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Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations. The mechanism by which FUS mutations cause familial ALS remains unclear. Here, the authors use mouse transgenic models to show that a toxic gain-of-function underlies motor neuron degeneration, and that the toxicity of mutant FUS does not depend on a loss or excess of FUS activity.

The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (IA) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced IA activation by targeted reduction of γ-MNs in SOD1G93A mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.

PurposeThe Zhang–Markusen (Z-M) inverse U-shape theory uses education as a human capital variable to investigate the impact of educational attainment on foreign direct investment (FDI) inflows to a country. The objective of this research is to empirically test this theory in a cross-country framework.Design/methodology/approachFixed effect panel regression has been used to test the Z-M hypothesis for 172 countries for the period 1990–2015. For the purpose of this study, countries were divided into four groups as per the World Bank classification: Low-income economies, lower middle-income countries, upper middle-income economies and high-income economies.FindingsThe findings of this study reinforce the proposition that macroeconomic factors are the major determinants of FDI inflows into various countries. The authors find that the size of the market measured by gross domestic product (GDP), the growth potential of the market measured by real GDP growth rate and the availability of infrastructure are the major factors that enhance the attractiveness of a country as an FDI destination.Originality/valueThough the Z-M theory has been empirically tested in cross-country frameworks, no consensus has been reached. Thus, it is interesting to look again at the validity of the Z-M hypothesis using data covering longer and more recent periods. The study includes both macroeconomic and human capital determinants of FDI, so as to arrive at a comprehensive model explaining the FDI flows into various countries.

An expanded GGGGCC hexanucleotide in C9ORF72 (C9) is the most frequent known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been proposed that expanded transcripts adopt G-quadruplex (G-Q) structures and associate with proteins, but whether this occurs and contributes to disease is unknown. Here we show first that the protein that predominantly associates with GGGGCC repeat RNA in vitro is the splicing factor hnRNP H, and that this interaction is linked to G-Q formation. We then show that G-Q RNA foci are more abundant in C9 ALS patient fibroblasts and astrocytes compared to those without the expansion, and more frequently colocalize with hnRNP H. Importantly, we demonstrate dysregulated splicing of multiple known hnRNP H-target transcripts in C9 patient brains, which correlates with elevated insoluble hnRNP H/G-Q aggregates. Together, our data implicate C9 expansion-mediated sequestration of hnRNP H as a significant contributor to neurodegeneration in C9 ALS/FTD.

Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. In this randomised controlled trial, we recruited postmenopausal women aged 50–74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202 638 women: 50 640 (25·0%) to MMS, 50 639 (25·0%) to USS, and 101 359 (50·0%) to no screening. 202 546 (>99·9%) women were eligible for analysis: 50 624 (>99·9%) women in the MMS group, 50 623 (>99·9%) in the USS group, and 101 299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345 570 MMS and 327 775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0–12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0–14 of 15% (95% CI −3 to 30; p=0·10) with MMS and 11% (−7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (−20 to 31) in years 0–7 and 23% (1–46) in years 7–14, and in the USS group, of 2% (−27 to 26) in years 0–7 and 21% (−2 to 42) in years 7–14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (−2 to 40) and a reduction of 8% (−27 to 43) in years 0–7 and 28% (−3 to 49) in years 7–14 in favour of MMS. Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7–14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

The present work describes the development of TiO 2 /SeO 2 nanostructure as a potential candidate for visible light photocatalysis as well as selective fluorophore for the sensing of picric acid. The obtained nanostructure consists of uniform globular nanoparticles having approximate size of 170 nm and possess an optical band gap of 2.33 eV with absorption maxima at 473 nm. The photocatalyst was able to achieve 90.34% degradation efficiency for 2, 4-dichlorophenol (2,4-DCP) with rate constant of 0.0046 min −1 in the visible region. Further the nanostructure was able to serve as a selective fluorophore for sensing of Picric acid portraying more than 95% of fluorescence quenching when the concentration of PA is 10 –4  M. Theoretical calculations indicate the interaction of organic pollutants with the nanostructure and reveal that both picric acid (− 66.21 kcal/mol) and 2,4-DCP (− 12.31 kcal/mol) possess more negative binding energy values demonstrating a strong interaction of both with the nanostructure, making it suitable for the degradation as well as sensing of organic pollutants. Thus this study explains the potential of prepared catalyst for waste water treatment.

According to International Energy Agency (IEA), India is expected to surpass China by 2024 to become the second largest consumer of oil in the world followed by the United States. High-Speed Diesel (HSD) has the biggest share in the total petroleum products consumed in India accounting for around 38% of the total consumption. Considering the volatile global oil market and an oil import dependency ratio of more than 80% during the last four years, the probability of supply disruptions is high in the Indian context. As any uncertainty about the supply of diesel can affect the smooth functioning of the economy and may create inflationary pressures. Accurate forecasting of HSD demand will be essential for appropriate supply management arrangements. Artificial Neural Networks (ANN) with Multi-Layer Perceptron (MLP) and extreme learning machines is used for forecasting diesel demand in this study. Demand forecasting has been carried out using monthly HSD demand data drawn from the “Indiastat” database for the period 1991-2022. Comparison of ANN with traditional forecasting methods of Autoregressive Integrated Moving Average(ARIMA)and Exponential Smoothing has also been undertaken in this study. This study identifies the deep learning technique of ANN with MLP as the best diesel demand forecasting technique.

