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Abstract Humans have a long history of transporting and trading plants, contributing to the evolution of domesticated plants. Theobroma cacao originated in the Neotropics from South America. However, little is known about its domestication and use in these regions. In this study, ceramic residues from a large sample of pre-Columbian cultures from South and Central America were analyzed using archaeogenomic and biochemical approaches. Here we show, for the first time, the widespread use of cacao in South America out of its native Amazonian area of origin, extending back 5000 years, likely supported by cultural interactions between the Amazon and the Pacific coast. We observed that strong genetic mixing between geographically distant cacao populations occurred as early as the middle Holocene, in South America, driven by humans, favoring the adaptation of T. cacao to new environments. This complex history of cacao domestication is the basis of today's cacao tree populations and its knowledge can help us better manage their genetic resources.

Abstract Muscle spindles encode mechanosensory information by mechanisms that remain only partially understood. Their complexity is expressed in mounting evidence of various molecular mechanisms that play essential roles in muscle mechanics, mechanotransduction and intrinsic modulation of muscle spindle firing behaviour. Biophysical modelling provides a tractable approach to achieve more comprehensive mechanistic understanding of such complex systems that would be difficult/impossible by more traditional, reductionist means. Our objective here was to construct the first integrative biophysical model of muscle spindle firing. We leveraged current knowledge of muscle spindle neuroanatomy and in vivo electrophysiology to develop and validate a biophysical model that reproduces key in vivo muscle spindle encoding characteristics. Crucially, to our knowledge, this is the first computational model of mammalian muscle spindle that integrates the asymmetric distribution of known voltage‐gated ion channels (VGCs) with neuronal architecture to generate realistic firing profiles, both of which seem likely to be of great biophysical importance. Results predict that particular features of neuronal architecture regulate specific characteristics of Ia encoding. Computational simulations also predict that the asymmetric distribution and ratios of VGCs is a complementary and, in some instances, orthogonal means to regulate Ia encoding. These results generate testable hypotheses and highlight the integral role of peripheral neuronal structure and ion channel composition and distribution in somatosensory signalling.

Abstract A metabotropic glutamate receptor coupled to phospholipase D (PLD‐mGluR) was discovered in the hippocampus over three decades ago. Its pharmacology and direct linkage to PLD activation are well established and indicate it is a highly atypical glutamate receptor. A receptor with the same pharmacology is present in spindle primary sensory terminals where its blockade can totally abolish, and its activation can double, the normal stretch‐evoked firing. We report here the first identification of this PLD‐mGluR protein, by capitalizing on its expression in primary mechanosensory terminals, developing an enriched source, pharmacological profiling to identify an optimal ligand, and then functionalizing it as a molecular tool. Evidence from immunofluorescence, western and far‐western blotting indicates PLD‐mGluR is homomeric GluK2, since GluK2 is the only glutamate receptor protein/receptor subunit present in spindle mechanosensory terminals. Its expression was also found in the lanceolate palisade ending of hair follicle, also known to contain the PLD‐mGluR. Finally, in a mouse model with ionotropic function ablated in the GluK2 subunit, spindle glutamatergic responses were still present, confirming it acts purely metabotropically. We conclude the PLD‐mGluR is a homomeric GluK2 kainate receptor signalling purely metabotropically and it is common to other, perhaps all, primary mechanosensory endings.

This paper is offered as a contribution to understanding historical trade. The method of input-output modelling is utilised to evaluate the evolution of cities (and their associated regions) in England and Wales between 1851 and 1911. The construction of input-output accounts for each city region is based on “heroic” data assumptions, which enable the construction of a demonstration model illustrating a new iterative approach to historical analysis. In its current application, the model enables estimates to be made of mesolevel trade between cities, which enhances our analysis of urban evolution in this period.

Stars that formed with an initial mass of over 50 M _⊙ are very rare today, but they are thought to be more common in the early Universe. The fates of those early, metal-poor, massive stars are highly uncertain. Most are expected to directly collapse to black holes, while some may explode as a result of rotationally powered engines or the pair-creation instability. We present the chemical abundances of J0931+0038, a nearby low-mass star identified in early follow-up of the SDSS-V Milky Way Mapper, which preserves the signature of unusual nucleosynthesis from a massive star in the early Universe. J0931+0038 has a relatively high metallicity ([Fe/H] = −1.76 ± 0.13) but an extreme odd–even abundance pattern, with some of the lowest known abundance ratios of [N/Fe], [Na/Fe], [K/Fe], [Sc/Fe], and [Ba/Fe]. The implication is that a majority of its metals originated in a single extremely metal-poor nucleosynthetic source. An extensive search through nucleosynthesis predictions finds a clear preference for progenitors with initial mass >50 M _⊙ , making J0931+0038 one of the first observational constraints on nucleosynthesis in this mass range. However, the full abundance pattern is not matched by any models in the literature. J0931+0038 thus presents a challenge for the next generation of nucleosynthesis models and motivates the study of high-mass progenitor stars impacted by convection, rotation, jets, and/or binary companions. Though rare, more examples of unusual early nucleosynthesis in metal-poor stars should be found in upcoming large spectroscopic surveys.

