Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomics, environment and balancing selection in behaviourally bimodal populations: The caribou case

Selection forces that favour different phenotypes in different environments can change frequencies of genes between populations along environmental clines. Clines are also compatible with balancing forces, such as negative frequency‐dependent selection (NFDS), which maintains phenotypic polymorphisms within populations. For example, NFDS is hypothesized to maintain partial migration, a dimorphic behavioural trait prominent in species where only a fraction of the population seasonally migrates. Overall, NFDS is believed to be a common phenomenon in nature, yet a scarcity of studies were published linking naturally occurring allelic variation with bimodal or multimodal phenotypes and balancing selection. We applied a Pool‐seq approach and detected selection on alleles associated with environmental variables along a North–South gradient in western North American caribou, a species displaying partially migratory behaviour. On 51 loci, we found a signature of balancing selection, which could be related to NFDS and ultimately the maintenance of the phenotypic polymorphisms known within these populations. Yet, remarkably, we detected directional selection on a locus when our sample was divided into two behaviourally distinctive groups regardless of geographic provenance (a subset of GPS‐collared migratory or sedentary individuals), indicating that, within populations, phenotypically homogeneous groups were genetically distinctive. Loci under selection were linked to functional genes involved in oxidative stress response, body development and taste perception. Overall, results indicated genetic differentiation along an environmental gradient of caribou populations, which we found characterized by genes potentially undergoing balancing selection. We suggest that the underlining balancing force, NFDS, plays a strong role within populations harbouring multiple haplotypes and phenotypes, as it is the norm in animals, plants and humans too.
The midgut V‐ATPase subunit A gene is associated with toxicity to crystal 2Aa and crystal 1Ca‐expressing transgenic rice in Chilo suppressalis

Insecticidal crystal (Cry) proteins produced by the bacterium Bacillus thuringiensis (Bt) are toxic to a diverse range of insects. Transgenic rice expressing Cry1A, Cry2A and Cry1C toxins have been developed that are lethal to Chilo suppressalis, a devastating insect pest of rice in China. Identifying the mechanisms underlying the interactions of Cry toxins with susceptible hosts will improve both our understanding of Cry protein toxicology and long‐term efficacy of Bt crops. In this study, we tested the hypothesis that V‐ATPase subunit A contributes to the action of Cry1Ab/1Ac, Cry2Aa and Cry1Ca toxins in C. suppressalis. The full‐length V‐ATPase subunit A transcript was initially cloned from the C. suppressalis larval midgut and then used to generate double‐stranded RNA (dsRNA)‐producing bacteria. Toxicity assays using transgenic rice lines TT51 (Cry1Ab and Cry1Ac fusion genes), T2A‐1 (Cry2Aa), and T1C‐19 (Cry1Ca) in conjunction with V‐ATPase subunit A dsRNA‐treated C. suppressalis larvae revealed significantly reduced larval susceptibility to T2A‐1 and T1C‐19 transgenic rice, but not to TT51 rice. These results suggest that the V‐ATPase subunit A plays a crucial role in mediating Cry2Aa and Cry1Ca toxicity in C. suppressalis. These findings will have significant implications on the development of future resistance management tools.
Ustekinumab exposure-outcome analysis in Crohn's disease only in part explains limited endoscopic remission rates.

Background and aims Ustekinumab, an anti-IL12/23p40 monoclonal antibody, has been approved for Crohn's disease (CD). Real-life data in CD patients receiving ustekinumab intravenously (IV) during induction followed by subcutaneous (SC) maintenance are lacking. We assessed efficacy of ustekinumab and studied exposure-response correlations. Methods We performed a prospective study in 86 CD patients predominantly refractory or intolerant to anti-tumour necrosis factor agents and/or vedolizumab. All received ustekinumab 6mg/kg IV induction, with 90mg SC q8w thereafter. Endoscopic response (50% decrease in Simple Endoscopic Score for CD (SES-CD) at week 24), endoscopic remission (SES-CD≤2), and clinical remission (daily stool frequency ≤2.8 and abdominal pain score ≤1) were assessed at week 4,8,16 and 24. Further serial analyses included patient reported outcomes (PRO2), faecal calprotectin (fCal) and ustekinumab serum levels. Results SES-CD decreased from 11.5 (8.0-18.0) at baseline to 9.0 (6.0-16.0) at w24 (p=0.0009), but proportions of patients achieving endoscopic response (20.5%) or endoscopic remission (7.1%) were low. Clinical remission rates were 39.5% at w24. After IV induction, fCal dropped from baseline (1242.9g/g) to w4 (529.0g/g) and w8 (372.2g/g), but increased again by w16 (537.4g/g) and w24 (749.0g/g). A clear exposure-response relationship was observed, both during induction as during maintenance therapy, with different thresholds depending on the targeted outcome. Conclusion In this cohort of refractory CD patients, ustekinumab showed good clinical remission rates, but limited endoscopic remission after 24 weeks. Our data suggest that higher doses may be required to achieve better endoscopic outcomes.
Hypoxia-Associated Factor (HAF) Mediates Neurofibromin Ubiquitination and Degradation Leading to Ras–ERK Pathway Activation in Hypoxia

Low oxygen or hypoxia is a feature of all solid tumors and has been associated with aggressive disease. Here, we describe a novel mechanism for the hypoxia-dependent degradation of the Ras-GTPase–activating protein neurofibromin, by hypoxia-associated factor (HAF). We have previously characterized HAF as an oxygen-independent ubiquitin ligase for HIF-1α. Here, we show that HAF promotes neurofibromin ubiquitination and degradation independently of oxygen and pVHL, resulting in Ras–ERK pathway activation. Hypoxia enhanced HAF:neurofibromin binding independently of HAF-SUMOylation, whereas HAF knockdown increased neurofibromin levels primarily in hypoxia, supporting the role of HAF as a hypoxia-specific neurofibromin regulator. HAF overexpression increased p-ERK levels and promoted resistance of clear cell kidney cancer (ccRCC) cells to sorafenib and sunitinib in both normoxia and hypoxia. However, a greater-fold increase in sorafenib/sunitinib resistance was observed during hypoxia, particularly in pVHL-deficient cells. Intriguingly, HAF-mediated resistance was HIF-2α–dependent in normoxia, but HIF-2α–independent in hypoxia indicating two potential mechanisms of HAF-mediated resistance: a HIF-2α–dependent pathway dominant in normoxia, and the direct activation of the Ras–ERK pathway through neurofibromin degradation dominant in hypoxia. Patients with ccRCC with high HAF transcript or protein levels showed significantly decreased overall survival compared with those with low HAF. Thus, we establish a novel, nonmutational pathway of neurofibromin inactivation through hypoxia-induced HAF-mediated degradation, leading to Ras–ERK activation and poor prognosis in ccRCC. Implications: We describe a novel mechanism of neurofibromin degradation induced by hypoxia that leads to activation of the prooncogenic Ras–ERK pathway and resistance to therapy.
Relation between cognitive and behavioral aspects of dysexecutive functioning in normal aging

Abstract The aim of this study was to investigate the relation between cognitive and behavioral symptoms of dysexecutive functioning, understood as two aspects of dysexecutive syndrome, in an elderly nonclinical sample. Most previous studies have concentrated on clinical population. However, nonclinical population of elderly adults is, in this context, a group of special interest due to a large body of evidence indicating that executive functions decrease pronouncedly in the course of normal aging. The data were collected from 40 participants aged 67–86 years. None presented symptoms of cognitive disorder or depression or reported psychiatric or neurological problems. The Dysexecutive Questionnaire was used as a measure of behavioral aspect of dysexecutive syndrome. Participants also performed experimental tasks referring to three cognitive aspects of executive functioning (i.e., updating, inhibition, and attentional shifting). Analysis resulted in weak and nonsignificant correlations between cognitive and behavioral aspects of dysexecutive syndrome. Results are discussed in the context of previous research and diagnostic criteria of dysexecutive syndrome.
Management and 1‐Year Outcomes of Patients With Newly Diagnosed Atrial Fibrillation and Chronic Kidney Disease: Results From the Prospective GARFIELD‐AF Registry

Background Using data from the GARFIELD‐AF (Global Anticoagulant Registry in the FIELD–Atrial Fibrillation), we evaluated the impact of chronic kidney disease (CKD) stage on clinical outcomes in patients with newly diagnosed atrial fibrillation (AF). Methods and Results GARFIELD‐AF is a prospective registry of patients from 35 countries, including patients from Asia (China, India, Japan, Singapore, South Korea, and Thailand). Consecutive patients enrolled (2013–2016) were classified with no, mild, or moderate‐to‐severe CKD, based on the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative guidelines. Data on CKD status and outcomes were available for 33 024 of 34 854 patients (including 9491 patients from Asia); 10.9% (n=3613) had moderate‐to‐severe CKD, 16.9% (n=5595) mild CKD, and 72.1% (n=23 816) no CKD. The use of oral anticoagulants was influenced by stroke risk (ie, post hoc assessment of CHA 2 DS 2‐VASc score), but not by CKD stage. The quality of anticoagulant control with vitamin K antagonists did not differ with CKD stage. After adjusting for baseline characteristics and antithrombotic use, both mild and moderate‐to‐severe CKD were independent risk factors for all‐cause mortality. Moderate‐to‐severe CKD was independently associated with a higher risk of stroke/systemic embolism, major bleeding, new‐onset acute coronary syndrome, and new or worsening heart failure. The impact of moderate‐to‐severe CKD on mortality was significantly greater in patients from Asia than the rest of the world (P=0.001). Conclusions In GARFIELD‐AF, moderate‐to‐severe CKD was independently associated with stroke/systemic embolism, major bleeding, and mortality. The effect of moderate‐to‐severe CKD on mortality was even greater in patients from Asia than the rest of the world. Clinical Trial Registration URL: http://www.clinicaltrials. gov. Unique identifier: NCT01090362.
Application of a combined model with seasonal autoregressive integrated moving average and support vector regression in forecasting hand-foot-mouth disease incidence in Wuhan, China

Abstract Hand-foot-mouth disease (HFMD) is a serious public health problem with increasing cases and substantial financial burden in China, especially in Wuhan city. Hence, there is an urgent need to construct a model to predict the incidence of HFMD that could make the prevention and control of this disease more effective. The incidence data of HFMD of Wuhan city from January 2009 to December 2016 were used to fit a combined model with seasonal autoregressive integrated moving average (SARIMA) model and support vector regression (SVR) model. Then, the SARIMA-SVR hybrid model was constructed. Subsequently, the fitted SARIMA-SVR hybrid model was applied to obtain the fitted HFMD incidence from 2009 to 2016. Finally, the fitted SARIMA-SVR hybrid model was used to forecast the incidence of HFMD of the year 2017. To assess the validity of the model, the mean square error (MSE) and mean absolute percentage error (MAPE) between the actual values and predicted values of HFMD incidence (2017) were calculated. From 2009 to 2017, a total of 107636 HFMD cases were reported in Wuhan City, Hubei Province, and the male-to-female ratio is 1.60:1. The age group of 0 to 5 years old accounts for 95.06% of all reported cases and scattered children made up the large proportion (accounted for 56.65%). There were 2 epidemic peaks, from April to July and September to December, respectively, with an emphasis on the former. High-prevalence areas mainly emerge in Dongxihu District, Jiangxia District, and Hongshan District. SARIMA (1,0,1)(0,0,2)[12] is the optimal model given with a minimum Akaike information criterion (AIC) (700.71), then SVR model was constructed by using the optimum parameter (C = 100000, =0.00001, =0.01). The forecasted incidences of single SARIMA model and SARIMA-SVR hybrid model from January to December 2017 match the actual data well. The single SARIMA model shows poor performance with large MSE and MAPE values in comparison to SARIMA-SVR hybrid model. The SARIMA-SVR hybrid model in this study showed that accurate forecasting of the HFMD incidence is possible. It is a potential decision supportive tool for controlling HFMD in Wuhan, China.
Is stool frequency associated with the richness and community composition of gut microbiota?

Background/Aims Recently, a number of studies have reported that the gut microbiota could contribute to human conditions, including obesity, inflammation, cancer development, and behavior. We hypothesized that the composition and distribution of gut microbiota are different according to stool frequency, and attempted to identify the association between gut microbiota and stool frequency. Methods We collected fecal samples from healthy individuals divided into 3 groups according to stool frequency: group 1, a small number of defecation (≤2 times/wk); group 2, normal defecation (1 time/day or 1 time/2 day); and group 3, a large number of defecation (≥2–3 times/day). We evaluated the composition and distribution of the gut microbiota in each group via 16S rRNA-based taxonomic profiling of the fecal samples. Results Fecal samples were collected from a total of 60 individuals (31 men and 29 women, aged 34.1±5.88 years), and each group comprised 20 individuals. The microbial richness of group 1 was significantly higher than that of group 3 and tended to decrease with increasing number of defecation (P<0.05). The biological community composition was fairly different according to the number of defecation, and Bacteroidetes to Firmicutes ratio was higher in group 1 than in the other groups. Moreover, we found specific strains at the family and genus levels in groups 1 and 3. Conclusions Bacteroidetes to Firmicutes ratio and the abundance of Bifidobacterium were different according to the stool frequency, and specific bacteria were identified in the subjects with large and small numbers of defecation, respectively. These findings suggest that stool frequency might be associated with the richness and community composition of the gut microbiota.
Glutamate Within the Marmoset Anterior Hippocampus Interacts with Area 25 to Regulate the Behavioral and Cardiovascular Correlates of High-Trait Anxiety

High-trait anxiety is a risk factor for the development of affective disorders and has been associated with decreased cardiovascular and behavioral responsivity to acute stressors in humans that may increase the risk of developing cardiovascular disease. Although human neuroimaging studies of high-trait anxiety reveals dysregulation in primate cingulate areas 25 and 32 and the anterior hippocampus (aHipp) and rodent studies reveal the importance of aHipp glutamatergic hypofunction, the causal involvement of aHipp glutamate and its interaction with these areas in the primate brain is unknown. Accordingly, we correlated marmoset trait anxiety scores to their postmortem aHipp glutamate levels and showed that low glutamate in the right aHipp is associated with high-trait anxiety in marmosets. Moreover, pharmacologically increasing aHipp glutamate reduced anxiety levels in highly anxious marmosets in two uncertainty-based tests of anxiety: exposure to a human intruder with uncertain intent and unpredictable loud noise. In the human intruder test, increasing aHipp glutamate decreased anxiety by increasing approach to the intruder. In the unpredictable threat test, animals showed blunted behavioral and cardiovascular responsivity after control infusions, which was normalized by increasing aHipp glutamate. However, this aHipp-mediated anxiolytic effect was blocked by simultaneous pharmacological inactivation of area 25, but not area 32, areas which when inactivated independently reduced and had no effect on anxiety, respectively. These findings provide causal evidence in male and female primates that aHipp glutamatergic hypofunction and its regulation by area 25 contribute to the behavioral and cardiovascular symptoms of endogenous high-trait anxiety. SIGNIFICANCE STATEMENT High-trait anxiety predisposes sufferers to the development of anxiety and depression. Although neuroimaging of these disorders and rodent modeling implicate dysregulation in hippocampal glutamate and the subgenual/perigenual cingulate cortices (areas 25/32), the causal involvement of these structures in endogenous high-trait anxiety and their interaction are unknown. Here, we demonstrate that increased trait anxiety in marmoset monkeys correlates with reduced hippocampal glutamate and that increasing hippocampal glutamate release in high-trait-anxious monkeys normalizes the aberrant behavioral and cardiovascular responsivity to potential threats. This normalization was blocked by simultaneous inactivation of area 25, but not area 32. These findings provide casual evidence in primates that hippocampal glutamatergic hypofunction regulates endogenous high-trait anxiety and the hippocampal–area 25 circuit is a potential therapeutic target.
Fluctuating Light Interacts with Time of Day and Leaf Development Stage to Reprogram Gene Expression1

Long-term acclimation to fluctuating light induces global reprogramming of gene expression in Arabidopsis, with strong interactions with time of day and leaf development stage. Natural light environments are highly variable. Flexible adjustment between light energy utilization and photoprotection is therefore of vital importance for plant performance and fitness in the field. Short-term reactions to changing light intensity are triggered inside chloroplasts and leaves within seconds to minutes, whereas long-term adjustments proceed over hours and days, integrating multiple signals. While the mechanisms of long-term acclimation to light intensity have been studied by changing constant growth light intensity during the day, responses to fluctuating growth light intensity have rarely been inspected in detail. We performed transcriptome profiling in Arabidopsis (Arabidopsis thaliana) leaves to investigate long-term gene expression responses to fluctuating light (FL). In particular, we examined whether responses differ between young and mature leaves or between morning and the end of the day. Our results highlight global reprogramming of gene expression under FL, including that of genes related to photoprotection, photosynthesis, and photorespiration and to pigment, prenylquinone, and vitamin metabolism. The FL-induced changes in gene expression varied between young and mature leaves at the same time point and between the same leaves in the morning and at the end of the day, indicating interactions of FL acclimation with leaf development stage and time of day. Only 46 genes were up- or down-regulated in both young and mature leaves at both time points. Combined analyses of gene coexpression and cis-elements pointed to a role of the circadian clock and light in coordinating the acclimatory responses of functionally related genes. Our results also suggest a possible cross talk between FL acclimation and systemic acquired resistance-like gene expression in young leaves.
Does Vascular Burden Contribute to the Progression of Mild Cognitive Impairment to Dementia?

Aims: To investigate the contribution of vascular risk factors (VRFs), vascular diseases (VDs) and white matter lesions (WMLs) to the progression of mild cognitive impairment (MCI) to dementia and Alzheimer’s disease (AD). Methods: Two hundred forty-five consecutive subjects with MCI (age 74.09 ± 6.92 years) were followed for an average of 2.4 years. The Hachinski Ischemic Score and the Framingham Stroke Risk Profile were used to summarize VRFs and VDs. WMLs were graded using the Age-Related White Matter Changes Scale. Results: One hundred twenty-nine (52.6%) out of 245 subjects at risk converted to dementia, including 87 cases of AD. When hypertension occurred in MCI with deep WMLs, a 1.8-fold increased risk of dementia was observed (95% CI = 1.0–3.4). When deep WMLs occurred in MCI with high scores (≥4) on the Hachinski scale, a 3.5-fold (95% CI = 1.6–7.4) and 3.8-fold (95% CI = 1.2–11.5) risk of progression to dementia and AD was observed, respectively. Analogously, the joint effect of WMLs and high scores (≥14) on the Framingham scale nearly doubled the risk of dementia (hazard ratio = 1.9, 95% CI = 1.1–3.3). Conclusions: Accelerated progression of MCI to dementia and AD is to be expected when VRFs and VDs occur together with WMLs.
Complete mitochondrial genome of Rhodeus ocellatus (Cypriniformes: Cyprinidae)

Abstract The complete mitogenome sequence of Rhodeus ocellatus (Kner) was determined using the next-generation sequencing (NGS). The genome was 16 761 bp in length and contained 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes and a control region. The overall nucleotide composition was 30.43% A, 27.50% T, 25.94% C, and 16.13% G, with an A + T bias of 57.93%. The gene composition and the arrangement of the R. ocellatus mitochondrial genome were similar to that of most other vertebrates. The complete mitochondrial genome sequence will help to study the evolutionary relationships and population genetics of Rhodeus fish.
Peritenon Extensor Tendon Inflammation in Psoriatic Arthritis Is an Enthesitis-related Lesion

Objective. To analyze the association between enthesitis, synovitis, and peritenon extensor tendon inflammation (PTI) in psoriatic arthritis (PsA). Methods. PsA patients with swelling of metacarpophalangeal joints were included. Greyscale and power Doppler (PD) were used for synovitis and PTI ultrasound identification. Madrid Sonographic Enthesis Index (MASEI) was used for enthesitis assessment. PD activity was evaluated using PD item of MASEI and PD Outcome Measures in Rheumatology (OMERACT) definition. Results. Synovitis had no association with enthesitis. PTI was associated with PD MASEI and PD OMERACT. Only PD OMERACT showed a positive correlation with PTI. Conclusion. In PsA, PTI is associated to enthesitis, as opposed to synovitis.