Miracle-dz/UniFAR-FTUs huggingface dataset:
Derivation of notochordal cells from human embryonic stem cells reveals unique regulatory networks by single cell‐transcriptomics

Intervertebral disc degeneration (IDD) is a public health dilemma as it is associated with low back and neck pain, a frequent reason for patients to visit the physician. During IDD, nucleus pulposus (NP), the central compartment of intervertebral disc (IVD) undergo degeneration. Stem cells have been adopted as a promising biological source to regenerate the IVD and restore its function. Here, we describe a simple, two‐step differentiation strategy using a cocktail of four factors (LDN, AGN, FGF, and CHIR) for efficient derivation of notochordal cells from human embryonic stem cells (hESCs). We employed a CRISPR/Cas9 based genome‐editing approach to knock‐in the mCherry reporter vector upstream of the 3′ untranslated region of the Noto gene in H9‐hESCs and monitored notochordal cell differentiation. Our data show that treatment of H9‐hESCs with the above‐mentioned four factors for 6 days successfully resulted in notochordal cells. These cells were characterized by morphology, immunostaining, and gene and protein expression analyses for established notochordal cell markers including FoxA2, SHH, and Brachyury. Additionally, pan‐genomic high‐throughput single cell RNA‐sequencing revealed an efficient and robust notochordal differentiation. We further identified a key regulatory network consisting of eight candidate genes encoding transcription factors including PAX6, GDF3, FOXD3, TDGF1, and SOX5, which are considered as potential drivers of notochordal differentiation. This is the first single cell transcriptomic analysis of notochordal cells derived from hESCs. The ability to efficiently obtain notochordal cells from pluripotent stem cells provides an additional tool to develop new cell‐based therapies for the treatment of IDD.
Nutrient and heavy metal removal from piggery wastewater and CH4 enrichment in biogas based on microalgae cultivation technology under different initial inoculum concentration

Three microalgae‐based treatment technologies were applied for removing nutrients in piggery wastewater and CO2 in biogas simultaneously. Chlorella vulgaris (C. vulgaris), Scenedesmus obliquus (S. obliquus), and Neochloris oleoabundans (N. oleoabundans) were selected for mono‐cultivation or co‐cultivation with fungi or activated sludge. The effects of initial inoculum concentration (low of 62.06 ± 6.23 mg/L, medium of 121 ± 9.34 mg/L, and high of 180 ± 12.78 mg/L) of microalgae/algal symbiont on the pollutant removal efficiency were evaluated. The results showed that cultivation of S. obliquus with activated sludge had a relatively high CO2 and nutrients removal efficiency at a medium concentration of initial inoculum. The highest removal efficiency of total organic carbon, total nitrogen, and total phosphorus in piggery wastewater was 87.29%, 87.26%, and 90.17% by co‐cultivation of S. obliquus with activated sludge. The highest CO2 removal of 64.28% could be achieved under co‐cultivation of S. obliquus and fungi at medium initial inoculum concentrations. This work will be helpful to promote the study of microalgae‐based biogas upgrading and piggery wastewater purification.
DDEL-07INTRAVENOUS TOCA 511 DELIVERY LEADS TO VIRAL DNA IN RESECTED HGG

Recurrent high grade glioma (HGG) remains resistant to standard therapies with survival ranging from 7.2-8.1 months. A Phase 1 clinical study using an investigational retroviral replicating vector (RRV), Toca 511, in combination with investigational oral Toca FC (extended-release 5-FC), is ongoing to evaluate intravenous (IV) delivery of Toca 511 prior to tumor resection in patients with recurrent HGG. Main objectives of this study (NCT01985256) are to identify the highest tolerated dose of Toca 511 administered intravenously followed by intracranial-parenchymal injection during resection, as well as to analyze resected tumor for presence of virus and transgene. Toca 511 doses have been escalated to 4.6 x 109 TU IV/day for 3 days (1.2 x 109 TU injected into tumor bed), followed by Toca FC at 220 mg/kg/day. The highest planned dose is 9.5 x 109 TU IV/day for 5 days. As of April 8 2015, 10 subjects have been dosed without complications. Treatment is well tolerated with no related grade ≥3 AEs, no DLTs and no subjects having discontinued Toca FC for toxicity. Pharmacokinetic analysis shows consistent dose response with virus in blood 24 hours after initial IV injection enabling multi-day dosing. Tumor samples demonstrated presence of viral DNA signal in a dose dependent manner, with 7/10 tumors having detectable, and 4/10 quantifiable signal. In the top dose group, 3/5 had quantifiable signal in the tumor. Expression of yCD transgene was detectable by IHC. Approximately 4-6 weeks after resection, virus could not be detected above the lower quantification limit in blood. Urine and saliva samples were negative with a single exception (saliva). All subjects remain alive with a maximum follow-up of 14 months (median 4 months). This study confirms the successful targeting of HGG by IV delivery of Toca 511 and tolerability at tested doses. Preliminary efficacy results will be presented.
Echocardiography in Low‐Risk Hypertensive Patients

Background It is debated whether echocardiography should be part of the diagnostic workup in all hypertensive patients. We identified some factors potentially associated with left ventricular hypertrophy (LVH) at echocardiography in untreated hypertensive patients. Methods and Results We studied 2150 patients without LVH at ECG. All patients underwent standard 12‐lead ECG and echocardiography. Mean age was 48.7 years, and mean office blood pressure was 154/97 mm Hg. Prevalence of echocardiographic LVH (LV mass >47.0 g/m2.7 in women and >50.0 g/m2.7 in men) was 37.1%. We developed a nomogram based on 7 items (age, smoking, body mass index, office systolic and diastolic blood pressure, Cornell voltage, and chronic kidney disease) on the basis of a multivariable logistic regression analysis. We internally validated the model by bootstrap recalibration and obtained a calibration curve to assess agreement in the validation data set. Probability of LVH at echocardiography ranged from <10% (score, ≤100 points) to >90% (score, ≥180 points). Proportion of patients with LVH progressively increased with the total score (χ2=444.8; P<0.001). Prevalence of LVH was <2% and 90% at the lower 5th and upper 95th percentile of its distribution, respectively. Conclusions We developed and validated a novel score to assess the probability of LVH at echocardiography in hypertensive patients without LVH at ECG. The score may guide the appropriateness of echocardiographic study in low‐risk hypertensive patients. Echocardiography appears most appropriate for score values >136 in men and >124 in women.
Cell-line specific RNA editing patterns in Trypanosoma brucei suggest a unique mechanism to generate protein variation in a system intolerant to genetic mutations

Abstract Trypanosoma brucei possesses a highly complex RNA editing system that uses guide RNAs to direct the insertion and deletion of uridines in mitochondrial mRNAs. These changes extensively alter the target mRNAs and can more than double them in length. Recently, analyses showed that several of the edited genes possess the capacity to encode two different protein products. The overlapped reading frames can be accessed through alternative RNA editing that shifts the translated reading frame. In this study, we analyzed the editing patterns of three putative dual-coding genes, ribosomal protein S12 (RPS12), the 5′ editing domain of NADH dehydrogenase subunit 7 (ND7 5′), and C-rich region 3 (CR3). We found evidence that alternatively 5′-edited ND7 5′ and CR3 transcripts are present in the transcriptome, providing evidence for the use of dual ORFs in these transcripts. Moreover, we found that CR3 has a complex set of editing pathways that vary substantially between cell lines. These findings suggest that alternative editing can work to introduce genetic variation in a system that selects against nucleotide mutations.
Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Short-Term Mortality After Sepsis

Supplemental Digital Content is available in the text. Antagonists of the renin-angiotensin-aldosterone system (RAAS), including ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers), may prevent organ failure. We, therefore, investigated whether specific RAAS inhibitors are associated with reduced mortality in patients with sepsis.We conducted a population-based retrospective cohort study using multivariable propensity score–based regression to control for differences among patients using different RAAS inhibitors. A multivariable-adjusted Cox proportional-hazards regression model was used to determine the association between RAAS inhibitors and sepsis outcomes. To directly compare ACEI users, ARB users, and nonusers, a 3-way propensity score matching approach was performed. Results were pooled with previous evidence via a random-effects meta-analysis. A total of 52 727 patients were hospitalized with sepsis, of whom 7642 were prescribed an ACEI and 4237 were prescribed an ARB. Using propensity score–matched analyses, prior ACEI use was associated with decreased 30-day mortality (hazard ratio, 0.84 [95% CI, 0.75–0.94]) and 90-day mortality (hazard ratio, 0.83 [95% CI, 0.75–0.92]) compared with nonuse. Prior ARB use was associated with an improved 90-day survival (hazard ratio, 0.88 [95% CI, 0.83–0.94]). These results persisted in sensitivity analyses focusing on patients without cancer and patients with hypertension. By contrast, no beneficial effect was found for antecedent β-blockers exposure (hazard ratio, 0.99 [95% CI, 0.94–1.05]). The pooled estimates obtained from the meta-analysis was 0.71 (95% CI, 0.58–0.87) for prior use of ACEI/ARB.The short-term mortality after sepsis was substantially lower among those who were already established on RAAS inhibitor treatment when sepsis occurred.
Effects of a Group-Mediated Cognitive Behavioral Lifestyle Intervention on Select Social Cognitive Outcomes in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy

Objective. To compare the effects of a group-mediated cognitive behavioral (GMCB) exercise and dietary (EX+D) intervention with those of standard-of-care (SC) treatment on select social cognitive outcomes in prostate cancer (PCa) patients undergoing androgen deprivation therapy (ADT). Methods. In the single-blind, 2-arm, randomized controlled Individualized Diet and Exercise Adherence–Pilot (IDEA-P) trial, 32 PCa patients (mean age = 66.2 years; SD = 7.8) undergoing ADT were randomly assigned to a 12-week EX+D intervention (n = 16) or SC treatment (n = 16). The exercise component of the personalized EX+D intervention integrated a combination of supervised resistance and aerobic exercise performed twice per week. The dietary component involved counseling and education to modify dietary intake and composition. Blinded assessments of social cognitive outcomes were obtained at baseline and 2-month and 3-month follow-up. Results. Intent-to-treat analysis of covariance demonstrated that the EX+D intervention resulted in significantly greater improvements in scheduling (P < .05), coping (P < .01), and exercise self-efficacy (P < .05), and satisfaction with function (P < .01) at 3 months relative to SC. Results of partial correlation analysis also demonstrated that select social cognitive outcomes were significantly correlated with primary trial outcomes of mobility performance and exercise participation (P < .05) at 3-month follow-up. Conclusions: The GMCB lifestyle intervention yielded more favorable improvements in relevant social cognitive outcomes relative to SC among PCa patients undergoing ADT. Additionally, more favorable social cognitive outcomes were associated with superior mobility performance and exercise participation following the independent maintenance phase of the EX+D intervention.
Identification of mixed and successive blood meals of mosquitoes using MALDI-TOF MS protein profiling

Abstract Background The accurate and rapid identification of mosquito blood meals is critical to study the interactions between vectors and vertebrate hosts and, subsequently, to develop vector control strategies. Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling has been shown to be a reliable and effective tool for identifying single blood meals from mosquitoes. Methods In this study, we developed MALDI-TOF MS profiling protocols to identify Anopheles gambiae Giles, Anopheles coluzzii and Aedes albopictus mosquitoes’ mixed blood meals and the last of successive blood meals. The mosquitoes were either successively artificially fed with distinct host bloods or engorged with mixed bloods from distinct vertebrate hosts, such as humans, sheep and dogs. Results Blind test analyses revealed a correct identification of mixed blood meals from mosquitoes using MALDI-TOF MS profiling. The 353 MS spectra from mixed blood meals were identified using log score values >1.8. All MS spectra (n = 244) obtained from mosquitoes' successive blood meals were reproducible and specific to the last blood meal, suggesting that the previous blood meals do not have an impact on the identification of the last one. Conclusion MALDI-TOF MS profiling approach appears to be an effective and robust technique to identify the last and mixed blood meals during medical entomological surveys.
Diet quality in late midlife is associated with faster walking speed in later life in women, but not men: findings from a prospective British birth cohort

