Alluvial fan records from southeast Arabia reveal multiple windows for human dispersal

The dispersal of human populations out of Africa into Arabia was most likely linked to episodes of climatic amelioration, when increased monsoon rainfall led to the activation of drainage systems, improved freshwater availability, and the development of regional vegetation. Here we present the first dated terrestrial record from southeast Arabia that provides evidence for increased rainfall and the expansion of vegetation during both glacial and interglacial periods. Findings from extensive alluvial fan deposits indicate that drainage system activation occurred during Marine Isotope Stage (MIS) 6 (ca. 160–150 ka), MIS 5 (ca. 130–75 ka), and during early MIS 3 (ca. 55 ka). The development of active freshwater systems during these periods corresponds with monsoon intensity increases during insolation maxima, suggesting that humid periods in Arabia were not confined to eccentricity-paced deglaciations, and providing paleoenvironmental support for multiple windows of opportunity for dispersal out of Africa during the late Pleistocene

Randomised, double-blind, placebo-controlled crossover study of single-dose guanfacine in unilateral neglect following stroke

OBJECTIVE: Unilateral neglect is a poststroke disorder that impacts negatively on functional outcome and lacks established, effective treatment. This multicomponent syndrome is characterised by a directional bias of attention away from contralesional space, together with impairments in several cognitive domains, including sustained attention and spatial working memory. This study aimed to test the effects of guanfacine, a noradrenergic alpha-2A agonist, on ameliorating aspects of neglect.METHODS: Thirteen right hemisphere stroke patients with leftward neglect were included in a randomised, double-blind, placebo-controlled proof-of-concept crossover study that examined the effects of a single dose of guanfacine. Patients were tested on a computerised, time-limited cancellation paradigm, as well as tasks that independently assessed sustained attention and spatial working memory.RESULTS: On guanfacine, there was a statistically significant improvement in the total number of targets found on the cancellation task when compared with placebo (mean improvement of 5, out of a possible 64). However, there was no evidence of a change in neglect patients' directional attention bias. Furthermore, Bayesian statistical analysis revealed reliable evidence against any effects of guanfacine on search organisation and performance on our sustained attention and spatial working memory tasks.CONCLUSIONS: Guanfacine improves search in neglect by boosting the number of targets found but had no effects on directional bias or search organisation, nor did it improve sustained attention or working memory on independent tasks. Further work is necessary to determine whether longer term treatment with guanfacine may be effective for some neglect patients and whether it affects functional outcome measures.TRIAL REGISTRATION NUMBER: NCT00955253.</p

Surface orientation, modulation frequency and the detection and perception of depth defined by binocular disparity and motion parallax

Binocular disparity and motion parallax provide information about the spatial structure and layout of the world. Descriptive similarities between the two cues have often been noted which have been taken as evidence of a close relationship between them. Here, we report two experiments which investigate the effect of surface orientation and modulation frequency on (i) a threshold detection task and (ii) a supra-threshold depth-matching task using sinusoidally corrugated surfaces defined by binocular disparity or motion parallax. For low frequency corrugations, an orientation anisotropy was observed in both domains, with sensitivity decreasing as surface orientation was varied from horizontal to vertical. In the depth-matching task, for surfaces defined by binocular disparity the greatest depth was seen for oblique orientations. For surfaces defined by motion parallax, perceived depth was found to increase as surface orientation was varied from horizontal to vertical. In neither case was perceived depth for supra-threshold surfaces related to threshold performance in any simple manner. These results reveal clear differences between the perception of depth from binocular disparity or motion parallax, and between perception at threshold and supra-threshold levels of performance. © 2006 Elsevier Ltd. All rights reserved

Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination

Antigen recognition by the T-cell receptor (TCR) is a hallmark of the adaptive immune system. When the TCR engages a peptide bound to the restricting major histocompatibility complex molecule (pMHC), it transmits a signal via the associated CD3 complex. How the extracellular antigen recognition event leads to intracellular phosphorylation remains unclear. Here, we used single-molecule localization microscopy to quantify the organization of TCR–CD3 complexes into nanoscale clusters and to distinguish between triggered and nontriggered TCR–CD3 complexes. We found that only TCR–CD3 complexes in dense clusters were phosphorylated and associated with downstream signaling proteins, demonstrating that the molecular density within clusters dictates signal initiation. Moreover, both pMHC dose and TCR–pMHC affinity determined the density of TCR–CD3 clusters, which scaled with overall phosphorylation levels. Thus, TCR–CD3 clustering translates antigen recognition by the TCR into signal initiation by the CD3 complex, and the formation of dense signaling-competent clusters is a process of antigen discrimination

Guidelines for the use of diagnostic imaging in musculoskeletal (MSK) pain conditions affecting the lower back, knee and shoulder: a scoping review

Musculoskeletal (MSK) pain is one of the most common reasons for primary care consultation, particularly pain in the lower back (LBP), knee, and shoulder. The use of diagnostic imaging for musculoskeletal pain is increasing but it is unclear whether this increase is justified based on clinical practice guideline (CPG) recommendations. Aim To identify and map the content of CPGs that inform the use of diagnostic imaging in those with non-traumatic LBP, knee, and shoulder pain in primary and intermediate care in the UK. Design and Setting A scoping review of CPGs. Methods This scoping review was conducted and is reported in accordance with PRISMA guidance. A broad search strategy included electronic searches of MEDLINE, CINAHL, PsychINFO and SPORTDiscus from 2009 to the 17th April 2019. This was conducted alongside a search of guideline repositories and was combined with a snowball search of Google, relevant professional bodies and use of social media. Results 31 relevant CPGs were included. Routine use of diagnostic imaging for those with non-traumatic LBP, knee or shoulder pain is generally discouraged in primary care or intermediate care. Diagnostic imaging should be reserved for when specific or serious pathology is suspected or where the person is not responding to initial non-surgical management and the imaging result is expected to change clinical management decisions. Conclusion Diagnostic imaging should not be routinely requested in primary or intermediate care for non-traumatic LBP, knee, or shoulder pain. CPGs do not justify the increasing imaging rates in the UK for musculoskeletal pain

A Role for Phosphatidic Acid in the Formation of “Supersized” Lipid Droplets

Lipid droplets (LDs) are important cellular organelles that govern the storage and turnover of lipids. Little is known about how the size of LDs is controlled, although LDs of diverse sizes have been observed in different tissues and under different (patho)physiological conditions. Recent studies have indicated that the size of LDs may influence adipogenesis, the rate of lipolysis and the oxidation of fatty acids. Here, a genome-wide screen identifies ten yeast mutants producing “supersized” LDs that are up to 50 times the volume of those in wild-type cells. The mutated genes include: FLD1, which encodes a homologue of mammalian seipin; five genes (CDS1, INO2, INO4, CHO2, and OPI3) that are known to regulate phospholipid metabolism; two genes (CKB1 and CKB2) encoding subunits of the casein kinase 2; and two genes (MRPS35 and RTC2) of unknown function. Biochemical and genetic analyses reveal that a common feature of these mutants is an increase in the level of cellular phosphatidic acid (PA). Results from in vivo and in vitro analyses indicate that PA may facilitate the coalescence of contacting LDs, resulting in the formation of “supersized” LDs. In summary, our results provide important insights into how the size of LDs is determined and identify novel gene products that regulate phospholipid metabolism

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability