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BackgroundIn May 2022, a global surge in mpox cases, typically endemic to Western and Central Africa, particularly affected gay, bisexual, and other men who have sex with men (gbMSM). This study examines gbMSM communities' experiences and perceptions around Ireland's public health response to the outbreak.MethodsA cross-sectional mixed-methods online survey was conducted. Qualitative data were analysed using reflexive thematic analysis informed by critical realism.FindingsA total of 163 gay and bisexual men took part in the survey. Participants accessed information from diverse sources, reporting varying levels of trustworthiness. Overall, participants were well-informed. Four themes were developed from the qualitative data: (1) Perceptions of the mpox response: divergence in urgency, priority, and care; (2) The mpox outbreak as a sign of otherness for gbMSM; (3) The potential for othering through mpox prevention practices; and (4) mpox, memory and fear.DiscussionWhile community-led initiatives were effective, significant challenges included stigmatisation, discrimination, and mistrust towards public health institutions, influenced by institutionalised homophobia. The study underscores the need for inclusive, culturally sensitive, and transparent public health strategies.ConclusionThe mpox outbreak highlights the importance of robust community collaboration in public health interventions. Future strategies must ensure equitable access to information, vaccination, and care, and address broader structural inequalities to foster trust and engagement within affected communities.

Cardiopulmonary and renal end organ (CPR) complications are associated with early mortality among individuals with sickle cell disease (SCD). However, there is limited knowledge regarding acute care utilization for individuals with SCD and CPR complications. Our objective was to determine the prevalence of CPR complications in a state specific SCD population and compare acute care utilization among individuals with and without CPR complications. We leveraged 2017-2020 data for individuals with SCD identified by the Sickle Cell Data Collection program in Wisconsin. The prevalence of CPR complications is determined for distinct age groups. Generalized linear models adjusted for age compared the rate of acute care visits/person/year among individuals who had cardiopulmonary only, renal only, both cardiopulmonary and renal, or no CPR complications. There were 1378 individuals with SCD, 52% females, mean (SD) age 28.3 (18.5) years; 48% had at least one CPR complication during the study period. The prevalence of CPR complications was higher in adults (69%) compared to pediatric (15%) and transition (51%) groups. Individuals with SCD and cardiopulmonary complications had higher acute visit rates than those without CPR complications (5.4 (IQR 5.0-5.8) vs 2.4 (IQR 2.1-2.5), p

Fibrosis is a pathognomonic feature of structural heart disease and counteracted by distinct cardioprotective mechanisms, e.g. activation of the phosphoinositide 3-kinase (PI3K) / AKT pro-survival pathway. The Cullin-RING E3 ubiquitin ligase 7 (CRL7) was identified as negative regulator of PI3K/AKT signalling in skeletal muscle, but its role in the heart remains to be elucidated. Here, we sought to determine whether CRL7 modulates to cardiac fibrosis following pressure overload and dissect its underlying mechanisms. For inactivation of CRL7, the Cullin 7 (Cul7) gene was deleted in cardiac myocytes (CM) by injection of adeno-associated virus subtype 9 (AAV9) vectors encoding codon improved Cre-recombinase (AAV9-CMV-iCre) in Cul7flox/flox mice. In addition, Myosin Heavy Chain 6 (Myh6; alpha-MHC)-MerCreMer transgenic mice with tamoxifen-induced CM-specific expression of iCre were used as alternate model. After transverse aortic constriction (TAC), causing chronic pressure overload and fibrosis, AAV9-CMV-iCre induced Cul7-/- mice displayed a ~50% reduction of interstitial cardiac fibrosis when compared to Cul7+/+ animals (6.7% vs. 3.4%, p

In patients with sickle cell disease (SCD), poor outcome measures compromise the potential success of clinical trials. Contrast-enhanced ultrasound (CEUS) is a technique that can non-invasively quantify deep tissue microvascular blood flow. We tested the hypothesis that CEUS of forearm skeletal muscle could be used to: 1) assess microvascular abnormalities that occur during vaso-occlusive crisis; and 2) test new therapies for SCD that are targeted to improving the status of the microcirculation. We performed a prospective study, CEUS perfusion imaging of resting forearm muscle was performed in adults with SCD: 1) during and after a pain episode, and 2) before, during, and after a 24-hour infusion of the investigative agent, regadenoson, an adenosine A2A agonist. CEUS destruction-replenishment time-intensity data were analyzed to measure microvascular blood flow, as well as its components, microvascular blood volume and flux rate. Serial CEUS measurements were obtained in 32 adults with SCD. For the studies during crisis, there was a 30% reduction in microvascular blood flow compared to steady-state (p = 0.031), a reduction that was largely due to microvascular flux rate. For the regadenoson group, a non-significant 25% increase in flux rate and 9% increase in microvascular blood flow compared to baseline were detected during infusion. In a study of adults with SCD, CEUS detected changes in microvascular blood flow associated with vaso-occlusive crises. No changes were found during an infusion of the adenosine A2A agonist, regadenoson. This study provides preliminary evidence that CEUS could detect blood flow changes consistent with SCD physiology.

