Evolutionary Conservation of a Modified Spermatogenesis Program in Rhabditis Nematodes with Skewed Sex Ratios

The cellular divisions in Rhabditis sp. SB347 male spermatogenesis have been modified to re-purpose an asymmetric division. This results in the dramatically skewed sex ratios observed in the progeny of males of this species. Here we confirm this asymmetry in the division of tubulin and major sperm protein (MSP). MSP, a necessary sperm component, is segregated exclusively into spermatids bearing the X chromosome while tubulin is segregated into the nullo-X sperm. Timing of the partitioning events reveals that MSP migration is not directly dependent on tubulin spindle asymmetry. Additionally, the endoplasmic reticulum is also segregated asymmetrically to the nullo-X spermatid during the partitioning phase of spermatogenesis. This results in only the X-bearing spermatids being functional, and thus the exclusive production of feminine offspring. This pattern of asymmetry appears to not be isolated to SB347. We investigated several other species in the Rhabditis clade including SB372, JU1809, and JU1782. Using MSP and tubulin as markers, each species was noted to display asymmetric divisions very similar to those in SB347. This corresponds with data suggesting that these species demonstrate similar skews in the sex ratios of offspring (Pires daSilva, unpublished). Not only do these species display unusual cellular divisions, but the size of the spermatids is greatly diminished compared to other closely related nematodes that have been studied. These two features make the species in the Rhabditis clade interesting subjects of study. They may serve as models to bolster our current understanding of cellular polarization in spermatogenesis and the mechanisms of distinction between residual body and spermatid. They may also yield important insights into the evolution of sex and gamete size. Lastly, evidence suggests that the non-functional sperm, lacking the X chromosome, produced by Rhabditis sp. SB347 form large clusters in the male gonad. The fate of these aggregates is unknown, but they appear to be removed from the spermatid population. This draws some parallels to the apoptotic fate of the residual body in C. elegans. Study of the Rhabditis nematodes is just beginning, but it promises some interesting findings and novel insights into nematode biology

3,4-and 3,5-disubstituted 2-pyridones using an intermolecular cycloaddition/cycloreversion strategy: toward the synthesis of aristopyridinone A

The intermolecular cycloaddition of pyrazinone precursors with alkyne substrates was evaluated. The resulting regioisomeric [2.2.2]-diketopiperazine alkene cycloadducts were diverted into 2-pyridone products through cycloreversion of the [2.2.2]-bicyclic intermediates. New insights into the regioselectivity of pyrazinone azadiene Diels-Alder reactions as well as cycloreversion reactivity were revealed in this study. Synthetic sequences using this [4+2]/r[4+2] strategy were determined that can produce predominantly the 3,5-disubstituted 2-pyridone alkaloid structures; pyridones featuring the 3,4-substitution pattern are observed as the minor regioisomeric products. (C) 2015 Elsevier Ltd. All rights reserved

Cytoskeletal variations in an asymmetric cell division support diversity in nematode sperm size and sex ratios

Asymmetric partitioning is an essential component of many developmental processes. As spermatogenesis concludes, sperm are streamlined by discarding unnecessary cellular components into cellular wastebags called residual bodies (RBs). During nematode spermatogenesis, this asymmetric partitioning event occurs shortly after anaphase II, and both microtubules and actin partition into a central RB. Here, we use fluorescence and transmission electron microscopy to elucidate and compare the intermediate steps of RB formation in Caenorhabditis elegans, Rhabditis sp. SB347 (recently named Auanema rhodensis) and related nematodes. In all cases, intact microtubules reorganize and move from centrosomal to non-centrosomal sites at the RB-sperm boundary whereas actin reorganizes through cortical ring expansion and clearance from the poles. However, in species with tiny spermatocytes, these cytoskeletal changes are restricted to one pole. Consequently, partitioning yields one functional sperm with the X-bearing chromosome complement and an RB with the other chromosome set. Unipolar partitioning may not require an unpaired X, as it also occurs in XX spermatocytes. Instead, constraints related to spermatocyte downsizing may have contributed to the evolution of a sperm cell equivalent to female polar bodies

YihQ is a sulfoquinovosidase that cleaves sulfoquinovosyl diacylglyceride sulfolipids

Sulfoquinovose is produced by photosynthetic organisms at a rate of 1010 tons per annum and is degraded by bacteria as a source of carbon and sulfur. We have identified Escherichia coli YihQ as the first dedicated sulfoquinovosidase and the gateway enzyme to sulfoglycolytic pathways. Structural and mutagenesis studies unveiled the sequence signatures for binding the distinguishing sulfonate residue and revealed that sulfoquinovoside degradation is widespread across the tree of life

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Nonlinear increases in extreme temperatures paradoxically dampen increases in extreme humid-heat

Nonlinear increases in warm season temperatures are projected for many regions, a phenomenon we show to be associated with relative surface drying. However, negative human health impacts are physiologically linked to combinations of high temperatures and high humidity. Since the amplified warming and drying are concurrent, the net effect on humid-heat, as measured by the wet bulb temperature ( T _W ), is uncertain. We demonstrate that globally, on the hottest days of the year, the positive effect of amplified warming on T _W is counterbalanced by a larger negative effect resulting from drying. As a result, the largest increases in T _W and T _x do not occur on the same days. Compared to a world with linear temperature change, the drying associated with nonlinear warming dampens mid-latitude T _W increases by up to 0.5 °C, and also dampens the rise in frequency of dangerous humid-heat ( T _W  > 27 °C) by up to 5 d per year in parts of North America and Europe. Our results highlight the opposing interactions among temperature and humidity changes and their effects on T _W , and point to the importance of constraining uncertainty in hydrological and warm season humidity changes to best position the management of future humid-heat risks

List of differentially expressed genes at all time points

The statistical metrics presented for each comparison include: log2 fold change (log2FC), average log2 counts per million (logCPM), quasi-likelihood F-statistic (F), p-value (PValue) and false discovery rate (FDR). The non-TB time zero baseline group from the GC6 study were the control group for all comparisons prior to TB diagnosis (i.e., 24, 18, 12 and 6 months before diagnosis) while the Catalysis study healthy controls served as the baseline for the TB comparison

PET scores for the catalysis study specimens

The PET score (low-PET, high-PET as defined in Methods) for the Catalysis study specimens used in the "Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six months before tuberculosis diagnosis" study