Summary: Borneo was a crossroad of ancient dispersals, with some of the earliest Southeast Asian human remains and rock art. The island is home to traditionally hunter-gatherer Punan communities, whose origins, whether of subsistence reversion or long-term foraging, are unclear. The connection between its past and present-day agriculturalist inhabitants, who currently speak Austronesian languages and have composite and complex genetic ancestry, is equally opaque. Here, we analyze the genetic ancestry of the northeastern Bornean Punan Batu (who still practice some mobile hunting and gathering), Tubu, and Aput. We find deep ancestry connections, with a shared Asian signal outgrouping modern and ancient Austronesian-ancestry proxies, suggesting a time depth of more than 7,500 years. They also largely lack the mainland Southeast Asian signals of agricultural Borneans, who are themselves genetically heterogeneous. Our results support long-term inhabitation of Borneo by some Punan ancestors and reveal unexpected complexity in the origins and dispersal of Austronesian-expansion-related ancestry.

Abstract Aims Stanniocalcin‐2 (STC2) has recently been implicated in human muscle mass variability by genetic analysis. Biochemically, STC2 inhibits the proteolytic activity of the metalloproteinase PAPP‐A, which promotes muscle growth by upregulating the insulin‐like growth factor (IGF) axis. The aim was to examine if STC2 affects skeletal muscle mass and to assess how the IGF axis mediates muscle hypertrophy induced by functional overload. Methods We compared muscle mass and muscle fiber morphology between Stc2−/− (n = 21) and wild‐type (n = 15) mice. We then quantified IGF1, IGF2, IGF binding proteins −4 and −5 (IGFBP‐4, IGFBP‐5), PAPP‐A and STC2 in plantaris muscles of wild‐type mice subjected to 4‐week unilateral overload (n = 14). Results Stc2−/− mice showed up to 10% larger muscle mass compared with wild‐type mice. This increase was mediated by greater cross‐sectional area of muscle fibers. Overload increased plantaris mass and components of the IGF axis, including quantities of IGF1 (by 2.41‐fold, p = 0.0117), IGF2 (1.70‐fold, p = 0.0461), IGFBP‐4 (1.48‐fold, p = 0.0268), PAPP‐A (1.30‐fold, p = 0.0154) and STC2 (1.28‐fold, p = 0.019). Conclusion Here we provide evidence that STC2 is an inhibitor of muscle growth upregulated, along with other components of the IGF axis, during overload‐induced muscle hypertrophy.

PurposeRetinal vein occlusion (RVO) is a sight-threatening condition typically treated with intravitreal injection of vascular endothelial growth factor (VEGF) antagonists. Treatment response to anti-VEGF therapies is highly variable, with poor visual outcomes and treatment response in patients with significant retinal nonperfusion following RVO. Recently, caspase-9 has been identified as a potent regulator of edema, gliosis, and neuronal dysfunction during acute retinal hypoxia. The purpose of this study was to compare the therapeutic effect of caspase-9 inhibition against VEGF-neutralization in an established mouse model of RVO.MethodsAdult male C57Bl/6 J mice were randomized to induction of RVO and treatment with either vehicle, intravitreal injection of anti-VEGF antibody, topical administration of a selective caspase-9 inhibitor (Pen1-XBir3), or a combination therapy. Animals were followed on days 1, 2, and 8 after RVO with fundus retinal imaging, and with optical coherence tomography (OCT) to capture retinal swelling, capillary nonperfusion (measured by disorganization of retinal inner layers, DRIL), hyperreflective foci (HRF), and retinal atrophy. Focal electroretinography (ERG) measurements were performed on day 7. Histology was performed on retinal sections from day 8.ResultsBoth VEGF neutralization and caspase-9 inhibition showed significant retinal protection from RVO compared to vehicle treatment arm. Retinal reperfusion of occluded veins was accelerated in eyes receiving caspase-9 inhibitor, but not significantly different from vehicle in the anti-VEGF group. Retinal edema was suppressed in all treatment groups, with approximately 2-fold greater edema reduction with caspase-9 inhibition compared to VEGF neutralization. HRF were reduced similarly across all treatment groups compared to vehicle. Retinal detachment was reduced only in eyes treated with caspase-9 inhibitor monotherapy. Caspase-9 inhibition reduced retinal atrophy and preserved ERG response; VEGF neutralization did not prevent neurodegeneration following RVO.ConclusionCaspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in the mouse laser-induced model of RVO.

IntroductionThe ultimate deficit in amyotrophic lateral sclerosis (ALS) is neuromuscular junction (NMJ) loss, producing permanent paralysis, ultimately in respiratory muscles. However, understanding the functional and structural deficits at NMJs prior to this loss is crucial for therapeutic strategy design. Should early interventions focus on reversing denervation, or supporting largely intact NMJs that are functionally impaired? We therefore determined when functional and structural deficits appeared in diaphragmatic NMJs relative to the onset of hindlimb tremor (the first overt motor symptoms) in vivo in the SOD1-G93A mouse model of ALS.Materials and methodsWe employed electrophysiological recording of NMJ postsynaptic potentials for spontaneous and nerve stimulation-evoked responses. This was correlated with fluorescent imaging microscopy of the postsynaptic acetylcholine receptor (AChR) distribution throughout the postnatal developmental timecourse from 2 weeks to early symptomatic ages.ResultsSignificant reduction in the amplitudes of spontaneous miniature endplate potentials (mEPPs) and evoked EPPs emerged only at early symptomatic ages (in our colony, 18-22 weeks). Reductions in mEPP frequency, number of vesicles per EPP, and EPP rise time were seen earlier, at 16weeks, but this reversed by early symptomatic ages. However, the earliest and most striking impairment was an inability to maintain EPP amplitude during a 20 Hz stimulus train, which appeared 6 weeks before overt in vivo motor symptoms. Despite this, fluorescent α-bungarotoxin labelling revealed no systematic, progressive changes in 11 comprehensive NMJ morphological parameters (area, shape, compactness, number of acetylcholine receptor, AChR, regions, etc.) with disease progression. Rather, while NMJs were largely normally-shaped, from 16 weeks there was a progressive and substantial disruption in AChR concentration and distribution within the NMJ footprint.DiscussionThus, NMJ functional deficits appear at least 6 weeks before motor symptoms in vivo, while structural deficits occur 4 weeks later, and predominantly within NMJs. These data suggest initial therapies focused on rectifying suboptimal NMJ function could produce effective relief of symptoms of weakness.