Chronic pain affects 50% of adults with sickle cell disease (SCD). Although central sensitization is thought to contribute to the pathogenesis of this chronic pain, no studies have examined differences in functional connectivity of the brain between patients with SCD with and without chronic pain. We performed an observational cohort study using resting-state functional MRI (rsfMRI) of the brain on adults with SCD with and without chronic pain. We tested the hypothesis that, compared to those without chronic pain, those with chronic pain would have differences in functional connectivity between the periaqueductal grey (PAG) and other regions of the brain. Twenty-two adults with SCD, 15 with chronic pain and 7 without chronic pain, as well as 10 African-American controls, underwent rsfMRI of the brain. When SCD patients with chronic pain were compared to those without chronic pain, significant differences in connectivity were noted between the PAG and 9 regions of the brain, including several in the default mode network, a network involved in introspection that has been implicated in other chronic pain syndromes. Changes in functional connectivity between patients with SCD with and without chronic pain suggest a mechanism for chronic pain that involves neuro-plastic changes to the brain.

OBJECTIVE:To (1) characterise the chemical and ultra-structural composition of ameroid constrictors, at a native state and during in vitro expansion and (2) determine the presence of irritant compounds at the surface or within the bulk of the constrictor. METHODS:Twelve sterile, commercially packaged ameroid constrictors (3 repeats of 3.5 mm, 5 mm, 6 mm and 7 mm internal diameter) were analysed by time-of-flight secondary ion mass spectrometry, Raman spectroscopy, attenuated total reflectance Fourier transform infrared spectroscopy and scanning electron microscopy. RESULTS:Ameroid constrictors have a composition commensurate with casein with little-to-no intra- or inter- constrictor variation. Microscopic analysis indicated that the topographical features of the constrictor surfaces were consistent between all constrictors. Following in vitro expansion there was a reproducible decrease in Ca+ ion content, little-to-no variation in secondary protein structure and morphological changes including the presence of surface aggregates present only at the inner surface of the ameroid constrictor. The potential irritant polydimethylsiloxane was found on the constrictor surface. A trace quantity of an ion fragment assigned as formaldehyde was detected; however, the extremely low level is thought highly unlikely to play a role as an inflammatory trigger clinically. DISCUSSION:There is a high degree of inter- and intra-constrictor homogeneity from different batches, and reproducible ultrastructural changes following in vitro expansion. Variations occur in both the surface chemistry and topography of the device during closure, which can potentially affect the biomaterial-host interface. Ameroid constrictor closure mechanism is likely involving calcium-mediated inter-protein interactions rather than the imbibition of water only.

Invariant NKT (iNKT) cells can be activated to stimulate a broad inflammatory response. In murine models of sickle cell disease (SCD), interruption of iNKT cell activity prevents tissue injury from vaso-occlusion. NKTT120 is an anti-iNKT cell monoclonal antibody that has the potential to rapidly and specifically deplete iNKT cells and, potentially, prevent vaso-occlusion. We conducted an open-label, multi-center, single-ascending-dose study of NKTT120 to determine its pharmacokinetics, pharmacodynamics and safety in steady-state patients with SCD. Doses were escalated in a 3+3 study design over a range from 0.001 mg/kg to 1.0 mg/kg. Twenty-one adults with SCD were administered NKTT120 as part of 7 dose cohorts. Plasma levels of NKTT120 predictably increased with higher doses. Median half-life of NKTT120 was 263 hours. All subjects in the higher dose cohorts (0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg) demonstrated decreased iNKT cells below the lower limit of quantification within 6 hours after infusion, the earliest time point at which they were measured. In those subjects who received the two highest doses of NKTT120 (0.3, 1 mg/kg), iNKT cells were not detectable in the peripheral blood for a range of 2 to 5 months. There were no serious adverse events in the study deemed to be related to NKTT120. In adults with SCD, NKTT120 produced rapid, specific and sustained iNKT cell depletion without any infusional toxicity or attributed serious adverse events. The next step is a trial to determine NKTT120's ability to decrease rate of vaso-occlusive pain episodes.clinicaltrials.gov NCT01783691.

