among patients with incident AF was associated with lower odds of all‐cause mortality, rehospitalization, and incident stroke at 18‐month follow‐up, supporting the provision of exercise‐based CR for patients with AF.

Despite the requirement for Scleraxis-lineage (ScxLin) cells during tendon development, the function of ScxLin cells during adult tendon repair, post-natal growth, and adult homeostasis have not been defined. Therefore, we inducibly depleted ScxLin cells (ScxLinDTR) prior to tendon injury and repair surgery and hypothesized that ScxLinDTR mice would exhibit functionally deficient healing compared to wild-type littermates. Surprisingly, depletion of ScxLin cells resulted in increased biomechanical properties without impairments in gliding function at 28 days post-repair, indicative of regeneration. RNA sequencing of day 28 post-repair tendons highlighted differences in matrix-related genes, cell motility, cytoskeletal organization, and metabolism. We also utilized ScxLinDTR mice to define the effects on post-natal tendon growth and adult tendon homeostasis and discovered that adult ScxLin cell depletion resulted in altered tendon collagen fibril diameter, density, and dispersion. Collectively, these findings enhance our fundamental understanding of tendon cell localization, function, and fate during healing, growth, and homeostasis.

While individuals infected with coronavirus disease 2019 (COVID-19) manifested a broad range in susceptibility and severity to the disease, the pre-existing immune memory to related pathogens cross-reactive against SARS-CoV-2 can influence the disease outcome in COVID-19. Here, we investigated the potential extent of T cell cross-reactivity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be conferred by other coronaviruses and influenza virus, and generated an in silico map of public and private CD8+ T cell epitopes between coronaviruses. We observed 794 predicted SARS-CoV-2 epitopes of which 52% were private and 48% were public. Ninety-nine percent of the public epitopes were shared with SARS-CoV and 5.4% were shared with either one of four common coronaviruses, 229E, HKU1, NL63, and OC43. Moreover, to assess the potential risk of self-reactivity and/or diminished T cell response for peptides identical or highly similar to the host, we identified predicted epitopes with high sequence similarity with human proteome. Lastly, we compared predicted epitopes from coronaviruses with epitopes from influenza virus deposited in IEDB, and found only a small number of peptides with limited potential for cross-reactivity between the two virus families. We believe our comprehensive in silico profile of private and public epitopes across coronaviruses would facilitate design of vaccines, and provide insights into the presence of pre-existing coronavirus-specific memory CD8+ T cells that may influence immune responses against SARS-CoV-2.

Environmental DNA (eDNA) is becoming a standard tool in environmental monitoring that aims to quantify spatiotemporal variation for the measurement and prediction of ecosystem change. eDNA surveys have complex workflows encompassing multiple decision-making steps in which uncertainties can accumulate due to field sampling design, molecular biology lab work, and bioinformatics analyses. We conducted a quantitative review of studies published prior to December 2017 (n = 431) that had sampled eDNA from a variety of ecosystems and that had explicitly accounted for variability and uncertainty associated with eDNA workflows, either in their study design (e.g., replication) or data analysis (e.g., statistically modeling the spatiotemporal variation). We recorded differences among research studies in their spatial and temporal study design, the detected scales of natural variation in the study taxa, and how researchers measured and addressed the multiple sources of variability and uncertainty associated with the eDNA workflow. We show that relatively few studies used eDNA to understand temporal variation in biodiversity compared to spatial variation, and fewer described how uncertainties were addressed. We recommend increasing the number of temporal studies and to account for both natural variation and sources of uncertainty, such as imperfect detection, when undertaking eDNA surveys. Of studies that quantified spatiotemporal variation, this review identified gaps in the scales over which researchers have observed these patterns. Increasing the number of long-term and broad-scale eDNA studies will improve understanding of how useful eDNA is at scales relevant for monitoring the effects of environmental changes such as climatic shifts or land use change. Even where sources of spatiotemporal variation and uncertainty were accounted for, the effort in quantifying this variation differed among the different steps in the eDNA process, from field, to laboratory and bioinformatics procedures, depending on the type of community studied (micro- vs. macro-organism communities). We recommend more consistent experimental and modeling methods, accounting for spatiotemporal variation, and uncertainty in eDNA collection, and analysis, and incorporation of prior knowledge of sources of variability via Bayesian modeling approaches to account for uncertainties such as imperfect detection, to generate robust diversity estimates and increase the comparability of eDNA datasets for environmental monitoring across space and time.

Abstract Background Cancer susceptibility germline variants generally require somatic alteration of the remaining allele to drive oncogenesis and, in some cases, tumor mutational profiles. Whether combined germline and somatic bi-allelic alterations are universally required for germline variation to influence tumor mutational profile is unclear. Here, we performed an exome-wide analysis of the frequency and functional effect of bi-allelic alterations in The Cancer Genome Atlas (TCGA). Methods We integrated germline variant, somatic mutation, somatic methylation, and somatic copy number loss data from 7790 individuals from TCGA to identify germline and somatic bi-allelic alterations in all coding genes. We used linear models to test for association between mono- and bi-allelic alterations and somatic microsatellite instability (MSI) and somatic mutational signatures. Results We discovered significant enrichment of bi-allelic alterations in mismatch repair (MMR) genes and identified six bi-allelic carriers with elevated MSI, consistent with Lynch syndrome. In contrast, we find little evidence of an effect of mono-allelic germline variation on MSI. Using MSI burden and bi-allelic alteration status, we reclassify two variants of unknown significance in MSH6 as potentially pathogenic for Lynch syndrome. Extending our analysis of MSI to a set of 127 DNA damage repair (DDR) genes, we identified a novel association between methylation of SHPRH and MSI burden. Conclusions We find that bi-allelic alterations are infrequent in TCGA but most frequently occur in BRCA1/2 and MMR genes. Our results support the idea that bi-allelic alteration is required for germline variation to influence tumor mutational profile. Overall, we demonstrate that integrating germline, somatic, and epigenetic alterations provides new understanding of somatic mutational profiles.

Abstract The measured B-meson semi-leptonic branching ratios R D and RD* $$ {R}_{D^{*}} $$ have long-standing deviations between theory and experiment. We introduce a model which explains both anomalies through a single interaction by introducing a right-handed neutrino as the missing energy particle. This interaction is mediated by a heavy charged vector boson (W ′) which couples only to right-handed quarks and leptons of the Standard Model through the mixing of these particles with new vector-like fermions. Previous W ′ models for the RD* $$ {R}_{D^{\left(*\right)}} $$ anomaly were strongly constrained from flavor changing neutral currents and direct collider searches for Z ′ → τ τ resonances. We show that relying on right-handed fermion mixing enables us to avoid these constraints, as well as other severe bounds from electroweak precision tests and neutrino mixing.

Abstract Injuries to flexor tendons can be complicated by fibrotic adhesions, which severely impair the function of the hand. Adhesions have been associated with TGF-β1, which causes upregulation of PAI-1, a master suppressor of protease activity, including matrix metalloproteinases (MMP). In the present study, the effects of inhibiting PAI-1 in murine zone II flexor tendon injury were evaluated utilizing knockout (KO) mice and local nanoparticle-mediated siRNA delivery. In the PAI-1 KO murine model, reduced adherence of injured tendon to surrounding subcutaneous tissue and accelerated recovery of normal biomechanical properties compared to wild type controls were observed. Furthermore, MMP activity was significantly increased in the injured tendons of the PAI-1 KO mice, which could explain their reduced adhesions and accelerated remodeling. These data demonstrate that PAI-1 mediates fibrotic adhesions in injured flexor tendons by suppressing MMP activity. In vitro siRNA delivery to silence Serpine1 expression after treatment with TGF-β1 increased MMP activity. Nanoparticle-mediated delivery of siRNA targeting Serpine1 in injured flexor tendons significantly reduced target gene expression and subsequently increased MMP activity. Collectively, the data demonstrate that PAI-1 can be a druggable target for treating adhesions and accelerating the remodeling of flexor tendon injuries.

Abstract In previous work, we identified an anomalous number of events in the LHC jets+MET searches characterized by low jet multiplicity and low-to-moderate transverse energy variables. Here, we update this analysis with results from a new ATLAS search in the monojet channel which also shows a consistent excess. As before, we find that this “monojet excess” is well-described by the resonant production of a heavy colored state decaying to a quark and a massive invisible particle. In the combined ATLAS and CMS data, we now find a local (global) preference of 3.3σ (2.5σ) for the new physics model over the Standard Model-only hypothesis. As the signal regions containing the excess are systematics-limited, we consider additional cuts to enhance the signal-to-background ratio. We show that binning finer in H T and requiring the jets to be more central can increase S/B by a factor of ∼1.5.

Vascular interventions result in the disruption of the tunica intima and the exposure of sub-endothelial matrix proteins. Nanoparticles designed to bind to these exposed matrices could provide targeted drug delivery systems aimed at inhibiting dysfunctional vascular remodeling and improving intervention outcomes. Here, we present the progress in the development of targeted liposomal nanocarriers designed for preferential collagen IV binding under simulated static vascular flow conditions. PEGylated liposomes (PLPs), previously established as effective delivery systems in vascular cells types, served as non-targeting controls. Collagen-targeting liposomes (CT-PLPs) were formed by conjugating established collagen-binding peptides to modified lipid heads via click chemistry (CTL), and inserting them at varying mol% either at the time of PLP assembly or via micellar transfer. All groups included fluorescently labeled lipid species for imaging and quantification. Liposomes were exposed to collagen IV matrices statically or via hemodynamic flow, and binding was measured via fluorometric analyses. CT-PLPs formed with 5 mol% CTL at the time of assembly demonstrated the highest binding affinity to collagen IV under static conditions, while maintaining a nanoparticle characterization profile of ~50 nm size and a homogeneity polydispersity index (PDI) of ~0.2 favorable for clinical translation. When liposomes were exposed to collagen matrices within a pressurized flow system, empirically defined CT-PLPs demonstrated significant binding at shear stresses mimetic of physiological through pathological conditions in both the venous and arterial architectures. Furthermore, when human saphenous vein explants were perfused with liposomes within a closed bioreactor system, CT-PLPs demonstrated significant ex vivo binding to diseased vascular tissue. Ongoing studies aim to further develop CT-PLPs for controlled targeting in a rodent model of vascular injury. The CT-PLP nanocarriers established here show promise as the framework for a spatially controlled delivery platform for future application in targeted vascular therapeutics.