Oriented Growth of In-Oxo Chain Based Metal-Porphyrin Framework Thin Film for High-Sensitive Photodetector

The potential of metal–organic frameworks (MOFs) for applications in optoelectronics results from a unique combination of interesting photophysical properties and straightforward tunability of organic and inorganic units. Here, it is demonstrated that using MOF approach chromophores can be assembled into well-ordered 1D arrays using metal-oxo strands as lead structure, and the resulting porphyrinic rows exhibit unique photophysical properties and allow the realization of highly sensitive photodetectors. A porphyrinic MOF thin film, In-TCPP surface-coordinated MOF thin films with [021] orientation is fabricated using a layer-by-layer method, from In(NO$_{3}$)$_{3}$ and TCPP (5,10,15,20-(4-carboxyphenyl)porphyrin). Detailed experimental and theoretical analysis reveals that the assembly yields a structure where In-oxo strands running parallel to the substrate fix the chromophoric linkers to yield 1D arrays of porphyrins. The frontier orbitals of this highly anisotropic arrangement are localized in these columnar arrangements of porphyrins and result in high photoactivity, which is exploited to fabricate a photodetector with record (as compared to other organic materials) responsivity in visible regime of 7.28 × 10$^{14}$ Jones and short rise/fall times (0.07/0.04 s). This oriented MOF thin film-based high-sensitive photodetector provides a new avenue to use inorganic, stable lead structures to assemble organic semiconductors into regular arrays, thus creating a huge potential for the fabrication of optoelectronic devices

PRMT1 promotes neuroblastoma cell survival through ATF5

Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma

Relative importance of climatic variables, soil properties and plant traits to spatial variability in net CO2 exchange across global forests and grasslands

Compared to the well-known drivers of spatial variability in gross primary productivity (GPP), the relative importance of climatic variables, soil properties and plant traits to the spatial variability in net ecosystem exchange of CO2 between terrestrial ecosystem and atmosphere (NEE) is poorly understood. We used principal component regression to analyze data from 147 eddy flux sites to disentangle effects of climatic variables, soil properties and plant traits on the spatial variation in annual NEE and its components (GPP and ecosystem respiration (RE)) across global forests and grasslands. Our results showed that the largest unique contribution (proportion of variance only explained by one class of variables) to NEE variance came from climatic variables for forests (24%-30%) and soil properties for grasslands (41%-54%). Specifically, mean annual precipitation and potential evapotranspiration were the most important climatic variables driving forest NEE, whereas available soil water capacity, clay content and cation exchange capacity mainly influenced grassland NEE. Plant traits showed a small unique contribution to NEE in both forests and grasslands. However, leaf phosphorus content strongly interacted with soil total nitrogen density and clay content, and these combined factors represented a major contribution for grassland NEE. For GPP and RE, the majority of spatial variance was attributed to the common contribution of climate, soil and plant traits (50% - 62%, proportion of variance explained by more than one class of variables), rather than their unique contributions. Interestingly, those factors with only minor influences on GPP and RE variability (e.g., soil properties) have significant contributions to the spatial variability in NEE. Such emerging factors and the interactions between climatic variables, soil properties and plant traits are not well represented in current terrestrial biosphere models, which should be considered in future model improvement to accurately predict the spatial pattern of carbon cycling across forests and grasslands globally.Peer reviewe

Worldwide tests of generic attractants, a promising tool for early detection of non-native cerambycid species

A large proportion of the insects which have invaded new regions and countries are emerging species, being found for the first time outside their native range. Being able to detect such species upon arrival at ports of entry before they establish in non-native countries is an urgent challenge. The deployment of traps baited with broad-spectrum semiochemical lures at ports-of-entry and other high-risk sites could be one such early detection tool. Rapid progress in the identification of semiochemicals for cerambycid beetles during the last 15 years has revealed that aggregation-sex pheromones and sex pheromones are often conserved at global levels for genera, tribes or subfamilies of the Cerambycidae. This possibly allows the development of generic attractants which attract multiple species simultaneously, especially when such pheromones are combined into blends. Here, we present the results of a worldwide field trial programme conducted during 2018-2021, using traps baited with a standardised 8-pheromone blend, usually com-plemented with plant volatiles. A total of 1308 traps were deployed at 302 sites covering simultaneously or sequentially 13 European countries, 10 Chinese provinces and some regions of the USA, Canada, Australia, Russia (Siberia) and the Caribbean (Martinique). We intended to test the following hypotheses: 1) if a species is regularly trapped in significant numbers by the blend on a continent, it increases the prob-ability that it can be detected when it arrives in other countries/continents and 2) if the blend exerts an effective, generic attraction to multiple species, it is likely that previously unknown and unexpected spe-cies can be captured due to the high degree of conservation of pheromone structures within related taxa. A total of 78,321 longhorned beetles were trapped, representing 376 species from eight subfamilies, with 84 species captured in numbers greater than 50 individuals. Captures comprised 60 tribes, with 10 tribes including more than nine species trapped on different continents. Some invasive species were captured in both the native and invaded continents. This demonstrates the potential of multipheromone lures as ef-fective tools for the detection of 'unexpected' cerambycid invaders, accidentally translocated outside their native ranges. Adding new pheromones with analogous well-conserved motifs is discussed, as well as the limitations of using such blends, especially for some cerambycid taxa which may be more attracted by the trap colour or other characteristics rather than to the chemical blend

Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Missense mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) cause the majority of familial and some sporadic forms of Parkinson’s disease (PD). The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity, promoting the development of LRRK2 kinase inhibitors as therapeutics. Many potent and specific small molecule LRRK2 inhibitors have been reported with promise. However, nearly all inhibitors are ATP competitive – some with unwanted side effects and unclear clinical outcome - alternative types of LRRK2 inhibitors are lacking. Herein we find 5’-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity. Multiple assays show that AdoCbl directly binds LRRK2, leading to the alterations of protein conformation and ATP binding in LRRK2. STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain. Furthermore, we provide evidence that AdoCbl modulates LRRK2 activity through disruption of LRRK2 dimerization. Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue, and importantly prevents neurotoxicity in primary rodent cultures as well as in transgenic C. elegans and D. melanogaster expressing LRRK2 disease variants. Finally, AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models. Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the futur

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Variant annotation was supported by software resources provided via the Caché Campus program of the InterSystems GmbH to Alexander Teumer

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study

Background: Many causes of vision impairment can be prevented or treated. With an ageing global population, the demands for eye health services are increasing. We estimated the prevalence and relative contribution of avoidable causes of blindness and vision impairment globally from 1990 to 2020. We aimed to compare the results with the World Health Assembly Global Action Plan (WHA GAP) target of a 25% global reduction from 2010 to 2019 in avoidable vision impairment, defined as cataract and undercorrected refractive error. Methods: We did a systematic review and meta-analysis of population-based surveys of eye disease from January, 1980, to October, 2018. We fitted hierarchical models to estimate prevalence (with 95% uncertainty intervals [UIs]) of moderate and severe vision impairment (MSVI; presenting visual acuity from <6/18 to 3/60) and blindness (<3/60 or less than 10° visual field around central fixation) by cause, age, region, and year. Because of data sparsity at younger ages, our analysis focused on adults aged 50 years and older. Findings: Global crude prevalence of avoidable vision impairment and blindness in adults aged 50 years and older did not change between 2010 and 2019 (percentage change −0·2% [95% UI −1·5 to 1·0]; 2019 prevalence 9·58 cases per 1000 people [95% IU 8·51 to 10·8], 2010 prevalence 96·0 cases per 1000 people [86·0 to 107·0]). Age-standardised prevalence of avoidable blindness decreased by −15·4% [–16·8 to −14·3], while avoidable MSVI showed no change (0·5% [–0·8 to 1·6]). However, the number of cases increased for both avoidable blindness (10·8% [8·9 to 12·4]) and MSVI (31·5% [30·0 to 33·1]). The leading global causes of blindness in those aged 50 years and older in 2020 were cataract (15·2 million cases [9% IU 12·7–18·0]), followed by glaucoma (3·6 million cases [2·8–4·4]), undercorrected refractive error (2·3 million cases [1·8–2·8]), age-related macular degeneration (1·8 million cases [1·3–2·4]), and diabetic retinopathy (0·86 million cases [0·59–1·23]). Leading causes of MSVI were undercorrected refractive error (86·1 million cases [74·2–101·0]) and cataract (78·8 million cases [67·2–91·4]). Interpretation: Results suggest eye care services contributed to the observed reduction of age-standardised rates of avoidable blindness but not of MSVI, and that the target in an ageing global population was not reached. Funding: Brien Holden Vision Institute, Fondation Théa, The Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation, Sightsavers International, and University of Heidelberg

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes