Factors influencing the stable carbon isotopic composition of suspended and sinking organic matter in the coastal Antarctic sea ice environment

A high resolution time-series analysis of stable carbon isotopic signatures in particulate organic carbon (δ<sup>13</sup>C<sub>POC</sub>) and associated biogeochemical parameters in sea ice and surface waters provides an insight into the factors affecting δ<sup>13</sup>C<sub>POC</sub> in the coastal western Antarctic Peninsula sea ice environment. The study covers two austral summer seasons in Ryder Bay, northern Marguerite Bay between 2004 and 2006. A shift in diatom species composition during the 2005/06 summer bloom to near-complete biomass dominance of <i>Proboscia inermis</i> is strongly correlated with a large ~10 ‰ negative isotopic shift in δ<sup>13</sup>C<sub>POC</sub> that cannot be explained by a concurrent change in concentration or isotopic signature of CO<sub>2</sub>. We hypothesise that the δ<sup>13</sup>C<sub>POC</sub> shift may be driven by the contrasting biochemical mechanisms and utilisation of carbon-concentrating mechanisms (CCMs) in different diatom species. Specifically, very low δ<sup>13</sup>C<sub>POC</sub> in <i>P. inermis</i> may be caused by the lack of a CCM, whilst some diatom species abundant at times of higher δ<sup>13</sup>C<sub>POC</sub> may employ CCMs. These short-lived yet pronounced negative δ<sup>13</sup>C<sub>POC</sub> excursions drive a 4 ‰ decrease in the seasonal average δ<sup>13</sup>C<sub>POC</sub> signal, which is transferred to sediment traps and core-top sediments and consequently has the potential for preservation in the sedimentary record. This 4 ‰ difference between seasons of contrasting sea ice conditions and upper water column stratification matches the full amplitude of glacial-interglacial Southern Ocean δ<sup>13</sup>C<sub>POC</sub> variability and, as such, we invoke phytoplankton species changes as a potentially important factor influencing sedimentary δ<sup>13</sup>C<sub>POC</sub>. We also find significantly higher δ<sup>13</sup>C<sub>POC</sub> in sea ice than surface waters, consistent with autotrophic carbon fixation in a semi-closed environment and possible contributions from post-production degradation, biological utilisation of HCO<sub>3</sub><sup>−</sup> and production of exopolymeric substances. This study demonstrates the importance of surface water diatom speciation effects and isotopically heavy sea ice-derived material for δ<sup>13</sup>C<sub>POC</sub> in Antarctic coastal environments and underlying sediments, with consequences for the utility of diatom-based δ<sup>13</sup>C<sub>POC</sub> in the sedimentary record

Pathways into services for offenders with intellectual disabilities : childhood experience, diagnostic information and offence variables

The patterns and pathways into intellectual disability (ID) offender services were studied through case file review for 477 participants referred in one calendar year to community generic, community forensic, and low, medium, and maximum secure services. Data were gathered on referral source, demographic information, index behavior, prior problem behaviors, diagnostic information, and abuse or deprivation. Community referrers tended to refer to community services and secure service referrers to secure services. Physical and verbal violence were the most frequent index behaviors, whereas contact sexual offenses were more prominent in maximum security. Age at first incident varied with security, with the youngest in maximum secure services. Attention-deficit/hyperactivity disorder or conduct disorder was the most frequently recorded diagnosis, and severe deprivation was the most frequent adverse developmental experience. Fire starting, theft, and road traffic offenses did not feature prominently. Generic community services accepted a number of referrals with forensic-type behavior and had higher proportions of both women and people with moderate or severe ID

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Rare genetic variants explain missing heritability in smoking

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this ‘missing heritability’. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability (hSNP2) was estimated from 0.13 to 0.28 (s.e., 0.10–0.13) in European ancestries, with 35–74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5–4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability (hped2, 0.18–0.34). In the African ancestry samples, hSNP2 was estimated from 0.03 to 0.33 (s.e., 0.09–0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking

Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction

The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies

WHO global research priorities for antimicrobial resistance in human health

The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely