KCNQ potassium channels modulate Wnt activity in gastro-oesophageal adenocarcinomas

Voltage-sensitive potassium channels play an important role in controlling membrane potential and ionic homeostasis in the gut and have been implicated in gastrointestinal (GI) cancers. Through large-scale analysis of 897 patients with gastro-oesophageal adenocarcinomas (GOAs) coupled with in vitro models, we find KCNQ family genes are mutated in ∼30% of patients, and play therapeutically targetable roles in GOA cancer growth. KCNQ1 and KCNQ3 mediate the WNT pathway and MYC to increase proliferation through resultant effects on cadherin junctions. This also highlights novel roles of KCNQ3 in non-excitable tissues. We also discover that activity of KCNQ3 sensitises cancer cells to existing potassium channel inhibitors and that inhibition of KCNQ activity reduces proliferation of GOA cancer cells. These findings reveal a novel and exploitable role of potassium channels in the advancement of human cancer, and highlight that supplemental treatments for GOAs may exist through KCNQ inhibitors

A novel Atg5-shRNA mouse model enables temporal control of Autophagy in vivo.

Macroautophagy/autophagy is an evolutionarily conserved catabolic pathway whose modulation has been linked to diverse disease states, including age-associated disorders. Conventional and conditional whole-body knockout mouse models of key autophagy genes display perinatal death and lethal neurotoxicity, respectively, limiting their applications for in vivo studies. Here, we have developed an inducible shRNA mouse model targeting Atg5, allowing us to dynamically inhibit autophagy in vivo, termed ATG5i mice. The lack of brain-associated shRNA expression in this model circumvents the lethal phenotypes associated with complete autophagy knockouts. We show that ATG5i mice recapitulate many of the previously described phenotypes of tissue-specific knockouts. While restoration of autophagy in the liver rescues hepatomegaly and other pathologies associated with autophagy deficiency, this coincides with the development of hepatic fibrosis. These results highlight the need to consider the potential side effects of systemic anti-autophagy therapies

Specialist physiotherapy for functional motor disorder in England and Scotland (Physio4FMD): a pragmatic, multicentre, phase 3 randomised controlled trial

Summary: Background: Functional motor disorder—the motor variant of functional neurological disorder—is a disabling condition that is commonly associated with poor health outcomes. Pathophysiological models have inspired new treatment approaches such as specialist physiotherapy, although evidence from large randomised controlled trials is absent. We aimed to assess the clinical effectiveness of a specialist physiotherapy intervention for functional motor disorder compared with treatment as usual. Methods: In this pragmatic, multicentre, phase 3 randomised controlled trial at 11 hospitals in England and Scotland, adults with a clinically definite diagnosis of functional motor disorder, diagnosed by a neurologist, were included. Participants were randomly assigned (1:1, stratified by site) using a remote web-based application to either specialist physiotherapy (a protocolised intervention of nine sessions plus follow-up) or treatment as usual (referral to local community neurological physiotherapy). Individuals working on data collection and analysis were masked to treatment allocation. The primary outcome was the physical functioning domain of the 36-item short form health questionnaire (SF36) at 12 months after randomisation. The primary analysis followed a modified intention-to-treat principle, using a complete case approach; participants who were unable to receive their randomised treatment due to the suspension of health-care services during the COVID-19 pandemic were excluded from the primary analysis. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN56136713, and is completed. Findings: Recruitment occurred between Oct 19, 2018, and March 11, 2020, pausing during the COVID-19 lockdown, and resuming from Aug 3, 2021, to Jan 31, 2022. Of 355 participants who were enrolled, 179 were randomly assigned to specialist physiotherapy and 176 to treatment as usual. 89 participants were excluded from the primary analysis due to COVID-19 interruption to treatment (27 were assigned to specialist physiotherapy and 62 to treatment as usual). After accounting for withdrawals (n=11) and loss to follow-up (n=14), the primary analysis included data from 241 participants (138 [91%] assigned specialist physiotherapy and 103 [90%] assigned treatment as usual). Physical functioning, as assessed by SF36, did not differ significantly between groups (adjusted mean difference 3·5, 95% CI –2·3 to 9·3; p=0·23). There were no serious adverse events related to the trial interventions. 35 serious adverse events were recorded in the specialist physiotherapy group by 24 participants (17·0%), and 24 serious adverse events were recorded in the treatment as usual group by 18 participants (17·0%); one death occurred in the specialist physiotherapy group (cause of death was recorded as suicide). All were considered unrelated to specialist physiotherapy. Interpretation: Although more participants who were assigned specialist physiotherapy self-rated their motor symptoms as improved and had better scores on subjective measures of mental health, the intervention did not result in better self-reported physical functioning at 12 months. Both the specialist and community neurological physiotherapy appeared to be a safe and a valued treatment for selected patients with functional motor disorder. Future research should continue to refine interventions for people with functional motor disorder and develop evidence-based methods to guide treatment triage decisions. Funding: National Institute for Health and Care Research and Health Technology Assessment Programme

Bean Golden Mosaic: Research Advances

El frijol (Phaseolus vulgaris L.) es una de las fuentes de proteina (15-35%) y calorías (ca. 340 caI./100 gr) más importantes en la América Latina. En esta región, centro de origen de esta especie, se producen más de cuatro millones de toneladas de frijol al año, lo cual equivale al 88% de la semilla de frijol producida en las regiones tropicales del mundo. Brasil, el mayor productor de frijol del mundo, posee un consumo per capita de cerca de 20 kg/año. En America Central, el frijol es igualmente importante, siendo consumido en la mayoría de los países centroamericanos hasta tres veces por día. Proporcionalmente, en la America Central se cultiva el doble del área que en Brasil, relativo a sus extensiones territoriales. El frijol es también producido en islas del Caribe, tales como Cuba (ca. 26.000 TM), Haití (56.000 TM) y República Dominicana (55.000 TM) según datos de 1990 (CIAT). México, el segundo productor de frijol en la America Latina, consume aproximadamente 1.2 millones de toneladas métricas de frijol al año. A pesar de que México cultiva cerca de 1.800.000 hectáreas de frijol, la demanda interna no es satisfecha en algunos años dado la baja productividad del cultivo. Esta baja productividad relativa del frijol, no solo en México sino también en el resto de la América Latina (700 kg/ha vs. 1.600 kg/ha en los Estados Unidos), es una consecuencia de los múltiples problemas bióticos y abióticos que inciden en el cultivo, en el trópico Americano. Es precisamente en las regiones productoras de frijol situadas en climas cálidos, de altitud baja a intermedia (0-1200 m.s.n.m), donde el mosaico dorado del frijol alcanza su mayor incidencia.The common bean (Phaseolus vulgaris L.) is an important source of protein and calories in Latin America. In this region, the center of origin of this legume species, over 4 million tons of dry beans are produced per year. Nevertheless, many Latin American countries, including two of the largest producers of beans in the world, Brazil and Mexico, have to import beans to meet internal demand. This shortage of beans is related to the low productivity of this crop in Latin America (700 kg /ha vs. 1,600 kg/ ha average in the USA). The low productivity in the main bean production regions of tropical America is associated to the incidence of several biotic and abiotic constraints. Among the biotic constraints, bean golden mosaic virus is undoubtedly the main bean production problem in the lowland tropics, particularly, during the dry seasons of the year.Programa Cooperativo Regional de Frijol para Centroamérica, México y el Caribe (PROFRIJOL)Cooperación Suiza para el Desarrollo (COSUDE)Centro Internacional de Agricultura Tropical (CIAT)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Agroalimentarias::Estación Experimental Agrícola Fabio Baudrit Moreno (EEAFBM

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

The Use of Deception to Avoid Conflict in Relationships

The current study examined the role of deception in conflict avoidance. In particular this study investigated the range of deception devices (e.g. lying, half-truth, distorting the truth, white lie, failed deception, and omission of the truth) utilized in relationships such as acquaintanceships, dating, and marriages. In addition, this study examined how destructive and dishonest deception can be in a relationship. Findings from this study suggested that some forms of deception are more common than others and that men are more likely to use some form of deception than women

Three Studies Examining the Effects of Prenatal or Adolescent Exposure to Alcohol and/or Nicotine in Rats: The Effects of “3rd trimester” Alcohol and Nicotine Exposure on Activity Levels in Rats

Kentucky ranks among the top states in pregnant smokers. There is also a strong relationship among pregnant drinkers and heavy smoking. Surprisingly, we currently know very little about the possible interactive effects of nicotine and alcohol on the developing offspring. One of the most frequently reported findings following prenatal alcohol or nicotine exposure is changes in activity levels. Using a rodent model, this study examined the effects of alcohol and nicotine exposure on offspring activity (see Project 1 above for description of treatment groups). Activity was recorded for 20 min daily in juvenile rats (19 –21 days of age). Animals were the most active during the first 10 minutes on each test day although there were alterations in this normal activity pattern depending on treatment group and gender. Female offspring exposed to nicotine and ethanol (in combination) displayed a reduction in activity that would not have been predicted based on exposure to either drug alone

Three Studies Examining the Effects of Prenatal or Adolescent Exposure to Alcohol and/or Nicotine in Rats:The Effects of “3rd trimester” Alcohol and Nicotine Exposure on Memory in Rats

Fetal alcohol syndrome is a condition caused by chronic alcohol exposure during pregnancy that causes deficits in learning and memory function. Although there is a high co-morbidity between alcohol and tobacco use during pregnancy, little research has been done to study the interaction between these two commonly used substances. Using a rodent model, rats were given these drugs neonatally during the “brain growth spurt” which occurs primarily during the 3rd trimester of human pregnancy. Rats were treated on postnatal days 1-7 with either alcohol, nicotine, or a combination of alcohol and nicotine (and appropriate controls). Memory was examined using a standard spatial learning task (the Radial Eight Arm Maze) during adolescence. Males with previous nicotine exposure showed improved performance during the 2nd week of testing. Nicotine (not smoking) has been shown to have cognitive enhancing properties (via stimulation of cholinergic neurons) and these data suggest that neonatal nicotine exposure (at least in males) showed this effect. Of significant importance, combining nicotine with ethanol eliminated any cognitive enhancement