We developed a grid of stellar rotation models for low-mass and solar-type classical T Tauri stars (CTTS; 0.3 M _⊙ < M _* < 1.2 M _⊙ ). These models incorporate the star–disk interaction and magnetospheric ejections to investigate the evolution of the stellar rotation rate as a function of the mass of the star M _* , the magnetic field ( B _* ), and stellar wind ( ${\dot{M}}_{\mathrm{wind}}$ ). We compiled and determined stellar parameters for 208 CTTS, such as projected rotational velocity $v\sin (i)$ , mass accretion rate ${\dot{M}}_{\mathrm{acc}}$ , stellar mass M _* , ages, and estimated rotational periods using Transiting Exoplanet Survey Satellite (TESS) data. We also estimated a representative value of the mass-loss rate for our sample using the [O i ] λ 6300 spectral line. Our results confirm that $v\sin (i)$ measurements in CTTS agree with the rotation rates provided by our spin models in the accretion-powered stellar winds picture. In addition, we used the approximate Bayesian computation technique to explore the connection between the model parameters and the observational properties of CTTS. We find that the evolution of $v\sin (i)$ with age might be regulated by variations in (1) the intensity of B _* and (2) the fraction of the accretion flow ejected in magnetic winds, removing angular momentum from these systems. The youngest stars in our sample (∼1 Myr) show a median branching ratio ${\dot{M}}_{\mathrm{wind}}/{\dot{M}}_{\mathrm{acc}}\sim 0.16$ and median B _* ∼ 2000 G, in contrast to ∼0.01 and 1000 G, respectively, for stars with ages ≳3 Myr.

We developed a tool that measures equivalent widths of various lines in low-resolution optical spectra, and it was applied to stellar spectra obtained as part of SDSS-V and LAMOST programs. These lines, such as Li i, which directly indicates stellar youth, or optical H i and Ca ii, which in emission indicate activity associated with stellar youth, are commonly seen in YSOs. We observe several notable differences in the properties of these lines between YSOs and the field stars. Using these data, we devise a set of criteria through which it is possible to confirm the youth of stars that have been observed by the ABYSS program, as well as to identify likely young stars that have serendipitously been observed by other programs. We examine the decrement of H lines seen in emission in CTTSs, and estimate the properties of the accretion stream that is responsible for the production of these lines. Finally, we examine the evolution of Li i as a function of age, and characterize the scatter in its abundance that appears to be intrinsic in young M dwarfs.

We present a catalog of fundamental stellar properties for ∼7500 evolved stars, including stellar radii and masses, determined from the combination of spectroscopic observations from the Apache Point Observatory Galactic Evolution Experiment, part of the Sloan Digital Sky Survey IV, and asteroseismology from K2. The resulting APO-K2 catalog provides spectroscopically derived temperatures and metallicities, asteroseismic global parameters, evolutionary states, and asteroseismically derived masses and radii. Additionally, we include kinematic information from Gaia. We investigate the multidimensional space of abundance, stellar mass, and velocity with an eye toward applications in Galactic archaeology. The APO-K2 sample has a large population of low-metallicity stars (∼288 with [M/H] ≤ −1), and their asteroseismic masses are larger than astrophysical estimates. We argue that this may reflect offsets in the adopted fundamental temperature scale for metal-poor stars rather than metallicity-dependent issues with interpreting asteroseismic data. We characterize the kinematic properties of the population as a function of α enhancement and position in the disk and identify those stars in the sample that are candidate components of the Gaia-Enceladus merger. Importantly, we characterize the selection function for the APO-K2 sample as a function of metallicity, radius, mass, ${\nu }_{\max }$ , color, and magnitude referencing Galactic simulations and target selection criteria to enable robust statistical inferences with the catalog.

Increases in adolescent anxiety over the past several years suggest a need for trauma-informed, culturally responsive interventions that help teens cope with environmental stressors like those associated with the COVID-19 pandemic. Although abundant evidence supports the efficacy of cognitive behavioral therapy (CBT) in treating adolescent anxiety, not all teens respond positively to CBT. CBT does not typically include strategies that address important family factors that may be impacting the teen’s functioning, such as the attachment relationship. Attachment-based family therapy (ABFT) addresses the attachment relationship and other factors that contribute to the adolescent’s anxiety and related distress. By enhancing positive parenting behaviors, such as acceptance and validation of the adolescent’s distress and promotion of their autonomy, ABFT sessions may repair the attachment relationship and increase the family’s ability and willingness to engage in CBT tasks aimed at reducing anxiety. This theoretical paper describes the ABFT model and proposes that implementing ABFT sessions prior to CBT could result in better clinical outcomes for adolescents with anxiety disorders by improving the context within which the anxiety symptoms and treatment are experienced. Given that ABFT is sensitive and responsive to family and other contextual factors, adolescents from marginalized communities and those from less individualistic cultures may find the model to be more acceptable and appropriate for addressing factors related to their anxiety. Thus, a combined ABFT+CBT model might result in better outcomes for adolescents who have not historically responded well to CBT alone.

We present photometric and spectroscopic observations of the extraordinary gamma-ray burst (GRB) 221009A in search of an associated supernova. Some past GRBs have shown bumps in the optical light curve that coincide with the emergence of supernova spectral features, but we do not detect any significant light-curve features in GRB 221009A, nor do we detect any clear sign of supernova spectral features. Using two well-studied GRB-associated supernovae (SN 2013dx, ${M}_{r,\max }=-19.54;$ SN 2016jca, ${M}_{r,\max }=-19.04$ ) at a similar redshift as GRB 221009A ( z = 0.151), we modeled how the emergence of a supernova would affect the light curve. If we assume the GRB afterglow to decay at the same rate as the X-ray data, the combination of afterglow and a supernova component is fainter than the observed GRB brightness. For the case where we assume the best-fit power law to the optical data as the GRB afterglow component, a supernova contribution should have created a clear bump in the light curve, assuming only extinction from the Milky Way. If we assume a higher extinction of E ( B − V ) = 1.74 mag (as has been suggested elsewhere), the supernova contribution would have been hard to detect, with a limit on the associated supernova of ${M}_{r,\max }\approx -$ 19.54. We do not observe any clear supernova features in our spectra, which were taken around the time of expected maximum light. The lack of a bright supernova associated with GRB 221009A may indicate that the energy from the explosion is mostly concentrated in the jet, leaving a lower energy budget available for the supernova.

Modern humans have admixed with multiple archaic hominins. Papuans, in particular, owe up to 5% of their genome to Denisovans, a sister group to Neanderthals whose remains have only been identified in Siberia and Tibet. Unfortunately, the biological and evolutionary significance of these introgression events remain poorly understood. Here we investigate the function of both Denisovan and Neanderthal alleles characterised within a set of 56 genomes from Papuan individuals. By comparing the distribution of archaic and non-archaic variants we assess the consequences of archaic admixture across a multitude of different cell types and functional elements. We observe an enrichment of archaic alleles within cis-regulatory elements and transcribed regions of the genome, with Denisovan variants strongly affecting elements active within immune-related cells. We identify 16,048 and 10,032 high-confidence Denisovan and Neanderthal variants that fall within annotated cis-regulatory elements and with the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, highlighting a likely mechanism by which introgressed DNA can impact phenotypes. Lastly, we experimentally validate these predictions by testing the regulatory potential of five Denisovan variants segregating within Papuan individuals, and find that two are associated with a significant reduction of transcriptional activity in plasmid reporter assays. Together, these data provide support for a widespread contribution of archaic DNA in shaping the present levels of modern human genetic diversity, with different archaic ancestries potentially affecting multiple phenotypic traits within non-Africans.

Abstract Exercise mobilizes angiogenic cells, which stimulate vascular repair. However, limited research suggests exercise-induced increase of endothelial progenitor cell (EPCs) is completely lacking in type 1 diabetes (T1D). Clarification, along with investigating how T1D influences exercise-induced increases of other angiogenic cells (hematopoietic progenitor cells; HPCs) and cell surface expression of chemokine receptor 4 (CXCR4) and 7 (CXCR7), is needed. Thirty T1D patients and 30 matched non-diabetes controls completed 45 min of incline walking. Circulating HPCs (CD34+, CD34+CD45dim) and EPCs (CD34+VEGFR2+, CD34+CD45dimVEGFR2+), and subsequent expression of CXCR4 and CXCR7, were enumerated by flow cytometry at rest and post-exercise. Counts of HPCs, EPCs and expression of CXCR4 and CXCR7 were significantly lower at rest in the T1D group. In both groups, exercise increased circulating angiogenic cells. However, increases was largely attenuated in the T1D group, up to 55% lower, with CD34+ (331 ± 437 Δcells/mL vs. 734 ± 876 Δcells/mL p = 0.048), CD34+VEGFR2+ (171 ± 342 Δcells/mL vs. 303 ± 267 Δcells/mL, p = 0.006) and CD34+VEGFR2+CXCR4+ (126 ± 242 Δcells/mL vs. 218 ± 217 Δcells/mL, p = 0.040) significantly lower. Exercise-induced increases of angiogenic cells is possible in T1D patients, albeit attenuated compared to controls. Decreased mobilization likely results in reduced migration to, and repair of, vascular damage, potentially limiting the cardiovascular benefits of exercise. Trial registration: ISRCTN63739203.

Abstract Background Patient empowerment can improve health‐related outcomes and is important in chronic conditions, such as arthritis. This study aimed to validate the Health Care Empowerment Questionnaire (HCEQ), a patient‐reported experience measure of empowerment, for use with patients with arthritis and other rheumatic diseases. Methods The HCEQ measures Patient Information Seeking (or Involvement in Decisions) and Healthcare Interaction Results (or Involvement in Interactions) and asks respondents to answer questions in two ways: whether they feel something happened and its importance to them. Face validity was assessed through qualitative data (n = 8, nominal group technique; n = 55, focus groups). Measure structure was assessed through confirmatory factor analysis (CFA); internal consistency was also assessed (n = 9226). Test‐retest reliability was assessed with sub‐sample of participants (n = 182). Results We found adequate face validity of the HCEQ for patients with arthritis. The CFA indicated good fit to the data for the two‐factor structure of the HCEQ (RMSEA = 0.075; CFI = 0.987; TLI = 0.978; SRMR = 0.026). Internal consistency was strong (α=0.94 for both subscales). Test‐retest reliability was moderate for Patient Information Seeking (ICC=0.67) and good for Healthcare Interaction Results (ICC=0.77). Conclusions The HCEQ, with modifications, demonstrated promising psychometric properties within this sample, laying the foundation for further assessment. This work supports the HCEQ as an appropriate instrument for examining experiences with and perceived importance of empowerment in individuals with arthritis and other rheumatic conditions. Patient Contribution Patients contributed to the assessment of face validity. As a measure of patient empowerment, the HCEQ’s use can enable further participation of patients in health care.

