Miracle-dz/UniFAR-FTUs huggingface dataset:
Excess TPX2 Interferes with Microtubule Disassembly and Nuclei Reformation at Mitotic Exit

The microtubule-associated protein TPX2 is a key mitotic regulator that contributes through distinct pathways to spindle assembly. A well-characterised function of TPX2 is the activation, stabilisation and spindle localisation of the Aurora-A kinase. High levels of TPX2 are reported in tumours and the effects of its overexpression have been investigated in cancer cell lines, while little is known in non-transformed cells. Here we studied TPX2 overexpression in hTERT RPE-1 cells, using either the full length TPX2 or a truncated form unable to bind Aurora-A, to identify effects that are dependent—or independent—on its interaction with the kinase. We observe significant defects in mitotic spindle assembly and progression through mitosis that are more severe when overexpressed TPX2 is able to interact with Aurora-A. Furthermore, we describe a peculiar, and Aurora-A-interaction-independent, phenotype in telophase cells, with aberrantly stable microtubules interfering with nuclear reconstitution and the assembly of a continuous lamin B1 network, resulting in daughter cells displaying doughnut-shaped nuclei. Our results using non-transformed cells thus reveal a previously uncharacterised consequence of abnormally high TPX2 levels on the correct microtubule cytoskeleton remodelling and G1 nuclei reformation, at the mitosis-to-interphase transition.
Sugar Feeding Patterns for Aedes aegypti and Culex quinquefasciatus (Diptera: Culicidae) Mosquitoes in South Texas

Abstract Effective mosquito surveillance and management depend on a thorough understanding of the biology and feeding patterns unique to species and sex. Given that a propensity to sugar feed is necessary for some mosquito surveillance and newer control strategies, we sought to document the amount of total sugar in wild Aedes aegypti (L.) and Culex quinquefasciatus (Say) captured from five different locations in the Lower Rio Grande Valley (LRGV) of South Texas over 2 yr. We used Biogents Sentinel 2 (BGS2) traps in year 1 and aspirators, BGS2, and CDC resting traps in years 2 and 3 to collect adult mosquitoes.The hot anthrone test was used to quantify total sugar content in each mosquito. Additionally, the cold and hot anthrone tests were used to distinguish fructose content from total sugars for mosquitoes captured in 2019. Overall, Ae. aegypti females had significantly lower total sugar content than Ae. aegypti males as well as both sexes of Cx. quinquefasciatus. However, the percentage of Ae. aegypti positive for fructose consumption was four to eightfold higher than Ae. aegypti previously reported in other regions. The difference between locations was significant for males of both species, but not for females. Seasonality and trapping method also revealed significant differences in sugar content of captured mosquitoes. Our results reinforce that sugar feeding in female Ae. aegypti is less than Cx. quinquefasciatus, although not absent.This study provides necessary data to evaluate the potential effectiveness of sugar baits in surveillance and control of both Ae. aegypti and Cx. quinquefasciatus mosquitoes.
Serum anti-recoverin antibodies is found in elderly patients with retinitis pigmentosa and cancer.

PURPOSE To screen for anti-recoverin antibodies in elderly patients with retinitis pigmentosa (RP) with or without cancer and cross-sectionally characterize the seropositive patients clinically. METHODS Serum from 75 RP patients who had been tested for mutations in a panel of 83 RP genes and 73 normal controls, all aged 50-80 years, were screened for anti-recoverin antibodies by Western blot using recombinant recoverin, retinal lysate from a marmoset and commercial anti-recoverin antibodies as a control. RESULTS Three RP patients with typical pigmentary degeneration of the 75 (4.0%) were seropositive for anti-recoverin antibody. Pathogenic mutations were identified in two seropositive RP patients. All three patients had visual impairment since childhood and were diagnosed as RP by the age of 30. The severity of the retinopathy varied greatly among these three patients, ranging in visual acuity from light perception OU to 20/30 OU. Retinitis pigmentosa (RP) patients with a history of cancer were more likely to have anti-recoverin antibodies (3/14; 21.4%) than those without (0/61; 0%; p = 0.005, Fischer exact test). All 73 healthy controls with no history of cancer were also seronegative. CONCLUSION Our results show that serum anti-recoverin antibodies can be detected in typical RP patients with identified pathogenic mutations and that a history of cancer may increase the risk of developing anti-recoverin antibodies.
Dapagliflozin Suppresses Hepcidin And Increases Erythropoiesis.

CONTEXT Dapagliflozin and other SGLT2 inhibitors are known to increase hematocrit possibly due to it diuretic effects and hemoconcentration. OBJECTIVE Since type 2 diabetes is a pro-inflammatory state and since hepcidin, a known suppressor of erythropoiesis, is increased in pro-inflammatory states, we investigated the possibility that dapagliflozin suppresses hepcidin concentrations and thus increases erythropoiesis. DESIGN Prospective, randomized and placebo controlled study. SETTING Single-endocrinology center. PATIENTS Fifty two obese type 2 diabetes patients. INTERVENTION Patients were randomized (1:1) to either dapagliflozin 10mg daily or placebo for 12 weeks. Blood samples were collected before and after treatments and serum, plasma and mononuclear cells (MNC) were prepared. MAIN OUTCOME MEASURE Hepcidin and other hematopoietic factor. RESULTS Following dapagliflozin treatment, there was a significant fall in HbA1c and a significant increase in hemoglobin concentration and in hematocrit. Dapagliflozin treatment significantly reduced circulating hepcidin and ferritin concentrations while it caused a significant increase in levels of the hepcidin inhibitor, erythroferrone and a transient increase in erythropoietin. Additionally, dapagliflozin increased plasma transferrin levels and expression of transferrin receptors 1 and 2 in MNC while there was no change in the expression of the iron cellular transporter, ferroportin. Dapagliflozin treatment also caused a decrease in hypoxia induced factor-1α expression in MNC while increased the expression of its inhibitor, prolyl hydroxylase-2. There were no significant changes in any of these indices in the placebo group. CONCLUSIONS We conclude that dapagliflozin increases erythropoiesis and hematocrit through mechanisms that involve suppression of hepcidin and modulation of other iron regulatory proteins.
Duration of Exposure Among Close Contacts of Patients With Infectious Tuberculosis and Risk of Latent Tuberculosis Infection.

BACKGROUND Predictors of latent tuberculosis infection (LTBI) among close contacts of persons with infectious tuberculosis (TB) are incompletely understood, particularly the number of exposure hours. METHODS We prospectively enrolled adult patients with culture-confirmed pulmonary TB and their close contacts at 9 health departments in the United States and Canada. Patients with TB were interviewed and close contacts were interviewed and screened for TB and LTBI during contact investigations. RESULTS LTBI was diagnosed in 1390 (46%) of 3040 contacts, including 624 (31%) of 2027 US/Canadian-born and 766 (76%) of 1013 non-US/Canadian-born contacts. In multivariable analysis, age ≥5 years, male sex, non-US/Canadian birth, smear-positive index patient, and shared bedroom with an index patient (P < .001 for each), as well as exposure to >1 index patient (P < .05), were associated with LTBI diagnosis. LTBI prevalence increased with increasing exposure duration, with an incremental prevalence increase of 8.2% per 250 exposure hours (P < .0001). For contacts with <250 exposure hours, no difference in prevalence was observed per 50 exposure hours (P = .63). CONCLUSIONS Hours of exposure to a patient with infectious TB is an important LTBI predictor, with a possible risk threshold of 250 hours. More exposures, closer exposure proximity, and more extensive index patient disease were additional LTBI predictors.
Discovery of the gut microbial signature driving the efficacy of prebiotic intervention in obese patients

Objective The gut microbiota has been proposed as an interesting therapeutic target for metabolic disorders. Inulin as a prebiotic has been shown to lessen obesity and related diseases. The aim of the current study was to investigate whether preintervention gut microbiota characteristics determine the physiological response to inulin. Design The stools from four obese donors differing by microbial diversity and composition were sampled before the dietary intervention and inoculated to antibiotic-pretreated mice (hum-ob mice; humanised obese mice). Hum-ob mice were fed with a high-fat diet and treated with inulin. Metabolic and microbiota changes on inulin treatment in hum-ob mice were compared with those obtained in a cohort of obese individuals supplemented with inulin for 3 months. Results We show that hum-ob mice colonised with the faecal microbiota from different obese individuals differentially respond to inulin supplementation on a high-fat diet. Among several bacterial genera, Barnesiella, Bilophila, Butyricimonas, Victivallis, Clostridium XIVa, Akkermansia, Raoultella and Blautia correlated with the observed metabolic outcomes (decrease in adiposity and hepatic steatosis) in hum-ob mice. In addition, in obese individuals, the preintervention levels of Anaerostipes, Akkermansia and Butyricicoccus drive the decrease of body mass index in response to inulin. Conclusion These findings support that characterising the gut microbiota prior to nutritional intervention with prebiotics is important to increase the positive outcome in the context of obesity and metabolic disorders.
Brain and behavioral alterations in subjects with social anxiety dominated by empathic embarrassment

Significance People are increasingly affected by social anxiety that includes emotional hypersensitivity and inaccurate interpretation of social encounters, and varies markedly in its subjective manifestations. We searched for insights into the underlying neurocognitive mechanisms of Taijin-kyofusho (TKS), a specific subtype of social-anxiety disorder common in East Asia and dominated by empathic or other-oriented embarrassment. We found TKS to be characterized by enhanced affective and reduced cognitive empathy. Moreover, analysis of functional MRI data—collected while subjects viewed videos of badly singing people—revealed disruption of the cognitive–empathy network, possibly obstructing flexible inference of others’ perspective or augmenting maladaptive feelings of embarrassment. Our findings shed light on how altered affective and cognitive processing can contribute to the development of imaginary fears. Social-anxiety disorder involves a fear of embarrassing oneself in the presence of others. Taijin-kyofusho (TKS), a subtype common in East Asia, additionally includes a fear of embarrassing others. TKS individuals are hypersensitive to others’ feelings and worry that their physical or behavioral defects humiliate others. To explore the underlying neurocognitive mechanisms, we compared TKS ratings with questionnaire-based empathic disposition, cognitive flexibility (set-shifting), and empathy-associated brain activity in 23 Japanese adults. During 3-tesla functional MRI, subjects watched video clips of badly singing people who expressed either authentic embarrassment (EMBAR) or hubristic pride (PRIDE). We expected the EMBAR singers to embarrass the viewers via emotion-sharing involving affective empathy (affEMP), and the PRIDE singers to embarrass via perspective-taking involving cognitive empathy (cogEMP). During affEMP (EMBAR > PRIDE), TKS scores correlated positively with dispositional affEMP (personal-distress dimension) and with amygdala activity. During cogEMP (EMBAR < PRIDE), TKS scores correlated negatively with cognitive flexibility and with activity of the posterior superior temporal sulcus/temporoparietal junction (pSTS/TPJ). Intersubject correlation analysis implied stronger involvement of the anterior insula, inferior frontal gyrus, and premotor cortex during affEMP than cogEMP and stronger involvement of the medial prefrontal cortex, posterior cingulate cortex, and pSTS/TPJ during cogEMP than affEMP. During cogEMP, the whole-brain functional connectivity was weaker the higher the TKS scores. The observed imbalance between affEMP and cogEMP, and the disruption of functional brain connectivity, likely deteriorate cognitive processing during embarrassing situations in persons who suffer from other-oriented social anxiety dominated by empathic embarrassment.
PEEP guided by electrical impedance tomography during one-lung ventilation in elderly patients undergoing thoracoscopic surgery.

Background To examine the influence of positive end-expiratory pressure (PEEP) settings on lung mechanics and oxygenation in elderly patients undergoing thoracoscopic surgery. Methods One hundred patients aged >65 years were randomly allocated into either the PEEP5 or the electrical impedance tomography (EIT) group (PEEPEIT). Each group underwent volume-controlled ventilation (tidal volume 6 mL/kg predicted body weight) with the PEEP either fixed at 5 cmH2O or set at an individualized EIT setting. The primary endpoint was the ratio of the arterial oxygen partial pressure to the fractional inspired oxygen (PaO2/FiO2). The secondary endpoints included the driving pressure, and dynamic respiratory system compliance (Cdyn). Other outcomes, such as the mean airway pressure (Pmean), mean arterial pressure (MAP), lung complications and the length of hospital stay were explored. Results The optimal PEEP set by EIT was significantly higher (range from 9-13 cmH2O) than the fixed PEEP. PaO2/FiO2 was 47 mmHg higher (95% CI: 7-86 mmHg; P=0.021), Cdyn was 4.3 mL/cmH2O higher (95% CI: 2.1-6.7 cmH2O; P<0.001), and the driving pressure was 3.7 cmH2O lower (95% CI: 2.2-5.1 mmH2O; P<0.001) at 0.5 h during one-lung ventilation (OLV) in the PEEPEIT group than in the PEEP5 group. At 1 h during OLV, PaO2/FiO2 was 93 mmHg higher (95% CI: 58-128 mmHg; P<0.001), Cdyn was 4.4 mL/cmH2O higher (95% CI: 1.9-6.9 mL/cmH2O; P=0.001), and the driving pressure was 4.9 cmH2O lower (95% CI: 3.8-6.1 cmH2O; P<0.001) in the PEEPEIT group than in the PEEP5 group. PaO2/FiO2 was 107 mmHg higher (95% CI: 56-158 mmHg; P<0.001) in the PEEPEIT group than in the PEEP5 group during double-lung ventilation at the end of surgery. Conclusions PEEP values determined with EIT effectively improved oxygenation and lung mechanics during one lung ventilation in elderly patients undergoing thoracoscopic surgery.
Acute effects of JUUL and IQOS in cigarette smokers

Background JUUL is an electronic cigarette that aerosolises a nicotine-containing liquid, while IQOS heats tobacco to produce an aerosol. Both are marketed to smokers, but their effects have seldom been examined in this population. Methods Eighteen cigarette smokers (13 men) with no JUUL or IQOS experience completed a within-subject, laboratory study assessing nicotine delivery and subjective effects after controlled (10 puffs, ~30 s interpuff interval) and ad libitum (90 min) use of JUUL, IQOS or own-brand (OB) cigarettes. Results JUUL increased mean plasma nicotine concentration significantly from 2.2 (SD=0.7) ng/mL to 9.8 (4.9) ng/mL after 10 puffs and to 11.5 (9.3) ng/mL after ad libitum use. IQOS increased mean plasma nicotine significantly from 2.1 (0.2) ng/mL to 12.7 (6.2) ng/mL after 10 puffs and to 11.3 (8.0) ng/mL after ad libitum use. OB increased mean plasma nicotine significantly from 2.1 (0.2) ng/mL to 20.4 (11.4) ng/mL after 10 puffs and to 21.0 (10.2) ng/mL after ad libitum use. Mean OB plasma nicotine concentration was significantly higher than JUUL and IQOS. OB increased expired carbon monoxide concentration, but IQOS and JUUL did not. ‘Craving a cigarette/nicotine’ and ‘Urges to smoke’ were reduced significantly for all products following the directed bout. Conclusions Among smokers, JUUL and IQOS delivered less nicotine than cigarettes. Also, in this sample, IQOS and OB reduced abstinence symptoms more effectively than JUUL. Additional work with experienced JUUL and IQOS users is needed, as their nicotine delivery profiles and subjective experiences may differ.
Foes or Friends? Bacteria Enriched in the Tumor Microenvironment of Colorectal Cancer

Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the third cause of cancer death in the world, while intestinal microbiota is a community of microbes living in human intestine that can potentially impact human health in many ways. Accumulating evidence suggests that intestinal microbiota, especially that from the intestinal bacteria, play a key role in the CRC development; therefore, identification of bacteria involved in CRC development can provide new targets for the CRC diagnosis, prevention, and treatment. Over the past decade, there have been considerable advances in applying 16S rDNA sequencing data to verify associated intestinal bacteria in CRC patients; however, due to variations of individual and environment factors, these results seem to be inconsistent. In this review, we scrutinized the previous 16S rDNA sequencing data of intestinal bacteria from CRC patients, and identified twelve genera that are specifically enriched in the tumor microenvironment. We have focused on their relationship with the CRC development, and shown that some bacteria could promote CRC development, acting as foes, while others could inhibit CRC development, serving as friends, for human health. Finally, we highlighted their potential applications for the CRC diagnosis, prevention, and treatment.
The primary mechanism of cytotoxicity of the chemotherapeutic agent CX-5461 is topoisomerase II poisoning