Thrombosis-associated pathologies, such as myocardial infarction and stroke, are major causes of morbidity and mortality worldwide. Because platelets are necessary for hemostasis and thrombosis, platelet directed therapies must balance inhibiting platelet function with bleeding risk. Glutamate receptor interacting protein 1 (GRIP1) is a large scaffolding protein that localizes and organizes interacting proteins in other cells, such as neurons. We have investigated the role of GRIP1 in platelet function to determine its role as a molecular scaffold in thrombus formation. Platelet-specific GRIP1-/- mice were used to determine the role of GRIP1 in platelets. GRIP1-/- mice had normal platelet counts, but a prolonged bleeding time and delayed thrombus formation in a FeCl3-induced vessel injury model. In vitro stimulation of WT and GRIP1-/- platelets with multiple agonists showed no difference in platelet activation. However, in vivo platelet rolling velocity after endothelial stimulation was significantly greater in GRIP1-/- platelets compared to WT platelets, indicating a potential platelet adhesion defect. Mass spectrometry analysis of GRIP1 platelet immunoprecipitation revealed enrichment of GRIP1 binding to GPIb-IX complex proteins. Western blots confirmed the mass spectrometry findings that GRIP1 interacts with GPIbα, GPIbβ, and 14-3-3. Additionally, in resting GRIP1-/- platelets, GPIbα and 14-3-3 have increased interaction compared to WT platelets. GRIP1 interactions with the GPIb-IX binding complex are necessary for normal platelet adhesion to a stimulated endothelium.

The aims of this study were to determine if pregnant women consumed the recommended vitamin D through diet alone or through diet and supplements, and if they achieved the current reference range vitamin D status when their reported dietary intake met the current recommendations.Data and banked blood samples collected in second trimester from a subset of 537 women in the APrON (Alberta Pregnant Outcomes and Nutrition) study cohort were examined. Frozen collected plasma were assayed using LC-MS/MS (liquid chromatography-tandem mass spectrometry) to determine 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D3 concentrations. Dietary data were obtained from questionnaires including a Supplement Intake Questionnaire and a 24-hour recall of the previous day's diet.Participants were 87% Caucasian; mean (SD) age of 31.3 (4.3); BMI 25.8 (4.7); 58% were primiparous; 90% had education beyond high school; 80% had a family income higher than CAN $70,000/year. 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3) were identified in all of the 537 plasma samples;3-epi-25(OH)D3 contributed 5% of the total vitamin D. The median (IQR) total 25(OH)D (D2+D3) was 92.7 (30.4) nmol/L and 20% of women had 25(OH)D concentration < 75 nmol/L. The median (IQR) reported vitamin D intake from diet and supplements was 600 (472) IU/day. There was a significant relationship between maternal reported dietary vitamin D intake (diet and supplement) and 25(OH)D and 3-epi-25(OH)D3 concentrations in an adjusted linear regression model.We demonstrated the current RDA (600 IU/ day) may not be adequate to achieve vitamin D status >75 nmol/L in some pregnant women who are residing in higher latitudes (Calgary, 51°N) in Alberta, Canada and the current vitamin D recommendations for Canadian pregnant women need to be re-evaluated.

Parthenogenetic stem cells (PSCs) are a promising candidate donor for cell therapy applications. Similar to embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), PSCs exhibit self-renewing capacity and clonogenic proliferation in vitro. PSCs exhibit largely haploidentical genotype, and as such may constitute an attractive population for allogenic applications. In this study, PSCs isolated from transgenic mice carrying a cardiomyocyte-restricted reporter transgene to permit tracking of donor cells were genetically modified to carry a cardiomyocyte-restricted aminoglycoside phosphotransferase expression cassette (MHC-neor/pGK-hygror) to permit the generation of highly enriched cardiomyocyte cultures from spontaneously differentiating PSCs by simple selection with the neomycin analogue G148. Following engraftment into isogenic recipient hearts, the selected cardiomyocytes formed a functional syncytium with the host myocardium as evidenced by the presence of entrained intracellular calcium transients. These cells thus constitute a potential source of therapeutic donor cells.

Neuregulin 1 signaling plays an important role in cardiac trabecular development, and in sustaining functional integrity in adult hearts. Treatment with neuregulin 1 enhances adult cardiomyocyte differentiation, survival and/or function in vitro and in vivo. It has also been suggested that recombinant neuregulin 1β1 (NRG1β1) induces cardiomyocyte proliferation in normal and injured adult hearts. Here we further explore the impact of neuregulin 1 signaling on adult cardiomyocyte cell cycle activity.Adult mice were subjected to 9 consecutive daily injections of recombinant NRG1β1 or vehicle, and cardiomyocyte DNA synthesis was quantitated via bromodeoxyuridine (BrdU) incorporation, which was delivered using mini-osmotic pumps over the entire duration of NRG1β1 treatment. NRG1β1 treatment inhibited baseline rates of cardiomyocyte DNA synthesis in normal mice (cardiomyocyte labelling index: 0.019±0.005% vs. 0.003±0.001%, saline vs. NRG1β1, P0.05).These data indicate that NRG1β1 treatment does not increase cardiomyocyte DNA synthesis (and consequently does not increase the rate of cardiomyocyte renewal) in normal or infarcted adult mouse hearts. Thus, any improvement in cardiac structure and function observed following neuregulin treatment of injured hearts likely occurs independently of overt myocardial regeneration.

Reperfusion injury following tissue ischemia occurs as a consequence of vaso-occlusion that is initiated by activation of invariant natural killer T (iNKT) cells. Sickle cell disease (SDC) results in widely disseminated microvascular ischemia and reperfusion injury as a result of vaso-occlusion by rigid and adhesive sickle red blood cells. In mice, iNKT cell activation requires NF-κB signaling and can be inhibited by the activation of anti-inflammatory adenosine A2A receptors (A2ARs). Human iNKT cells are divided into subsets of CD4+ and CD4- cells. In this study we found that human CD4+ iNKT cells, but not CD4- cells undergo rapid NF-κB activation (phosphorylation of NF-κB on p65) and induction of A2ARs (detected with a monoclonal antibody 7F6-G5-A2) during SCD painful vaso-occlusive crises. These findings indicate that SCD primarily activates the CD4+ subset of iNKT cells. Activation of NF-κB and induction of A2ARs is concordant, i.e. only CD4+ iNKT cells with activated NF-κB expressed high levels of A2ARs. iNKT cells that are not activated during pVOC express low levels of A2AR immunoreactivity. These finding suggest that A2AR transcription may be induced in CD4+ iNKT cells as a result of NF-κB activation in SCD. In order to test this hypothesis further we examined cultured human iNKT cells. In cultured cells, blockade of NF-κB with Bay 11-7082 or IKK inhibitor VII prevented rapid induction of A2AR mRNA and protein upon iNKT activation. In conclusion, NF-κB-mediated induction of A2ARs in iNKT cells may serve as a counter-regulatory mechanism to limit the extent and duration of inflammatory immune responses. As activated iNKT cells express high levels of A2ARs following their activation, they may become highly sensitive to inhibition by A2AR agonists.

Scaling relationships between skeletal dimensions and body mass in extant birds are often used to estimate body mass in fossil crown-group birds, as well as in stem-group avialans. However, useful statistical measurements for constraining the precision and accuracy of fossil mass estimates are rarely provided, which prevents the quantification of robust upper and lower bound body mass estimates for fossils. Here, we generate thirteen body mass correlations and associated measures of statistical robustness using a sample of 863 extant flying birds. By providing robust body mass regressions with upper- and lower-bound prediction intervals for individual skeletal elements, we address the longstanding problem of body mass estimation for highly fragmentary fossil birds. We demonstrate that the most precise proxy for estimating body mass in the overall dataset, measured both as coefficient determination of ordinary least squares regression and percent prediction error, is the maximum diameter of the coracoid's humeral articulation facet (the glenoid). We further demonstrate that this result is consistent among the majority of investigated avian orders (10 out of 18). As a result, we suggest that, in the majority of cases, this proxy may provide the most accurate estimates of body mass for volant fossil birds. Additionally, by presenting statistical measurements of body mass prediction error for thirteen different body mass regressions, this study provides a much-needed quantitative framework for the accurate estimation of body mass and associated ecological correlates in fossil birds. The application of these regressions will enhance the precision and robustness of many mass-based inferences in future paleornithological studies.

In birds and feathered non-avian dinosaurs, within-feather pigmentation patterns range from discrete spots and stripes to more subtle patterns, but the latter remain largely unstudied. A ∼55 million year old fossil contour feather with a dark distal tip grading into a lighter base was recovered from the Fur Formation in Denmark. SEM and synchrotron-based trace metal mapping confirmed that this gradient was caused by differential concentration of melanin. To assess the potential ecological and phylogenetic prevalence of this pattern, we evaluated 321 modern samples from 18 orders within Aves. We observed that the pattern was found most frequently in distantly related groups that share aquatic ecologies (e.g. waterfowl Anseriformes, penguins Sphenisciformes), suggesting a potential adaptive function with ancient origins.

BackgroundIn horned dinosaurs, taxonomy is complicated by the fact that the cranial ornament that distinguishes species changes with age. Based on this observation, it has been proposed that the genera Triceratops and Torosaurus are in fact synonymous, with specimens identified as Torosaurus representing the adult form of Triceratops. The hypothesis of synonymy makes three testable predictions: 1) the species in question should have similar geographic and stratigraphic distributions, 2) specimens assigned to Torosaurus should be more mature than those assigned to Triceratops, and 3) intermediates should exist that combine features of Triceratops and Torosaurus. The first condition appears to be met, but it remains unclear whether the other predictions are borne out by the fossil evidence.Methodology/principal findingsWe assessed the relative maturity of Torosaurus and Triceratops specimens by coding skulls for characters that vary with maturity, and then using a clustering analysis to arrange them into a growth series. We found that a well-defined sequence of changes exists in horned dinosaurs: development of cranial ornament occurs in juveniles, followed by fusion of the skull roof in subadults, and finally, the epoccipitals, epijugals, and rostral fuse to the skull in adults. Using this scheme, we identified mature and immature individuals of both Torosaurus and Triceratops. Furthermore, we describe the ventral depressions on the frill of Triceratops, and show that they differ in shape and position from the parietal fenestrae of Torosaurus. Thus, we conclude that these structures are not intermediates between the solid frill of Triceratops and the fenestrated frill of Torosaurus.Conclusions/significanceTorosaurus is a distinct genus of horned dinosaur, not the adult of Triceratops. Our method provides a framework for assessing the hypothesis of synonymy through ontogeny in the fossil record.

Interstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease.Fibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology.These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.

The RpoE and CpxR regulated envelope stress responses are extremely important for Salmonella Typhimurium to cause infection in a range of hosts. Until now the role for BaeSR in both the Salmonella Typhimurium response to stress and its contribution to infection have not been fully elucidated. Here we demonstrate stationary phase growth, iron and sodium tungstate as novel inducers of the BaeRregulon, with BaeR critically required for Salmonella resistance to sodium tungstate. We show that functional overlap between the resistance nodulation-cell division (RND) multidrug transporters, MdtA, AcrD and AcrB exists for the waste disposal of tungstate from the cell. We also point to a role for enterobactinsiderophores in the protection of enteric organisms from tungstate, akin to the scenario in nitrogen fixing bacteria. Surprisingly, BaeR is the first envelope stress response pathway investigated in S. Typhimurium that is not required for murine typhoid in either ity(S) or ity(R) mouse backgrounds. BaeR is therefore either required for survival in larger mammals such as pigs or calves, an avian host such as chickens, or survival out with the host altogether where Salmonella and related enterics must survive in soil and water.

Cerebral malaria continues to be a difficult to treat complication of Plasmodium falciparum infection in children. We have shown that platelets can have major deleterious immune functions in experimental cerebral malaria (ECM). One of the platelet derived mediators we have identified as particularly important is platelet factor 4/CXCL4. Our prior work demonstrated that PF4(-/-) mice are protected from ECM, have reduced plasma cytokines, and have reduced T-cell trafficking to the brain. We now show that PF4 drives monocyte cytokine production in a Kruppel like factor 4 (KLF4) dependent manner. Monocyte depleted Plasmodium berghei infected mice have improved survival, and KLF4 is greatly increased in control, but not monocyte depleted mice. PF4(-/-) mice have less cerebral monocyte trafficking and no change in KLF4 expression. These data indicate that PF4 induction of monocyte KLF4 expression may be an important step in the pathogenesis of ECM.

Cultured cardiac explants produce a heterogeneous population of cells including a distinctive population of refractile cells described here as small round cardiac explant derived cells (EDCs). The aim of this study was to explore the source, morphology and cardiogenic potential of EDCs.Transgenic MLC2v-Cre/ZEG, and actin-eGFP mice were used for lineage-tracing of EDCs in vitro and in vivo. C57B16 mice were used as cell transplant recipients of EDCs from transgenic hearts, as well as for the general characterisation of EDCs. The activation of cardiac-specific markers were analysed by: immunohistochemistry with bright field and immunofluorescent microscopy, electron microscopy, PCR and RT-PCR. Functional engraftment of transplanted cells was further investigated with calcium transient studies.Production of EDCs was highly dependent on the retention of blood-derived cells or factors in the cultured explants. These cells shared some characteristics of cardiac myocytes in vitro and survived engraftment in the adult heart in vivo. However, EDCs failed to differentiate into functional cardiac myocytes in vivo as demonstrated by the absence of stimulation-evoked intracellular calcium transients following transplantation into the peri-infarct zone.This study highlights that positive identification based upon one parameter alone such as morphology or immunofluorescene is not adequate to identify the source, fate and function of adult cardiac explant derived cells.

