Synaptonemal Complex Components Persist at Centromeres and Are Required for Homologous Centromere Pairing in Mouse Spermatocytes

Recent studies in simple model organisms have shown that centromere pairing is important for ensuring high-fidelity meiotic chromosome segregation. However, this process and the mechanisms regulating it in higher eukaryotes are unknown. Here we present the first detailed study of meiotic centromere pairing in mouse spermatogenesis and link it with key events of the G2/metaphase I transition. In mouse we observed no evidence of the persistent coupling of centromeres that has been observed in several model organisms. We do however find that telomeres associate in non-homologous pairs or small groups in B type spermatogonia and pre-leptotene spermatocytes, and this association is disrupted by deletion of the synaptonemal complex component SYCP3. Intriguingly, we found that, in mid prophase, chromosome synapsis is not initiated at centromeres, and centromeric regions are the last to pair in the zygotene-pachytene transition. In late prophase, we first identified the proteins that reside at paired centromeres. We found that components of the central and lateral element and transverse filaments of the synaptonemal complex are retained at paired centromeres after disassembly of the synaptonemal complex along diplotene chromosome arms. The absence of SYCP1 prevents centromere pairing in knockout mouse spermatocytes. The localization dynamics of SYCP1 and SYCP3 suggest that they play different roles in promoting homologous centromere pairing. SYCP1 remains only at paired centromeres coincident with the time at which some kinetochore proteins begin loading at centromeres, consistent with a role in assembly of meiosis-specific kinetochores. After removal of SYCP1 from centromeres, SYCP3 then accumulates at paired centromeres where it may promote bi-orientation of homologous centromeres. We propose that, in addition to their roles as synaptonemal complex components, SYCP1 and SYCP3 act at the centromeres to promote the establishment and/or maintenance of centromere pairing and, by doing so, improve the segregation fidelity of mammalian meiotic chromosomes

The MindfulBreather: Motion Guided Mindfulness.

For millennia, humans have focused their attention on the breath to develop mindfulness, but finding a scientific way to harness mindful breathing has proven elusive. Existing attempts to objectively measure and feedback on mindfulness have relied on specialist external hardware including electroencephalograms or respirometers that have been impractical for the majority of people learning to meditate. Consequently, training in the key skill of breath-awareness has lacked practical objective measures and guidance to enhance training. Here, we provide a brief technology report on an invention, The MindfulBreather® that addresses these issues. The technology is available to download embedded in a smartphone app that targets, measures and feedbacks on mindfulness of breathing in realtime to enhance training. The current article outlines only the technological concept with future studies quantifying efficacy, validity and reliability to be reported elsewhere. The MindfulBreather works by generating Motion Guided Mindfulness through interacting gyroscopic and touchscreen sensors in a three phase process: Mindfulness Induction (Phase I) gives standardized instruction to users to place their smartphone on their abdomen, breathe mindfully and to tap only at the peak of their inhalation. The smartphone's gyroscope detects periodic tilts during breathing to generate sinusoidal waveforms. Waveform-tap patterns are analyzed to determine whether the user is mindfully tapping only at the correct phase of the breathing cycle, indicating psychobiological synchronization. Mindfulness Maintenance (Phase II) provides reinforcing pleasant feedback sounds each time a breath is mindfully tapped at the right time, and the App records a mindful breath. Lastly, data-driven Insights are fed back to the user (Phase III), including the number of mindful breaths tapped and breathing rate reductions associated with parasympathetic engagement during meditation. The new MGM technology is then evaluated and contrasted with traditional mindfulness approaches and a novel Psychobiological Synchronization Model is proposed. In summary, unlike existing technology, the MindfulBreather requires no external hardware and repurposes regular smartphones to deliver app-embedded Motion-Guided Mindfulness. Technological applications include reducing mindwandering and down-regulation of the brain's default mode through enhanced mindful awareness. By objectively harnessing breath awareness, The MindfulBreather aims to realize the ancient human endeavor of mindfulness for the 21st century

Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGFβ-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated

Interpopulation Variation in Contour Feather Structure Is Environmentally Determined in Great Tits

Background: The plumage of birds is important for flying, insulation and social communication. Contour feathers cover most of the avian body and among other functions they provide a critical insulation layer against heat loss. Feather structure and composition are known to vary among individuals, which in turn determines variation in the insulation properties of the feather. However, the extent and the proximate mechanisms underlying this variation remain unexplored. Methodology/Principal Findings: We analyzed contour feather structure from two different great tit populations adapted to different winter regimes, one northern population in Oulu (Finland) and one southern population in Lund (Sweden). Great tits from the two populations differed significantly in feather structure. Birds from the northern population had a denser plumage but consisting of shorter feathers with a smaller proportion containing plumulaceous barbs, compared with conspecifics from the southern population. However, differences disappeared when birds originating from the two populations were raised and moulted in identical conditions in a common-garden experiment located in Oulu, under ad libitum nutritional conditions. All birds raised in the aviaries, including adult foster parents moulting in the same captive conditions, developed a similar feather structure. These feathers were different from that of wild birds in Oulu but similar to wild birds in Lund, the latter moulting in more benign conditions than those of Oulu. Conclusions/Significance: Wild populations exposed to different conditions develop contour feather differences either due to plastic responses or constraints. Environmental conditions, such as nutrient availability during feather growth play a crucial role in determining such differences in plumage structure among populations

A second horizon scan of biogeography:golden ages, Midas touches, and the Red Queen

Are we entering a new ‘Golden Age’ of biogeography, with continued development of infrastructure and ideas? We highlight recent developments, and the challenges and opportunities they bring, in light of the snapshot provided by the 7th biennial meeting of the International Biogeography Society (IBS 2015). We summarize themes in and across 15 symposia using narrative analysis and word clouds, which we complement with recent publication trends and ‘research fronts’. We find that biogeography is still strongly defined by core sub-disciplines that reflect its origins in botanical, zoological (particularly bird and mammal), and geographic (e.g., island, montane) studies of the 1800s. That core is being enriched by large datasets (e.g. of environmental variables, ‘omics’, species’ occurrences, traits) and new techniques (e.g., advances in genetics, remote sensing, modeling) that promote studies with increasing detail and at increasing scales; disciplinary breadth is being diversified (e.g., by developments in paleobiogeography and microbiology) and integrated through the transfer of approaches and sharing of theory (e.g., spatial modeling and phylogenetics in evolutionary–ecological contexts). Yet some subdisciplines remain on the fringe (e.g., marine biogeography, deep-time paleobiogeography), new horizons and new theory may be overshadowed by popular techniques (e.g., species distribution modelling), and hypotheses, data, and analyses may each be wanting. Trends in publication suggest a shift away from traditional biogeography journals to multidisciplinary or open access journals. Thus, there are currently many stewardship of, the planet (e.g., Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services). As in the past, biogeographers doubtless will continue to be engaged by new data and methods in exploring the nexus between biology and geography for decades into the future. But golden ages come and go, and they need not touch every domain in a discipline nor affect subdisciplines at the same time; moreover, what appears to be a Golden Age may sometimes have an undesirable ‘Midas touch’. Contexts within and outwith biogeography—e.g., methods, knowledge, climate, biodiversity, politics—are continually changing, and at times it can be challenging to establish or maintain relevance. In so many races with the Red Queen, we suggest that biogeography will enjoy greatest success if we also increasingly engage with the epistemology of our disciplinePeer reviewe

Joint Resummation for Higgs Production

We study the application of the joint resummation formalism to Higgs production via gluon-gluon fusion at the LHC, defining inverse transforms by analytic continuation. We work at next-to-leading logarithmic accuracy. We find that at low Q_T the resummed Higgs Q_T distributions are comparable in the joint and pure-Q_T formalisms, with relatively small influence from threshold enhancement in this range. We find a modest (about ten percent) decrease in the inclusive cross section, relative to pure threshold resummation.Comment: 22 pages, LaTeX, 5 figures as eps file