3-3′-Diindolylmethane (DIM) is a biologically active dimer derived from the endogenous conversion of indole-3-carbinol (I3C), a naturally occurring glucosinolate found in many cruciferous vegetables (i.e., Brassicaceae). DIM was the first pure androgen receptor antagonist isolated from the Brassicaceae family and has been recently investigated for its potential pharmacological use in prostate cancer prevention and treatment. Interestingly, there is evidence that DIM can also interact with cannabinoid receptors. In this context, by considering the well-known involvement of the endocannabinoid system in prostate cancer, we have pharmacologically characterized the properties of DIM on both CB1 and CB2 cannabinoid receptors in two human prostate cancer cell lines: PC3 (androgen-independent/androgen receptor negative) and LNCaP (androgen-dependent). In the PC3 cell line, DIM was able to activate CB2 receptors and potentially associated apoptotic pathways. On the other hand, although DIM was also able to activate CB2 receptors in the LNCaP cell line, no apoptotic effects were observed. Our evidence confirms that DIM is a CB2 receptor ligand and, moreover, it has a potential anti-proliferative effect on androgen-independent/androgen receptor-negative prostate cancer cells.

BackgroundMany individuals with type 1 diabetes retain residual beta-cell function. Sustained endogenous insulin and C-peptide secretion is associated with reduced diabetes related complications, but underlying mechanisms remain unclear. Lower circulating numbers of endothelial and hematopoietic progenitor cells (EPCs and HPCs), and the inability to increase the count of these cells in response to exercise, are also associated with increased diabetes complications and cardiovascular disease. It is unknown whether residual beta-cell function influences HPCs and EPCs. Thus, this study examined the influence of residual beta-cell function in type 1 diabetes upon exercise-induced changes in haematopoietic (HPCs) and endothelial progenitor cells (EPCs).MethodsParticipants with undetectable stimulated C-peptide (n=11; Cpepund), 10 high C-peptide (Cpephigh; >200 pmol/L), and 11 non-diabetes controls took part in this observational exercise study, completing 45 minutes of intensive walking at 60% V˙O2peak. Clinically significant HPCs (CD34+) and EPCs (CD34+VEGFR2+) phenotypes for predicting future adverse cardiovascular outcomes, and subsequent cell surface expression of chemokine receptor 4 (CXCR4) and 7 (CXCR7), were enumerated at rest and immediately post-exercise by flow cytometry.ResultsExercise increased HPCs and EPCs phenotypes similarly in the Cpephigh and control groups (+34-121% across phenotypes, p

Retinal vein occlusion can cause blindness, and features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here the authors report a non-apoptotic role of endothelial caspase-9 in regulating blood-retina barrier integrity and neuronal survival, which can be therapeutically targeted in a mouse model of retinal vein occlusion.

Aza-peptide aldehydes and ketones are a new class of reversible protease inhibitors that are specific for the proteasome and clan CD cysteine proteases. We designed and synthesised aza-Leu derivatives that were specific for the chymotrypsin-like active site of the proteasome, aza-Asp derivatives that were effective inhibitors of caspases-3 and -6, and aza-Asn derivatives that inhibited S. mansoni and I. ricinus legumains. The crystal structure of caspase-3 in complex with our caspase-specific aza-peptide methyl ketone inhibitor with an aza-Asp residue at P1 revealed a covalent linkage between the inhibitor carbonyl carbon and the active site cysteinyl sulphur. Aza-peptide aldehydes and ketones showed no cross-reactivity towards cathepsin B or chymotrypsin. The initial in vitro selectivity of these inhibitors makes them suitable candidates for further development into therapeutic agents to potentially treat multiple myeloma, neurodegenerative diseases, and parasitic infections.

Theories of early cooperation in human society often draw from a small sample of ethnographic studies of surviving populations of hunter–gatherers, most of which are now sedentary. Borneo hunter–gatherers (Punan, Penan) have seldom figured in comparative research because of a decades-old controversy about whether they are the descendants of farmers who adopted a hunting and gathering way of life. In 2018 we began an ethnographic study of a group of still-nomadic hunter–gatherers who call themselves Punan Batu (Cave Punan). Our genetic analysis clearly indicates that they are very unlikely to be the descendants of neighbouring agriculturalists. They also preserve a song language that is unrelated to other languages of Borneo. Dispersed travelling groups of Punan Batu with fluid membership use message sticks to stay in contact, co-operate and share resources as they journey between rock shelters and forest camps. Message sticks were once widespread among nomadic Punan in Borneo, but have largely disappeared in sedentary Punan villages. Thus the small community of Punan Batu offers a rare glimpse of a hunting and gathering way of life that was once widespread in the forests of Borneo, where prosocial behaviour extended beyond the face-to-face community, facilitating successful collective adaptation to the diverse resources of Borneo's forests.

We present a spectroscopic analysis of a sample of 48 M-dwarf stars (0.2 M _⊙ < M < 0.6 M _⊙ ) from the Hyades open cluster using high-resolution H -band spectra from the Sloan Digital Sky Survey/Apache Point Observatory Galactic Evolution Experiment (APOGEE) survey. Our methodology adopts spectrum synthesis with LTE MARCS model atmospheres, along with the APOGEE Data Release 17 line list, to determine effective temperatures, surface gravities, metallicities, and projected rotational velocities. The median metallicity obtained for the Hyades M dwarfs is [M/H] = 0.09 ± 0.03 dex, indicating a small internal uncertainty and good agreement with optical results for Hyades red giants. Overall, the median radii are larger than predicted by stellar models by 1.6% ± 2.3% and 2.4% ± 2.3%, relative to a MIST and DARTMOUTH isochrone, respectively. We emphasize, however, that these isochrones are different, and the fractional radius inflation for the fully and partially convective regimes have distinct behaviors depending on the isochrone. Using a MIST isochrone there is no evidence of radius inflation for the fully convective stars, while for the partially convective M dwarfs the radii are inflated by 2.7% ± 2.1%, which is in agreement with predictions from models that include magnetic fields. For the partially convective stars, rapid rotators present on average higher inflation levels than slow rotators. The comparison with SPOTS isochrone models indicates that the derived M-dwarf radii can be explained by accounting for stellar spots in the photosphere of the stars, with 76% of the studied M dwarfs having up to 20% spot coverage, and the most inflated stars with ∼20%–40% spot coverage.

The Sloan Digital Sky Survey IV APOGEE-2 primary science goal was to observe red giant stars throughout the Galaxy to study its dynamics, morphology, and chemical evolution. The APOGEE instrument, a high-resolution 300-fiber H -band (1.55–1.71 μ m) spectrograph, is also ideal to study other stellar populations in the Galaxy, among which are a number of star-forming regions and young open clusters. We present the results of the determination of six stellar properties ( T _eff , $\mathrm{log}\,g$ , [Fe/H], L / L _⊙ , M / M _⊙ , and age) for a sample that is composed of 3360 young stars, of subsolar to supersolar types, in 16 Galactic star formation and young open cluster regions. Those sources were selected by using a clustering method that removes most of the field contamination. Samples were also refined by removing targets affected by various systematic effects of the parameter determination. The final samples are presented in a comprehensive catalog that includes all six estimated parameters. This overview study also includes parameter spatial distribution maps for all regions and Hertzsprung–Russell ( $\mathrm{log}L/{L}_{\odot }$ vs. T _eff ) diagrams. This study serves as a guide for detailed studies on individual regions and paves the way for the future studies on the global properties of stars in the pre-main-sequence phase of stellar evolution using more robust samples.

We report the characterization of 28 low-mass (0.02 M _⊙ ≤ M _2 ≤ 0.25 M _⊙ ) companions to Kepler objects of interest (KOIs), eight of which were previously designated confirmed planets. These objects were detected as transiting companions to Sunlike stars (G and F dwarfs) by the Kepler mission and are confirmed as single-lined spectroscopic binaries in the current work using the northern multiplexed Apache Point Observatory Galactic Evolution Experiment near-infrared spectrograph (APOGEE-N) as part of the third and fourth Sloan Digital Sky Surveys. We have observed hundreds of KOIs using APOGEE-N and collected a total of 43,175 spectra with a median of 19 visits and a median baseline of ∼1.9 yr per target. We jointly model the Kepler photometry and APOGEE-N radial velocities to derive fundamental parameters for this subset of 28 transiting companions. The radii for most of these low-mass companions are overinflated (by ∼10%) when compared to theoretical models. Tidally locked M dwarfs on short-period orbits show the largest amount of inflation, but inflation is also evident for companions that are well separated from the host star. We demonstrate that APOGEE-N data provide reliable radial velocities when compared to precise high-resolution spectrographs that enable detailed characterization of individual systems and the inference of orbital elements for faint ( H > 12) KOIs. The data from the entire APOGEE-KOI program are public and present an opportunity to characterize an extensive subset of the binary population observed by Kepler.

In this study, we have investigated a possible mechanism that enables CB1/M3 receptor cross-talk, using SH-SY5Y cells as a model system. Our results show that M3 receptor activation initiates signaling that rapidly upregulates the CNR1 gene, resulting in a greatly potentiated CB1 receptor response to agonists. Calcium homeostasis plays an essential intermediary role in this functional CB1/M3 receptor cross-talk. We show that M3 receptor-triggered calcium release greatly increases CB1 receptor expression via both transcriptional and translational activity, by enhancing CNR1 promoter activity. The co-expression of M3 and CB1 receptors in brain areas such as the nucleus accumbens and amygdala support the hypothesis that the altered synaptic plasticity observed after exposure to cannabinoids involves cross-talk with the M3 receptor subtype. In this context, M3 receptors and their interaction with the cannabinoid system at the transcriptional level represent a potential pharmacogenomic target not only for the develop of new drugs for addressing addiction and tolerance. but also to understand the mechanisms underpinning response stratification to cannabinoids.

In a tragedy of the commons, individual competition over a resource can reduce the resource itself, and thus reduce the fitness of the whole group. An extreme example is evolutionary suicide, which is predicted to occur when the selfish interests of free-riders and cheaters overwhelm cooperative behaviors, and the social good on which they depend ceases to exist. Case studies cite many different and seemingly interacting factors for success. Here we propose an equation-based theoretical model to predict changes in this balance, which determine whether the tragedy of the commons is observed in a particular scenario. Using survey data from 20 Balinese subaks, we explore the explanatory power of two theoretical traditions that are currently used to analyze commons management institutions, revealing multiple regimes with correlated responses to environmental threats. To explore case studies from a comparative perspective requires both theory and methods that can account for differences between regimes and explore transitions between them.

Summary: Zoonotic pathogens, such as COVID-19, reside in animal hosts before jumping species to infect humans. The Carnivora, like mink, carry many zoonoses, yet how diversity in host immune genes across species affect pathogen carriage is poorly understood. Here, we describe a progressive evolutionary downregulation of pathogen-sensing inflammasome pathways in Carnivora. This includes the loss of nucleotide-oligomerization domain leucine-rich repeat receptors (NLRs), acquisition of a unique caspase-1/-4 effector fusion protein that processes gasdermin D pore formation without inducing rapid lytic cell death, and the formation of a caspase-8 containing inflammasome that inefficiently processes interleukin-1β. Inflammasomes regulate gut immunity, but the carnivorous diet has antimicrobial properties that could compensate for the loss of these immune pathways. We speculate that the consequences of systemic inflammasome downregulation, however, can impair host sensing of specific pathogens such that they can reside undetected in the Carnivora.

PurposeElevated postprandial glycaemia [PPG] increases the risk of cardiometabolic complications in insulin-resistant, centrally obese individuals. Therefore, strategies that improve PPG are of importance for this population. Consuming large doses of whey protein [WP] before meals reduces PPG by delaying gastric emptying and stimulating the secretion of the incretin peptides, glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide 1 [GLP-1]. It is unclear if these effects are observed after smaller amounts of WP and what impact central adiposity has on these gastrointestinal processes.MethodsIn a randomised-crossover design, 12 lean and 12 centrally obese adult males performed two 240 min mixed-meal tests, ~5–10 d apart. After an overnight fast, participants consumed a novel, ready-to-drink WP shot (15 g) or volume-matched water (100 ml; PLA) 10 min before a mixed-nutrient meal. Gastric emptying was estimated by oral acetaminophen absorbance. Interval blood samples were collected to measure glucose, insulin, GIP, GLP-1, and acetaminophen.ResultsWP reduced PPG area under the curve [AUC0–60] by 13 and 18.2% in the centrally obese and lean cohorts, respectively (both p

Aims: Percutaneous mitral balloon valvotomy PMBV is an acceptable alternative to Mitral valve surgery for patients with mitral stenosis. The purpose of this study was to explore the immediate results of PMBV with respect to echocardiographic changes, outcomes, and complications, using a meta-analysis approach. Methods: MEDLINE, and EMBASE databases were searched (01/2012 to 10/2018) for original research articles regarding the efficacy and safety of PMBV. Two reviewers independently screened references for inclusion and abstracted data including article details and echocardiographic parameters before and 24–72 h after PMBV, follow-up duration, and acute complications. Disagreements were resolved by third adjudicator. Quality of all included studies was evaluated using the Newcastle-Ottawa Scale NOS. Results: 44/990 references met the inclusion criteria representing 6537 patients. Our findings suggest that PMBV leads to a significant increase in MVA (MD = 0.81 cm2; 0.76–0.87, p

Introduction Exercise acutely alters markers of bone resorption and formation. As risk of fracture is increased in patients with type 1 diabetes, understanding if exercise-induced bone turnover is affected within this population is prudent. We assessed bone turnover responses to acute exercise in individuals with long-duration type 1 diabetes and matched controls.Research design and methods Participants with type 1 diabetes (n=15; age: 38.7±13.3; glycosylated hemoglobin: 60.5±6.7 mmol/mol; diabetes duration: 19.3±11.4 years) and age-matched, fitness-matched, and body mass index-matched controls (n=15) completed 45 min of incline walking (60% peak oxygen uptake). Blood samples were collected at baseline and immediately, 30 min, and 60 min postexercise. Markers of bone resorption (β-C-terminal cross-linked telopeptide of type 1 collagen, β-CTx) and formation (procollagen type-1 amino-terminal propeptide, P1NP), parathyroid hormone (PTH), phosphate, and calcium (albumin-adjusted and ionized) were measured. Data (mean±SD) were analyzed by a mixed-model analysis of variance.Results Baseline concentrations of P1NP and β-CTx were comparable between participants with type 1 diabetes and controls. P1NP did not change with exercise (p=0.20) but β-CTx decreased (p0.39). Participants with type 1 diabetes had reduced albumin and ionized calcium at all sample points (p

Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.

Very young ( t ≲ 10 Myr) stars possess strong magnetic fields that channel ionized gas from the interiors of their circumstellar disks to the surface of the star. Upon impacting the stellar surface, the shocked gas recombines and emits hydrogen spectral lines. To characterize the density and temperature of the gas within these accretion streams, we measure equivalent widths of Brackett (Br) 11–20 emission lines detected in 1101 APOGEE spectra of 326 likely pre-main-sequence accretors. For sources with multiple observations, we measure median epoch-to-epoch line strength variations of 10% in Br11 and 20% in Br20. We also fit the measured line ratios to predictions of radiative transfer models by Kwan & Fischer. We find characteristic best-fit electron densities of n _e = 10 ^11 –10 ^12 cm ^−3 , and excitation temperatures that are inversely correlated with electron density (from T ∼ 5000 K for n _e ∼ 10 ^12 cm ^−3 to T ∼ 12,500 K at n _e ∼ 10 ^11 cm ^−3 ). These physical parameters are in good agreement with predictions from modeling of accretion streams that account for the hydrodynamics and radiative transfer within the accretion stream. We also present a supplementary catalog of line measurements from 9733 spectra of 4255 Brackett emission-line sources in the APOGEE Data Release 17 data set.

