Early Ipswichian (last interglacial) sea level rise in the channel region : Stone Point Site of Special Scientific Interest, Hampshire, England

Constraining the speed of sea level rise at the start of an interglacial is important to understanding the size of the ‘window of opportunity’ available for hominin migration. This is particularly important during the last interglacial when there is no evidence for significant hominin occupation anywhere in Britain. There are very few finer grained fossiliferous sequences in the Channel region that can be used to constrain sea level rise and they are preserved only to the north of the Channel, in England. Of these, the sequence at Stone Point SSSI is by far the most complete. Data from this sequence has been previously reported, and discussed at a Quaternary Research Association Field Meeting, where a number of further questions were raised that necessitated further data generation. In this paper, we report new data from this sequence – thin section analysis, isotopic determinations on ostracod shells, new Optical Stimulated Luminescence ages and Amino Acid Recem analyses. These show early sea level rise in this sequence, starting during the pre-temperate vegetation zone IpI, but no early warming. The implications of this almost certainly last interglacial sequence for the human colonisation of Britain and our understanding of the stratigraphic relationship of interglacial estuarine deposits with their related fluvial terrace sequences is explored

Cytoskeletal protein kinases: titin and its relations in mechanosensing

Titin, the giant elastic ruler protein of striated muscle sarcomeres, contains a catalytic kinase domain related to a family of intrasterically regulated protein kinases. The most extensively studied member of this branch of the human kinome is the Ca2+–calmodulin (CaM)-regulated myosin light-chain kinases (MLCK). However, not all kinases of the MLCK branch are functional MLCKs, and about half lack a CaM binding site in their C-terminal autoinhibitory tail (AI). A unifying feature is their association with the cytoskeleton, mostly via actin and myosin filaments. Titin kinase, similar to its invertebrate analogue twitchin kinase and likely other “MLCKs”, is not Ca2+–calmodulin-activated. Recently, local protein unfolding of the C-terminal AI has emerged as a common mechanism in the activation of CaM kinases. Single-molecule data suggested that opening of the TK active site could also be achieved by mechanical unfolding of the AI. Mechanical modulation of catalytic activity might thus allow cytoskeletal signalling proteins to act as mechanosensors, creating feedback mechanisms between cytoskeletal tension and tension generation or cellular remodelling. Similar to other MLCK-like kinases like DRAK2 and DAPK1, TK is linked to protein turnover regulation via the autophagy/lysosomal system, suggesting the MLCK-like kinases have common functions beyond contraction regulation

Molecular mechanisms and cellular functions of cGAS-STING signalling

The cGAS–STING signalling axis, comprising the synthase for the second messenger cyclic GMP–AMP (cGAS) and the cyclic GMP–AMP receptor stimulator of interferon genes (STING), detects pathogenic DNA to trigger an innate immune reaction involving a strong type I interferon response against microbial infections. Notably however, besides sensing microbial DNA, the DNA sensor cGAS can also be activated by endogenous DNA, including extranuclear chromatin resulting from genotoxic stress and DNA released from mitochondria, placing cGAS–STING as an important axis in autoimmunity, sterile inflammatory responses and cellular senescence. Initial models assumed that co-localization of cGAS and DNA in the cytosol defines the specificity of the pathway for non-self, but recent work revealed that cGAS is also present in the nucleus and at the plasma membrane, and such subcellular compartmentalization was linked to signalling specificity of cGAS. Further confounding the simple view of cGAS–STING signalling as a response mechanism to infectious agents, both cGAS and STING were shown to have additional functions, independent of interferon response. These involve non-catalytic roles of cGAS in regulating DNA repair and signalling via STING to NF-κB and MAPK as well as STING-mediated induction of autophagy and lysosome- dependent cell death. We have also learnt that cGAS dimers can multimerize and undergo liquid–liquid phase separation to form biomolecular condensates that could importantly regulate cGAS activation. Here, we review the molecular mechanisms and cellular functions underlying cGAS–STING activation and signalling, particularly highlighting the newly emerging diversity of this signalling pathway and discussing how the specificity towards normal, damage-induced and infection-associated DNA could be achieved

Early Ipswichian (last interglacial) sea level rise in the channel region : Stone Point Site of Special Scientific Interest, Hampshire, England

Constraining the speed of sea level rise at the start of an interglacial is important to understanding the size of the ‘window of opportunity’ available for hominin migration. This is particularly important during the last interglacial when there is no evidence for significant hominin occupation anywhere in Britain. There are very few finer grained fossiliferous sequences in the Channel region that can be used to constrain sea level rise and they are preserved only to the north of the Channel, in England. Of these, the sequence at Stone Point SSSI is by far the most complete. Data from this sequence has been previously reported, and discussed at a Quaternary Research Association Field Meeting, where a number of further questions were raised that necessitated further data generation. In this paper, we report new data from this sequence – thin section analysis, isotopic determinations on ostracod shells, new Optical Stimulated Luminescence ages and Amino Acid Recem analyses. These show early sea level rise in this sequence, starting during the pre-temperate vegetation zone IpI, but no early warming. The implications of this almost certainly last interglacial sequence for the human colonisation of Britain and our understanding of the stratigraphic relationship of interglacial estuarine deposits with their related fluvial terrace sequences is explored

Childhood cognitive ability and adult mental health in the British 1946 birth cohort

We examined whether childhood cognitive ability was associated with two mental health outcomes at age 53 years: the 28 item General Health Questionnaire (GHQ-28) as a measure of internalising symptoms of anxiety and depression, and the CAGE screen for potential alcohol abuse as an externalising disorder. A total of 1875 participants were included from the Medical Research Council National Survey of Health and Development, also known as the British 1946 birth cohort. The results indicated that higher childhood cognitive ability was associated with reporting fewer symptoms of anxiety and depression GHQ-28 scores in women, and increased risk of potential alcohol abuse in both men and women. Results were adjusted for educational attainment, early socioeconomic status (SES) and adverse circumstances, and adult SES, adverse circumstances, and negative health behaviours. After adjusting for childhood cognitive ability, greater educational attainment was associated with reporting greater symptoms of anxiety and depression on the GHQ-28. Although undoubtedly interrelated, our evidence on the diverging effects of childhood cognitive ability and educational attainment on anxiety and depression in mid-adulthood highlights the need for the two to be considered independently. While higher childhood cognitive ability is associated with fewer internalising symptoms of anxiety and depression in women, it places both men and women at higher risk for potential alcohol abuse. Further research is needed to examine possible psychosocial mechanisms that may be associated with both higher childhood cognitive ability and greater risk for alcohol abuse. In addition, the underlying mechanisms responsible for the gender-specific link between childhood cognitive ability and the risk of experiencing internalising disorders in mid-adulthood warrants further consideration

Childhood cognitive ability and adult mental health in the British 1946 birth cohort

We examined whether childhood cognitive ability was associated with two mental health outcomes at age 53 years: the 28 item General Health Questionnaire (GHQ-28) as a measure of internalising symptoms of anxiety and depression, and the CAGE screen for potential alcohol abuse as an externalising disorder. A total of 1875 participants were included from the Medical Research Council National Survey of Health and Development, also known as the British 1946 birth cohort. The results indicated that higher childhood cognitive ability was associated with reporting fewer symptoms of anxiety and depression GHQ-28 scores in women, and increased risk of potential alcohol abuse in both men and women. Results were adjusted for educational attainment, early socioeconomic status (SES) and adverse circumstances, and adult SES, adverse circumstances, and negative health behaviours. After adjusting for childhood cognitive ability, greater educational attainment was associated with reporting greater symptoms of anxiety and depression on the GHQ-28. Although undoubtedly interrelated, our evidence on the diverging effects of childhood cognitive ability and educational attainment on anxiety and depression in mid-adulthood highlights the need for the two to be considered independently. While higher childhood cognitive ability is associated with fewer internalising symptoms of anxiety and depression in women, it places both men and women at higher risk for potential alcohol abuse. Further research is needed to examine possible psychosocial mechanisms that may be associated with both higher childhood cognitive ability and greater risk for alcohol abuse. In addition, the underlying mechanisms responsible for the gender-specific link between childhood cognitive ability and the risk of experiencing internalising disorders in mid-adulthood warrants further consideration.UK Adult mental health Prospective cohort Childhood cognitive ability Educational attainment Gender

Long-term psychological distress trajectories and the COVID-19 pandemic in three British birth cohorts: A multi-cohort study.

BackgroundGrowing evidence suggests that population mental health outcomes have worsened since the pandemic started. The extent that these changes have altered common age-related trends in psychological distress, where distress typically rises until midlife and then falls after midlife in both sexes, is unknown. We aimed to analyse whether long-term pre-pandemic psychological distress trajectories were disrupted during the pandemic, and whether these changes have been different across cohorts and by sex.Methods and findingsWe used data from three nationally representative birth cohorts comprising all people born in Great Britain in a single week of 1946 (National Survey of Health and Development, NSHD), 1958 (National Child Development Study, NCDS), or 1970 (British Cohort Study, BCS70). The follow-up data used spanned 39 years in NSHD (1982 to 2021), 40 years in NCDS (1981 to 2001), and 25 years in BCS70 (1996 to 2021). We used psychological distress factor scores, as measured by validated self-reported questionnaires (NSHD: Present State Examination, Psychiatric Symptoms Frequency, and 28- and 12-item versions of General Health Questionnaire; NCDS and BCS70: Malaise Inventory; all: 2-item versions of Generalized Anxiety Disorder scale and Patient Health Questionnaire). We used a multilevel growth curve modelling approach to model the trajectories of distress across cohorts and sexes and obtained estimates of the differences between the distress levels observed during the pandemic and those observed at the most recent pre-pandemic assessment and at the peak in the cohort-specific pre-pandemic distress trajectory, located at midlife. We further analysed whether pre-existing cohort and sex inequalities had changed with the pandemic onset using a difference-in-differences (DiD) approach. The analytic sample included 16,389 participants. By September/October 2020, distress levels had reached or exceeded the levels of the peak in the pre-pandemic life-course trajectories, with larger increases in younger cohorts (standardised mean differences [SMD] and 95% confidence intervals of SMDNSHD,pre-peak = -0.02 [-0.07, 0.04], SMDNCDS,pre-peak = 0.05 [0.02, 0.07], and SMDBCS70,pre-peak = 0.09 [0.07, 0.12] for the 1946, 1958, and 1970 birth cohorts, respectively). Increases in distress were larger among women than men, widening pre-existing sex inequalities (DiD and 95% confidence intervals of DiDNSHD,sex,pre-peak = 0.17 [0.06, 0.28], DiDNCDS,sex,pre-peak = 0.11 [0.07, 0.16], and DiDBCS70,sex,pre-peak = 0.11 [0.05, 0.16] when comparing sex inequalities in the pre-pandemic peak in midlife to those observed by September/October 2020). As expected in cohort designs, our study suffered from high proportions of attrition with respect to the original samples. Although we used non-response weights to restore sample representativeness to the target populations (those born in the United Kingdom in 1946, 1958, and 1970, alive and residing in the UK), results may not be generalisable to other sections within the UK population (e.g., migrants and ethnic minority groups) and countries different than the UK.ConclusionsPre-existing long-term psychological distress trajectories of adults born between 1946 and 1970 were disrupted during the COVID-19 pandemic, particularly among women, who reached the highest levels ever recorded in up to 40 years of follow-up data. This may impact future trends of morbidity, disability, and mortality due to common mental health problems