The sweat bee Halictus rubicundus is an important pollinator with a large latitudinal range and many potential barriers to gene flow. Alongside typical physical barriers, including mountain ranges and oceans, the climate may also impose restrictions on gene flow in this species. The climate influences voltinism and sociality in H. rubicundus, which is bivoltine and can nest socially at warmer lower latitudes but tends to be univoltine and solitary in the cooler north. Variation in voltinism could result in phenological differences, potentially limiting gene flow, but a previous study found no evidence for this in H. rubicundus populations in mainland Britain. Here we extend the previous study to consider populations of H. rubicundus at extreme northern and southern latitudes in the UK. We found that bees from a population in the far north of Scotland were genetically differentiated from bees collected in Cornwall in the south-west of England. In contrast, bees collected across the Irish Sea in Northern Ireland showed slight genetic overlap with both the Scottish and Cornish bees. Our results suggest that when populations at extreme latitudes are considered, phenology and the climate may act alongside physical barriers such as the Scottish Highlands and the Irish Sea to restrict gene flow in H. rubicundus. We discuss the implications of our results for local adaptation in the face of rapidly changing selection pressures which are likely under climate change., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Michels et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The world's elderly population is growing at a rapid pace. This has led to an increase in demand on the health and welfare systems due to age-related disorders, with musculoskeletal complaints driving the need for rehabilitation services. However, there are concerns about health services' ability to meet this demand. While chiropractic care is gaining recognition for its benefits in treating older adults with musculoskeletal disorders, there is limited scientific literature on chiropractors' role and experiences in this area. To bridge this gap, we interviewed 21 chiropractors in Great Britain, the Netherlands, Norway, and Sweden. Inductive qualitative content analysis was used to analyse the interviews, and despite differences in integration and regulation between the countries, several common facilitators and barriers in caring for and managing older patients with musculoskeletal complaints emerged. While participants expressed optimism about future collaborations with other healthcare professionals and the integration of chiropractic into national healthcare systems, they also highlighted significant concerns regarding the existing healthcare infrastructure. The participants also felt that chiropractors, with their non-surgical and holistic approach, were well-positioned to be the primary point of contact for older patients. However, there were some common barriers, such as the affordability of care, limited integration of chiropractic, and the need to prioritise musculoskeletal complaints within public healthcare. Our findings suggest that chiropractors experience their clinical competencies as an underutilised resource in the available healthcare systems and that they could contribute to and potentially reduce the escalating burden of musculoskeletal complaints and associated costs among older patients. Additionally, our findings highlight the desire among the participants to foster collaboration among healthcare professionals and integrate chiropractic into the national public healthcare system. Integrating chiropractors as allied health professionals was also perceived to improve coordinated, patient-centred healthcare for older adults., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bergström et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Eusociality, where workers typically forfeit their own reproduction to assist their mothers in raising siblings, is a fundamental paradox in evolutionary biology. By sacrificing personal reproduction, helpers pay a significant cost, which must be outweighed by indirect fitness benefits of helping to raise siblings. In 1983, Jon Seger developed a model showing how in the haplodiploid Hymenoptera (ants, wasps and bees), a partially bivoltine life cycle with alternating sex ratios may have promoted the evolution of eusociality. Seger predicted that eusociality would be more likely to evolve in hymenopterans where a foundress produces a male-biased first brood sex ratio and a female-biased second brood. This allows first brood females to capitalize on super-sister relatedness through helping to produce the female-biased second brood. In Seger's model, the key factor driving alternating sex ratios was that first brood males survive to mate with females of both the second and the first brood, reducing the reproductive value of second brood males. Despite being potentially critical in the evolution of eusociality, however, male survivorship has received little empirical attention. Here, we tested whether first brood males survive across broods in the facultatively eusocial sweat bee Halictus rubicundus. We obtained high estimates of survival and, while recapture rates were low, at least 10% of first brood males survived until the second brood. We provide empirical evidence supporting Seger's model. Further work, measuring brood sex ratios and comparing abilities of first and second brood males to compete for fertilizations, is required to fully parameterize the model., Competing Interests: The authors have declared that no competing interests exist.

Since the early 2000s, unconventional natural gas development (UNGD) has rapidly grown throughout Pennsylvania. UNGD extracts natural gas using a relatively new method known as hydraulic fracturing (HF). Here we addressed the association of HF with asthma Hospitalization Admission Rates (HAR) using publicly available data. Using public county-level data from the Pennsylvania Department of Health (PA-DOH) and the Pennsylvania Department of Environmental Protection for the years 2001-2014, we constructed regression models to study the previously observed association between asthma exacerbation and HF. After considering multicollinearity, county-level demographics and area-level covariables were included to account for known asthma risk factors. We found a significant positive association between the asthma HAR and annual well density for all the counties in the state (3% increase in HAR attributable to HF, p<0.001). For a sensitivity analysis, we excluded urban counties (urban counties have higher asthma exacerbations) and focused on rural counties for the years 2005-2014 and found a significant association (3.31% increase in HAR attributable to HF in rural counties, p<0.001). An even stronger association was found between asthma hospitalization admission rates (HAR) and PM2.5 levels (7.52% increase in HAR attributable to PM2.5, p<0.001). As expected, asthma HAR was significantly higher in urban compared to rural counties and showed a significant racial disparity. We conclude that publicly available data at the county-level supports an association between an increase in asthma HAR and UNGD in rural counties in Pennsylvania., Competing Interests: The authors declare that they have no known conflicts of interests that could appear to influence the work in this manuscript.

Cooperation among kin is common in animal societies. Kin groups may form by individuals directly discriminating relatives based on kin recognition cues, or form passively through natal philopatry and limited dispersal. We describe the genetic landscape for a primitively eusocial wasp, Polistes dominula, and ask whether individuals choose cooperative partners that are nearby and/or that are genetic relatives. Firstly, we genotyped an entire sub-population of 1361 wasps and found genetic structuring on an extremely fine scale: the probability of finding genetic relatives decreases exponentially within just a few meters of an individual's nest. At the same time, however, we found a lack of genetic structuring between natural nest aggregations within the population. Secondly, in a separate dataset where ~2000 wasps were genotyped, we show that wasps forced experimentally to make a new nest choice tended to choose new nests near to their original nests, and that these nests tended to contain some full sisters. However, a significant fraction of wasps chose nests that did not contain sisters, despite sisters being present in nearby nests. Although we cannot rule out a role for direct kin recognition or natal nest-mate recognition, our data suggest that kin groups may form via a philopatric rule-of-thumb, whereby wasps simply select groups and nesting sites that are nearby. The result is that most subordinate helpers obtain indirect fitness benefits by breeding cooperatively., Competing Interests: The authors have declared that no competing interests exist.