In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50–74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04–13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4–13·0; p=0·042) at 18 years (21% [95% CI 15·6–26·2] vs 14% [95% CI 10·5–17·4]). To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal.

Hyperexcitability has been suggested to contribute to motoneuron degeneration in amyotrophic lateral sclerosis (ALS). If this is so, and given that the physiological type of a motor unit determines the relative susceptibility of its motoneuron in ALS, then one would expect the most vulnerable motoneurons to display the strongest hyperexcitability prior to their degeneration, whereas the less vulnerable should display a moderate hyperexcitability, if any. We tested this hypothesis in vivo in two unrelated ALS mouse models by correlating the electrical properties of motoneurons with their physiological types, identified based on their motor unit contractile properties. We found that, far from being hyperexcitable, the most vulnerable motoneurons become unable to fire repetitively despite the fact that their neuromuscular junctions were still functional. Disease markers confirm that this loss of function is an early sign of degeneration. Our results indicate that intrinsic hyperexcitability is unlikely to be the cause of motoneuron degeneration. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a fatal disorder of the nervous system. Early symptoms include muscle weakness, unsteadiness and slurred speech. These symptoms arise because the neurons that control muscles – the motoneurons – lose their ability to make the muscles contract. Eventually, the muscles become paralyzed, with more and more muscles affected over time. Most patients die within a few years of diagnosis when the disease destroys the muscles that control breathing. Muscles are made up of muscle fibers. Each motoneuron controls a bundle of muscle fibers, and the motoneuron and its muscle fibers together make up a motor unit. A single muscle contains hundreds of motor units. These consist of several different types, which differ in how many muscle fibers they contain, how fast those muscle fibers can contract, and how fatigable the muscle fibers are. In ALS, motoneurons become detached from their muscle fibers, causing motor units to break down. But what triggers this process? One long-standing idea is that motoneurons begin to respond excessively to commands from the brain and spinal cord. In other words, they become hyperexcitable, which ultimately leads to their death. But some more recent studies of ALS suggest the opposite, namely that motoneurons become less active, or hypoexcitable. To distinguish between these possibilities, Martinez-Silva et al. took advantage of the fact that different types of motor unit break down at different rates in ALS. Large motor units containing fast-contracting muscle fibers break down before smaller motor units. By measuring the activity of motor units in two mouse models of ALS, Martinez-Silva et al. showed that large motoneurons are hypoexcitable. In other words, the motoneurons that are most vulnerable to ALS respond too little to commands from the nervous system, rather than too much. Studies of specific proteins inside the cells confirmed that hypoexcitable motoneurons are further along in the disease process than other motoneurons. Hypoexcitability is thus a key player in the ALS disease process. Developing drugs to target this hypoexcitability may be a promising strategy for the future of this condition.

Background Attractive toxic sugar bait (ATSB) is a promising “attract and kill”-based approach for mosquito control. It is a combination of flower nectar/fruit juice to attract the mosquitoes, sugar solution to stimulate feeding, and a toxin to kill them. Selecting an effective attractant and optimizing concentration of toxicant is significant in the formulation of ATSB. Methods Current study formulated an ATSB using fruit juice, sugar and deltamethrin, a synthetic pyrethroid. It was evaluated against two laboratory strains of Anopheles stephensi . Initial studies evaluated comparative attractiveness of nine different fruit juices to An . stephensi adults. Nine ASBs were prepared by adding fermented juices of plum, guava, sweet lemon, orange, mango, pineapple, muskmelon, papaya, and watermelon with 10% sucrose solution (w/v) in 1:1 ratio. Cage bioassays were conducted to assess relative attraction potential of ASBs based on the number of mosquito landings on each and the most effective ASB was identified. Ten ATSBs were prepared by adding the identified ASB with different deltamethrin concentrations (0.015625–8.0 mg/10 mL) in 1:9 ratio. Each ATSB was assessed for the toxic potential against both the strains of An . stephensi . The data was statistically analysed using PASW (SPSS) software 19.0 program. Results The cage bioassays with nine ASBs revealed higher efficacy ( p  < 0.05) of Guava juice-ASB > Plum juice-ASB > Mango juice-ASB in comparison to rest of the six ASB’s. The bioassay with these three ASB’s ascertained the highest attractancy potential of guava juice-ASB against both the strains of An . stephensi . The ATSB formulations resulted in 5.1–97.9% mortality in Sonepat (NIMR strain) with calculated LC 30 , LC 50, and LC 90 values of 0.17 mg deltamethrin/10 mL, 0.61 mg deltamethrin/10 mL, and 13.84 mg deltamethrin/10 mL ATSB, respectively. Whereas, 6.12–86.12% mortality was recorded in the GVD-Delhi (AND strain) with calculated LC 30 , LC 50 , and LC 90 values of 0.25 mg deltamethrin/10 mL, 0.73 mg deltamethrin/10 mL and 10.22 mg deltamethrin/10 mL ATSB, respectively. Conclusion The ATSB formulated with guava juice-ASB and deltamethrin (0.0015625–0.8%) in 9:1 ratio showed promising results against two laboratory strains of An . stephensi . Field assessment of these formulations is being conducted to estimate their feasibility for use in mosquito control.