The Flemish Child Welfare System (CWS) is in great need of a shared empirically informed clinical strategy for working with depressed adolescents and their families. Many evidence-based practices (EBP) exist, but little is known as to whether they can be successfully imported in the CWS. Therefore, the current study explores the implementation of a particular EBP, Attachment-Based Family Therapy (ABFT), in home-based services of the Flemish CWS in Belgium. Specifically, the study focused on (1) the acceptability of ABFT by counselors and whether negative attitudes about EBP can be changed ('n' = 73 counselors), and (2) the feasibility of implementing ABFT ('n' = 43 adolescents, 11–17 years old, 72% female) by exploring initial effectiveness. The results suggest that (1) initial negative attitudes of counselors towards ABFT were significantly more positive after attending training and discussions about ABFT, and that (2) ABFT could be used by counselors to successfully reduce adolescent depressive symptoms. Future research should include a control group to draw stronger causal conclusions. Strengths and limitations of the study’s design and implications for further dissemination are discussed.

BackgroundOsteoarthritis (OA) is the most prevalent arthritis worldwide, but the evolution of pain in relation to joint damage and biochemical markers are not well understood. We evaluated the relation between clinical pain measures and evoked pain in relation to structural damage and biochemical biomarkers in knee OA.MethodsA cross-sectional study in people with knee OA and healthy controls was conducted. A total of 130 participants with advanced OA requiring total knee replacement (TKR) (n = 78), mild OA having standard care (n = 42) and non-OA controls (n = 6), with four drop-outs were assessed. Pain scoring was performed by the Western Ontario and McMaster Universities OA Index (WOMAC_P) and the Visual Analog Scale (VAS). Pain sensitization was assessed by pain pressure thresholds (PPTs). Knee magnetic resonance imaging (MRI) assessed joint damage using the MRI Knee OA Score (MOAKS). Overall MOAKS scores were created for bone marrow lesions (BMLs), cartilage degradation (CD), and effusion/Hoffa synovitis (tSyn). Type II collagen cleavage products (CTX-II) were determined by ELISA.ResultsThe advanced OA group had a mean age of 68.9 ± 7.7 years and the mild group 63.1 ± 9.6. The advanced OA group had higher levels of pain, with mean WOMAC_P of 58.8 ± 21.7 compared with the mild OA group of 40.6 ± 26.0. All OA subjects had pain sensitization by PPT compared with controls (p < 0.05). WOMAC_P correlated with the total number of regions with cartilage damage (nCD) (R = 0.225, p = 0.033) and total number of BMLs (nBML) (R = 0.195, p = 0.065) using body mass index (BMI), age, and Hospital Anxiety and Depression Scale (HADS) as covariates. Levels of CTX-II correlated with tSyn (R = 0.313, p = 0.03), nBML (R = 0.252, p = 0.019), number of osteophytes (R = 0.33, p = 0.002), and nCD (R = 0.218, p = 0.042), using BMI and age as covariates. A multivariate analysis indicated that BMI and HADS were the most significant predictors of pain scores (p < 0.05).ConclusionPeople with both mild and advanced OA show features of pain sensitization. We found that increasing MRI-detected joint damage was associated with higher levels of CTX-II, suggesting that increasing disease severity can be assessed by MRI and CTX-II biomarkers to evaluate OA disease progression.

Population genetics has been successful at identifying the relationships between human groups and their interconnected histories. However, the link between genetic demography inferred at large scales and the individual human behaviours that ultimately generate that demography is not always clear. While anthropological and historical context are routinely presented as adjuncts in population genetic studies to help describe the past, determining how underlying patterns of human sociocultural behaviour impact genetics still remains challenging. Here, we analyse patterns of genetic variation in village-scale samples from two islands in eastern Indonesia, patrilocal Sumba and a matrilocal region of Timor. Adopting a ‘process modelling’ approach, we iteratively explore combinations of structurally different models as a thinking tool. We find interconnected socio-genetic interactions involving sex-biased migration, lineage-focused founder effects, and on Sumba, heritable social dominance. Strikingly, founder ideology, a cultural model derived from anthropological and archaeological studies at larger regional scales, has both its origins and impact at the scale of villages. Process modelling lets us explore these complex interactions, first by circumventing the complexity of formal inference when studying large datasets with many interacting parts, and then by explicitly testing complex anthropological hypotheses about sociocultural behaviour from a more familiar population genetic standpoint.

Summary: Neutrophil granule serine proteases contribute to immune responses through cleavage of microbial toxins and structural proteins. They induce tissue damage and modulate inflammation if levels exceed their inhibitors. Here, we show that the intracellular protease inhibitors Serpinb1a and Serpinb6a contribute to monocyte and neutrophil survival in steady-state and inflammatory settings by inhibiting cathepsin G (CatG). Importantly, we found that CatG efficiently cleaved gasdermin D (GSDMD) to generate the signature N-terminal domain GSDMD-p30 known to induce pyroptosis. Yet GSDMD deletion did not rescue neutrophil survival in Sb1a.Sb6a−/− mice. Furthermore, Sb1a.Sb6a−/− mice released high levels of pro-inflammatory cytokines upon endotoxin challenge in vivo in a CatG-dependent manner. Canonical inflammasome activation in Sb1a.Sb6a−/− macrophages showed increased IL-1β release that was dependent on CatG and GSDMD. Together, our findings demonstrate that cytosolic serpins expressed in myeloid cells prevent cell death and regulate inflammatory responses by inhibiting CatG and alternative activation of GSDMD. : Burgener et al. show that cytosolic protease inhibitors Serpinb1a and Serpinb6a inhibit the granule serine protease cathepsin G to prevent neutrophil and monocyte death and cytokine release upon LPS challenge. Mechanistically, activation of gasdermin D by cathepsin G is required for inflammation but not for neutrophil death. Keywords: inflammation, cell death, neutrophil, pyroptosis, apoptosis, serpin, proteinase, cathepsin, elastase, gasdermin