Background: An association between low socioeconomic status (SES) and lung cancer has been observed in several studies, but often without adequate control for smoking behavior. We studied the association between lung cancer and occupationally derived SES, using data from the international pooled SYNERGY study., Methods: Twelve case-control studies from Europe and Canada were included in the analysis. Based on occupational histories of study participants we measured SES using the International Socio-Economic Index of Occupational Status (ISEI) and the European Socio-economic Classification (ESeC). We divided the ISEI range into categories, using various criteria. Stratifying by gender, we calculated odds ratios (OR) and 95% confidence intervals (CI) by unconditional logistic regression, adjusting for age, study, and smoking behavior. We conducted analyses by histological subtypes of lung cancer and subgroup analyses by study region, birth cohort, education and occupational exposure to known lung carcinogens., Results: The analysis dataset included 17,021 cases and 20,885 controls. There was a strong elevated OR between lung cancer and low SES, which was attenuated substantially after adjustment for smoking, however a social gradient persisted. SES differences in lung cancer risk were higher among men (lowest vs. highest SES category: ISEI OR 1.84 (95% CI 1.61-2.09); ESeC OR 1.53 (95% CI 1.44-1.63)), than among women (lowest vs. highest SES category: ISEI OR 1.54 (95% CI 1.20-1.98); ESeC OR 1.34 (95% CI 1.19-1.52))., Conclusion: SES remained a risk factor for lung cancer after adjustment for smoking behavior.

Austronesian speaking peoples left Southeast Asia and entered the Western Pacific c.4000-3000 years ago, continuing on to colonise Remote Oceania for the first time, where they became the ancestral populations of Polynesians. Understanding the impact of these peoples on the mainland of New Guinea before they entered Remote Oceania has eluded archaeologists. New research from the archaeological site of Wañelek in the New Guinea Highlands has broken this silence. Petrographic and geochemical data from pottery and new radiocarbon dating demonstrates that Austronesian influences penetrated into the highland interior by 3000 years ago. One potsherd was manufactured along the northeast coast of New Guinea, whereas others were manufactured from inland materials. These findings represent the oldest securely dated pottery from an archaeological context on the island of New Guinea. Additionally, the pottery comes from the interior, suggesting the movements of people and technological practices, as well as objects at this time. The antiquity of the Wañelek pottery is coincident with the expansion of Lapita pottery in the Western Pacific. Such occupation also occurs at the same time that changes have been identified in subsistence strategies in the archaeological record at Kuk Swamp suggesting a possible link between the two.

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS.

Study Objective: Examine the effect of experimental sleep restriction (SR) on adolescents' subjective hunger and perceived appeal of sweet/dessert foods versus other foods. A secondary goal was to replicate previous findings on the effects of SR on dietary intake., Design: Randomized cross-over sleep restriction-extension paradigm., Setting: Sleep was obtained and monitored at home. Outcome measures were gathered during office visits., Participants: 31 typically-developing adolescents aged 14-17 years., Interventions: The three-week protocol consisted of a baseline week, followed randomly by five consecutive nights of SR (6.5 hours in bed) versus healthy sleep duration (HS; 10 hours in bed), a 2-night wash-out period, and a 5-night cross-over., Measurements: Sleep was monitored via actigraphy. The morning after each experimental condition, teens rated their hunger, underwent a 24-hour diet recall interview, and rated the appeal of a series of pictures of sweet/dessert foods (e.g., ice cream, candy) and non-sweets (meat, eggs, fruits, vegetables)., Results: Teens rated pictures of sweet/dessert foods to be more appealing after SR than after HS (Cohen's d = .41, t = 2.07, p = .045). The sleep manipulation did not affect self-reported hunger or the appeal of non-sweet foods (p >.10). Consistent with our prior work, intake of overall calories was 11% higher and consumption of sweet/dessert servings was 52% greater during SR than HS., Conclusions: Adolescent SR appears to increase the subjective appeal of sweet/dessert foods, indicating a potential mechanism by which SR might contribute to weight gain and the risk for obesity and chronic illness.

Multiple sclerosis (MS) is a debilitating, chronic demyelinating disease of the central nervous system affecting over 2 million people worldwide. The TAM family of receptor tyrosine kinases (TYRO3, AXL and MERTK) have been implicated as important players during demyelination in both animal models of MS and in the human disease. We therefore conducted an association study to identify single nucleotide polymorphisms (SNPs) within genes encoding the TAM receptors and their ligands associated with MS. Analysis of genotype data from a genome-wide association study which consisted of 1618 MS cases and 3413 healthy controls conducted by the Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene) revealed several SNPs within the MERTK gene (Chromosome 2q14.1, Accession Number NG&#95;011607.1) that showed suggestive association with MS. We therefore interrogated 28 SNPs in MERTK in an independent replication cohort of 1140 MS cases and 1140 healthy controls. We found 12 SNPs that replicated, with 7 SNPs showing p-values of less than 10(-5) when the discovery and replication cohorts were combined. All 12 replicated SNPs were in strong linkage disequilibrium with each other. In combination, these data suggest the MERTK gene is a novel risk gene for MS susceptibility.