High sensitivity measurements of the CMB power spectrum with the extended Very Small Array

We present deep Ka-band ($\nu \approx 33$ GHz) observations of the CMB made with the extended Very Small Array (VSA). This configuration produces a naturally weighted synthesized FWHM beamwidth of $\sim 11$ arcmin which covers an $\ell$-range of 300 to 1500. On these scales, foreground extragalactic sources can be a major source of contamination to the CMB anisotropy. This problem has been alleviated by identifying sources at 15 GHz with the Ryle Telescope and then monitoring these sources at 33 GHz using a single baseline interferometer co-located with the VSA. Sources with flux densities \gtsim 20 mJy at 33 GHz are subtracted from the data. In addition, we calculate a statistical correction for the small residual contribution from weaker sources that are below the detection limit of the survey. The CMB power spectrum corrected for Galactic foregrounds and extragalactic point sources is presented. A total $\ell$-range of 150-1500 is achieved by combining the complete extended array data with earlier VSA data in a compact configuration. Our resolution of $\Delta \ell \approx 60$ allows the first 3 acoustic peaks to be clearly delineated. The is achieved by using mosaiced observations in 7 regions covering a total area of 82 sq. degrees. There is good agreement with WMAP data up to $\ell=700$ where WMAP data run out of resolution. For higher $\ell$-values out to $\ell = 1500$, the agreement in power spectrum amplitudes with other experiments is also very good despite differences in frequency and observing technique.Comment: 16 pages. Accepted in MNRAS (minor revisions

Theoretical Determination of the pK a Values of Betalamic Acid Related to the Free Radical Scavenger Capacity: Comparison Between Empirical and Quantum Chemical Methods

Health benefits of dietary phytochemicals have been suggested in recent years. Among 1000s of different compounds, Betalains, which occur in vegetables of the Cariophyllalae order (cactus pear fruits and red beet), have been considered because of reducing power and potential to affect redox-modulated cellular processes. The antioxidant power of Betalains is strictly due to the dissociation rate of the acid moieties present in all the molecules of this family of phytochemicals. Experimentally, only the pK a values of betanin were determined. Recently, it was evidenced it was evidenced as the acid dissociation, at different environmental pHs, affects on its electron-donating capacity, and further on its free radical scavenging power. The identical correlation was studied on another Betalains family compound, Betalamic Acid. Experimental evidences showed that the free radical scavenging capacity of this compound drastically decreases at pH > 5, but pK a values were experimentally not measured. With the aim to justify the Betalamic Acid behavior as free radical scavenger, in this paper we tried to predict in silico the pK a values by means different approaches. Starting from the known experimental pK as of acid compounds, both phytochemicals and small organic, two empirical approaches and quantum-mechanical calculation were compared to give reliable prediction of the pK as of Betalamic Acid. Results by means these computational approaches are consistent with the experimental evidences. As shown herein, in silico, the totally dissociated species, at the experimental pH > 5 in solution, is predominant, exploiting the higher electron-donating capability (HOMO energy). Therefore, the computational estimated pK a values of Betalamic Acid resulted very reliable

Mindfulness-based programmes for mental health promotion in adults in nonclinical settings: A systematic review and meta-analysis of randomised controlled trials

