Coupled evolution of temperature and carbonate chemistry during the Paleocene–Eocene; new trace element records from the low latitude Indian Ocean

This is the final version. Available on open access from Elsevier via the DOI in this recordThe early Paleogene represents the most recent interval in Earth’s history characterized by global greenhouse warmth on multi-million year timescales, yet our understanding of long-term climate and carbon cycle evolution in the low latitudes, and in particular the Indian Ocean, remains very poorly constrained. Here we present the first long-term sub-eccentricity-resolution stable isotope (δ13 30 C and δ 18 O) and trace element (Mg/Ca and B/Ca) records spanning the late Paleocene–early Eocene (~58– 53 Ma) across a surface–deep hydrographic reconstruction of the northern Indian Ocean, resolving late Paleocene 405-kyr paced cyclicity and a portion of the PETM recovery. Our new records reveal a long-term warming of ~4–5°C at all depths in the water column, with absolute surface ocean temperatures and magnitudes of warming comparable to the low latitude Pacific. As a result of warming, we observe a long-term increase in δ 18 Osw of the mixed layer, implying an increase in net evaporation. We also observe a collapse in the temperature gradient between mixed layer- and thermocline-dwelling species from ~57–54 Ma, potentially due to either the development of a more homogeneous water column with a thicker mixed layer, or depth migration of the Morozovella in response to warming. Synchronous warming at both low and high latitudes, along with decreasing B/Ca ratios in planktic foraminifera indicating a decrease in ocean pH and/or increasing dissolved inorganic carbon, suggest that global climate was forced by rising atmospheric CO2 concentrations during this time.European Consortium for Ocean Research Drilling (ECORD)International Association of Sedimentologists (IAS)NSFNatural Environment Research Council (NERC

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Coupled evolution of temperature and carbonate chemistry during the Paleocene-Eocene; new trace element records from the low latitude Indian Ocean

The early Paleogene represents the most recent interval in Earth's history characterized by global greenhouse warmth on multi-million year timescales, yet our understanding of long-term climate and carbon cycle evolution in the low latitudes, and in particular the Indian Ocean, remains very poorly constrained. Here we present the first long-term sub-eccentricity-resolution stable isotope (δ13C and δ18O) and trace element (Mg/Ca and B/Ca) records spanning the late Paleocene-early Eocene (similar to 58-53 Ma) across a surface-deep hydrographic reconstruction of the northern Indian Ocean, resolving late Paleocene 405-kyr paced cyclicity and a portion of the PETM recovery. Our new records reveal a long-term warming of similar to 4-5 °C at all depths in the water column, with absolute surface ocean temperatures and magnitudes of warming comparable to the low latitude Pacific. As a result of warming, we observe a long-term increase in δ18Osw of the mixed layer, implying an increase in net evaporation. We also observe a collapse in the temperature gradient between mixed layer- and thermocline-dwelling species from similar to 57-54 Ma, potentially due to either the development of a more homogeneous water column with a thicker mixed layer, or depth migration of the Morozovellain response to warming. Synchronous warming at both low and high latitudes, along with decreasing B/Ca ratios in planktic foraminifera indicating a decrease in ocean pH and/or increasing dissolved inorganic carbon, suggest that global climate was forced by rising atmospheric CO2 concentrations during this time.</p

Recommendations for Premature Ovarian Insufficiency Surveillance for Female Survivors of Childhood, Adolescent, and Young Adult Cancer : A Report From the International Late Effects of Childhood Cancer Guideline Harmonization Group in Collaboration With the PanCareSurFup Consortium

PURPOSE: Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors' access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening. PATIENTS AND METHODS: The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations were developed by using a transparent process and are intended to facilitate care for survivors of CAYA cancer. RESULTS AND CONCLUSION: The harmonized set of POI surveillance recommendations is intended to be scientifically rigorous, to positively influence health outcomes, and to facilitate the care for female survivors of CAYA cancer

Serologic Responses to Recombinant Pneumocystis jirovecii Major Surface Glycoprotein among Ugandan Patients with Respiratory Symptoms

BACKGROUND: Little is known about the serologic responses to Pneumocystis jirovecii major surface glycoprotein (Msg) antigen in African cohorts, or the IgM responses to Msg in HIV-positive and HIV-negative persons with respiratory symptoms. METHODS: We conducted a prospective study of 550 patients, both HIV-positive (n = 467) and HIV-negative (n = 83), hospitalized with cough ≥2 weeks in Kampala, Uganda, to evaluate the association between HIV status, CD4 cell count, and other clinical predictors and antibody responses to P. jirovecii. We utilized ELISA to measure the IgM and IgG serologic responses to three overlapping recombinant fragments that span the P. jirovecii major surface glycoprotein: MsgA (amino terminus), MsgB (middle portion) and MsgC1 (carboxyl terminus), and to three variations of MsgC1 (MsgC3, MsgC8 and MsgC9). RESULTS: HIV-positive patients demonstrated significantly lower IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 compared to HIV-negative patients. We found the same pattern of low IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 among HIV-positive patients with a CD4 cell count <200 cells/µl compared to those with a CD4 cell count ≥200 cells/µl. HIV-positive patients on PCP prophylaxis had significantly lower IgM responses to MsgC3 and MsgC9, and lower IgG responses to MsgA, MsgC1, MsgC3, and MsgC8. In contrast, cigarette smoking was associated with increased IgM antibody responses to MsgC1 and MsgC3 but was not associated with IgG responses. We evaluated IgM and IgG as predictors of mortality. Lower IgM responses to MsgC3 and MsgC8 were both associated with increased in-hospital mortality. CONCLUSIONS: HIV infection and degree of immunosuppression are associated with reduced IgM responses to Msg. In addition, low IgM responses to MsgC3 and MsgC8 are associated with increased mortality