Background: Cell survival depends on the balance between protective and apoptotic signals. When the balance of signals tips towards apoptosis, cells undergo programmed cell death. This balance has profound implications in diseases including cancer. Oncogenes and tumor suppressors are mutated to promote cell survival during tumor development, and many chemotherapeutic drugs kill tumor cells by stimulating apoptosis. BAD is a pro-apoptotic member of the Bcl-2 family of proteins, which can be phosphorylated on numerous sites to modulate binding to Bcl-2 and 14-3-3 proteins and inhibit its pro-apoptotic activities. One of the critical phosphorylation sites is the serine 112 (S112), which can be phosphorylated by several kinases including Pak1., Methodology/principal Findings: We mapped the Pak phosphorylation sites by making serine to alanine mutations in BAD and testing them as substrates in in vitro kinase assays. We found that the primary phosphorylation site is not S112 but serine 111 (S111), a site that is sometimes found phosphorylated in vivo. In transfection assays of HEK293T cells, we showed that Pak1 required Raf-1 to stimulate phosphorylation on S112. Mutating either S111 or S112 to alanine enhanced binding to Bcl-2, but the double mutant S111/112A bound better to Bcl-2. Moreover, BAD phosphorylation at S111 was observed in several other cell lines, and treating one of them with the Pak1 inhibitor 2,2'-Dihydroxy-1,1'-dinaphthyldisulfide (IPA-3) reduced phosphorylation primarily at S112 and to a smaller extent at S111, while Raf inhibitors only reduced phosphorylation at S112., Conclusion/significance: Together, these findings demonstrate that Pak1 phosphorylates BAD directly at S111, but phosphorylated S112 through Raf-1. These two sites of BAD serve as redundant regulatory sites for Bcl-2 binding.

We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6)). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001) and were highly significant in the combined dataset (P ≤ 6 x 10(-8)). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9), replication set P = 7 x 10(-4), combined P = 2 x 10(-10)). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

The paper wasp Polistes dominulus is unique among the social insects in that nearly one-third of co-foundresses are completely unrelated to the dominant individual whose offspring they help to rear and yet reproductive skew is high. These unrelated subordinates stand to gain direct fitness through nest inheritance, raising the question of whether their behaviour is adaptively tailored towards maximizing inheritance prospects. Unusually, in this species, a wealth of theory and empirical data allows us to predict how unrelated subordinates should behave. Based on these predictions, here we compare helping in subordinates that are unrelated or related to the dominant wasp across an extensive range of field-based behavioural contexts. We find no differences in foraging effort, defense behaviour, aggression or inheritance rank between unrelated helpers and their related counterparts. Our study provides no evidence, across a number of behavioural scenarios, that the behaviour of unrelated subordinates is adaptively modified to promote direct fitness interests.

Recent association studies in multiple sclerosis (MS) have identified and replicated several single nucleotide polymorphism (SNP) susceptibility loci including CLEC16A, IL2RA, IL7R, RPL5, CD58, CD40 and chromosome 12q13-14 in addition to the well established allele HLA-DR15. There is potential that these genetic susceptibility factors could also modulate MS disease severity, as demonstrated previously for the MS risk allele HLA-DR15. We investigated this hypothesis in a cohort of 1006 well characterised MS patients from South-Eastern Australia. We tested the MS-associated SNPs for association with five measures of disease severity incorporating disability, age of onset, cognition and brain atrophy. We observed trends towards association between the RPL5 risk SNP and time between first demyelinating event and relapse, and between the CD40 risk SNP and symbol digit test score. No associations were significant after correction for multiple testing. We found no evidence for the hypothesis that these new MS disease risk-associated SNPs influence disease severity.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system of unknown etiology with both genetic and environmental factors playing a role in susceptibility. To date, the HLA DR15/DQ6 haplotype within the major histocompatibility complex on chromosome 6p, is the strongest genetic risk factor associated with MS susceptibility. Additional alleles of IL7 and IL2 have been identified as risk factors for MS with small effect. Here we present two independent studies supporting an allelic association of MS with polymorphisms in the ST8SIA1 gene, located on chromosome 12p12 and encoding ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 1. The initial association was made in a single three-generation family where a single-nucleotide polymorphism (SNP) rs4762896, was segregating together with HLA DR15/DQ6 in MS patients. A study of 274 family trios (affected child and both unaffected parents) from Australia validated the association of ST8SIA1 in individuals with MS, showing transmission disequilibrium of the paternal alleles for three additional SNPs, namely rs704219, rs2041906, and rs1558793, with p = 0.001, p = 0.01 and p = 0.01 respectively. These findings implicate ST8SIA1 as a possible novel susceptibility gene for MS.