Background: There is an urgent need for mental health promotion in nonclinical settings. Mindfulness–based programmes (MBPs) are being widely implemented to reduce stress, but a comprehensive evidence synthesis is lacking. We reviewed trials to assess whether MBPs promote mental health relative to no intervention or comparator interventions. Methods and findings: Following a detailed preregistered protocol (PROSPERO CRD42018105213) developed with public and professional stakeholders, 13 databases were searched to August 2020 for randomised controlled trials (RCTs) examining in–person, expert–defined MBPs in nonclinical settings. Two researchers independently selected, extracted, and appraised trials using the Cochrane Risk–of–Bias Tool 2.0. Primary outcomes were psychometrically validated anxiety, depression, psychological distress, and mental well–being questionnaires at 1 to 6 months after programme completion. Multiple testing was performed using p < 0.0125 (Bonferroni) for statistical significance. Secondary outcomes, meta–regression and sensitivity analyses were prespecified. Pairwise random–effects multivariate meta–analyses and prediction intervals (PIs) were calculated. A total of 11,605 participants in 136 trials were included (29 countries, 77% women, age range 18 to 73 years). Compared with no intervention, in most but not all scenarios MBPs improved average anxiety (8 trials; standardised mean difference (SMD) = −0.56; 95% confidence interval (CI) −0.80 to −0.33; p–value < 0.001; 95% PI −1.19 to 0.06), depression (14 trials; SMD = −0.53; 95% CI −0.72 to −0.34; p–value < 0.001; 95% PI −1.14 to 0.07), distress (27 trials; SMD = −0.45; 95% CI −0.58 to −0.31; p–value < 0.001; 95% PI −1.04 to 0.14), and well–being (9 trials; SMD = 0.33; 95% CI 0.11 to 0.54; p–value = 0.003; 95% PI −0.29 to 0.94). Compared with nonspecific active control conditions, in most but not all scenarios MBPs improved average depression (6 trials; SMD = −0.46; 95% CI −0.81 to −0.10; p–value = 0.012, 95% PI −1.57 to 0.66), with no statistically significant evidence for improving anxiety or distress and no reliable data on well–being. Compared with specific active control conditions, there is no statistically significant evidence of MBPs’ superiority. Only effects on distress remained when higher–risk trials were excluded. USA–based trials reported smaller effects. MBPs targeted at higher–risk populations had larger effects than universal MBPs. The main limitation of this review is that confidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach is moderate to very low, mainly due to inconsistency and high risk of bias in many trials. Conclusions: Compared with taking no action, MBPs of the included studies promote mental health in nonclinical settings, but given the heterogeneity between studies, the findings do not support generalisation of MBP effects across every setting. MBPs may have specific effects on some common mental health symptoms. Other preventative interventions may be equally effective. Implementation of MBPs in nonclinical settings should be partnered with thorough research to confirm findings and learn which settings are most likely to benefit

Increased production of IL-4 and IL-12p40 from bronchoalveolar lavage cells are biomarkers of Mycobacterium tuberculosis in the sputum

BACKGROUND: Tuberculosis (TB) causes 1.45 million deaths annually world wide, the majority of which occur in the developing world. Active TB disease represents immune failure to control latent infection from airborne spread. Acid-fast bacillus (AFB) seen on sputum smear is a biomarker for contagiousness. METHODS: We enrolled 73 tuberculosis patients with extensive infiltrates into a research study using bronchoalveolar lavage (BAL) to sample lung immune cells and assay BAL cell cytokine production. All patients had sputum culture demonstrating Mycobacterium tuberculosis and 59/73 (81%) had AFB identified by microscopy of the sputum. Compared with smear negative patients, smear positive patients at presentation had a higher proportion with smoking history, a higher proportion with temperature >38.5 0 C, higher BAL cells/ml, lower percent lymphocytes in BAL, higher IL-4 and IL-12p40 in BAL cell supernatants. There was no correlation between AFB smear and other BAL or serum cytokines. Increasing IL-4 was associated with BAL PMN and negatively associated with BAL lymphocytes. Each 10-fold increase in BAL IL-4 and IL-12p40 increased the odds of AFB smear positivity by 7.4 and 2.2-fold, respectively, in a multi-variable logistic model. CONCLUSION: Increasing IL-4 and IL-12p40 production by BAL cells are biomarkers for AFB in sputum of patients who present with radiographically advanced TB. They likely reflect less effective immune control of pathways for controlling TB, leading to patients with increased infectiousness