Significance Small molecules can directly and indirectly interfere with multiple cellular processes simultaneously. However, there is a difference between what a molecule can do and what mechanisms cause cellular cytotoxicity. Genetic logic using CRISPR works well when discriminating between essential and nonessential target hypotheses. However, discriminating between competing hypotheses across multiple essential pathways is more challenging. Here we combine three complementary data-driven approaches to create multimodal measurements of the mechanism of cytotoxicity. Our multimodal data mining approach coupled to genetic, cell biologic, and biochemical experiments allowed us to detangle essential processes and reannotate CX-5461 as a topoisomerase II poison. Correct annotation is critical for charting a clinical development path and effectively using CX-5461 as a chemical genetic probe. Small molecules can affect many cellular processes. The disambiguation of these effects to identify the causative mechanisms of cell death is extremely challenging. This challenge impacts both clinical development and the interpretation of chemical genetic experiments. CX-5461 was developed as a selective RNA polymerase I inhibitor, but recent evidence suggests that it may cause DNA damage and induce G-quadraplex formation. Here we use three complimentary data mining modalities alongside biochemical and cell biological assays to show that CX-5461 exerts its primary cytotoxic activity through topoisomerase II poisoning. We then show that acquired resistance to CX-5461 in previously sensitive lymphoma cells confers collateral resistance to the topoisomerase II poison doxorubicin. Doxorubicin is already a frontline chemotherapy in a variety of hematopoietic malignancies, and CX-5461 is being tested in relapse/refractory hematopoietic tumors. Our data suggest that the mechanism of cell death induced by CX-5461 is critical for rational clinical development in these patients. Moreover, CX-5461 usage as a specific chemical genetic probe of RNA polymerase I function is challenging to interpret. Our multimodal data-driven approach is a useful way to detangle the intended and unintended mechanisms of drug action across diverse essential cellular processes.
A top-down approach of sources and non-photosynthetic sinks of carbonyl sulfide from atmospheric measurements over multiple years in the Paris region (France)

Carbonyl sulfide (COS) has been proposed as a proxy for carbon dioxide (CO2) taken up by plants at the leaf and ecosystem scales. However, several additional production and removal processes have been identified which could complicate its use at larger scales, among which are soil uptake, dark uptake by plants, and soil and anthropogenic emissions. This study evaluates the significance of these processes at the regional scale through a top-down approach based on atmospheric COS measurements at Gif-sur-Yvette (GIF), a suburban site near Paris (France). Over a period of four and a half years, hourly measurements at 7 m above ground level were performed by gas chromatography and combined with 222Radon measurements to calculate nocturnal COS fluxes using the Radon-Tracer Method. In addition, the vertical distribution of COS was investigated at a second site, 2 km away from GIF, where a fast gas analyzer deployed on a 100 m tower for several months during winter 2015–2016 recorded mixing ratios at 3 heights (15, 60 and 100 m). COS appears to be homogeneously distributed both horizontally and vertically in the sampling area. The main finding is that the area is a persistent COS sink even during wintertime episodes of strong pollution. Nighttime net uptake rates ranged from -1.5 to -32.8 pmol m-2 s-1, with an average of -7.3 ± 4.5 pmol m-2 s-1 (n = 253). However, episodes of biogenic emissions happened each year in June-July (11.9 ± 6.2 pmol m-2 s-1, n = 24). Preliminary analyses of simulated footprints of source areas influencing the recorded COS data suggest that long-range transport of COS from anthropogenic sources located in Benelux, Eastern France and Germany occasionally impacts the Paris area during wintertime. These production and removal processes may limit the use of COS to assess regional-scale CO2 uptake in Europe by plants through inverse modeling.
Interventional Influence of the Intestinal Microbiome Through Dietary Intervention and Bowel Cleansing Might Improve Motor Symptoms in Parkinson’s Disease

The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson’s disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with a better understanding of the intestinal microbiome, a link to the misfolding and spread of alpha-synuclein via inflammatory processes within the gut is discussed. In a case-control study, we assessed the gut microbiome of 54 PD patients and 32 healthy controls (HC). Additionally, we tested in this proof-of-concept study whether dietary intervention alone or additional physical colon cleaning may lead to changes of the gut microbiome in PD. 16 PD patients underwent a well-controlled balanced, ovo-lacto vegetarian diet intervention including short fatty acids for 14 days. 10 of those patients received additional treatment with daily fecal enema over 8 days. Stool samples were collected before and after 14 days of intervention. In comparison to HC, we could confirm previously reported PD associated microbiome changes. The UDPRS III significantly improved and the levodopa-equivalent daily dose decreased after vegetarian diet and fecal enema in a one-year follow-up. Additionally, we observed a significant association between the gut microbiome diversity and the UPDRS III and the abundance of Ruminococcaceae. Additionally, the abundance of Clostridiaceae was significantly reduced after enema. Dietary intervention and bowel cleansing may provide an additional non-pharmacologic therapeutic option for PD patients.