Abstract Healthy diet has been linked to better age-related functioning, but evidence on the relationship of diet quality in late midlife and measures of physical capability in later life is limited. Research on potential sex differences in this relationship is scarce. The aim was to investigate the prospective association between overall diet quality, as assessed by the Healthy Eating Index-2015 (HEI-2015) at 60–64 years and measures of walking speed 7 years later, among men and women from the Insight 46, a neuroscience sub-study of the Medical Research Council National Survey of Health and Development. Diet was assessed at 60–64 years using 5-d food diaries, from which total HEI-2015 was calculated. At 69–71 years, walking speed was estimated during four 10-m walks at self-selected pace, using inertial measurement units. Multivariable linear regression models with sex as a modifier, controlling for age, follow-up, lifestyle, health/social variables and physical performance, were used. The final sample consists of 164 women and 167 men (n 331). Women had higher HEI-2015 and slower walking speed than men. A 10-point increase in HEI-2015 was associated with faster walking speed among women (B 0·024, 95 % CI 0·006, 0·043), but not men. The association remained significant in the multivariable model (B 0·021, 95 % CI 0·003, 0·040). In women, higher diet quality in late midlife is associated with faster walking speed. A healthy diet in late midlife is likely to contribute towards better age-related physical capability, and sex differences are likely to affect this relationship.
Molecular epidemiology of peste des petits ruminants in Niger: An update.

Like many West African countries outbreaks of peste des petits ruminants (PPR), an economically important disease of goats and sheep, are regularly reported in Niger. The causative virus, peste des petits ruminants virus (PPRV), can be differentiated into four genetically distinct lineages. A publication in 2018 identified three PPRV lineages circulating in the country in 2001 (lineages I and II) and 2013 (lineage IV), respectively. In this present study more recent samples were collected from goats and sheep in locations throughout Niger between 2011 and 2017. Twelve PPRV positive samples were characterized by sequencing of a segment of the nucleocapsid protein (N) gene. Phylogenetic analysis of the sequences identified viruses from lineages II and IV only. The analysis also indicated a shared origin of the viruses from Niger with PPRVs from neighbouring countries suggesting transboundary movement.
Microaggressions towards people affected by mental health problems: a scoping review

Abstract Aims This review aims to understand the scope of the literature regarding mental health-related microaggressions towards people affected by mental health problems. Methods A scoping review was conducted to explore this question. Four electronic health-oriented databases were searched alongside Google Scholar. As per scoping review principles, the inclusion criteria were developed iteratively. The results of included studies were synthesised using a basic narrative synthesis approach, utilising principles of thematic analysis and thematic synthesis where appropriate. Results A total of 1196 records were identified, of which 17 met inclusion criteria. Of these, 12 were peer-reviewed journal articles, three were research degree theses and two were book chapters. Six included empirical studies were qualitative, four were quantitative and two employed a mixed-methods design. Within these, five qualitative studies aimed to describe the nature of mental health microaggressions experienced by people with mental health problems. Themes identified in a thematic synthesis of these five studies included stereotypes about mental illness, invalidating peoples' experience and blaming people with mental illness for their condition. The included publications informed on the perpetration of mental health microaggressions by family, friends, health professionals and social workers. In addition, two studies created scales, which were then used in cross-sectional surveys of the general public and community members to assess characteristics, such as right-wing political views, associated with endorsement of mental health microaggressions. A consensus definition of microaggressions emerged from the included studies: microaggressions are brief, everyday slights, snubs or insults, that may be subtle or ambiguous, but communicate a negative message to a target person based on their membership of a marginalised group, in this case, people affected by mental illness. Conclusions The study of mental health microaggressions is an emerging, heterogeneous field, embedded in the wider stigma and discrimination literature. It has been influenced by earlier work on racial microaggressions. Both can be ambiguous and contradictory, which creates difficulty defining the boundaries of the concept, but also underpins the key theoretical basis for the negative impact of microaggressions. Mental illness is a more concealable potential type of identity, so it follows that the reported perpetrators of microaggressions are largely friends, family and professionals. This has implications for intervening to reduce the impact of microaggressions. There are several challenges facing research in this area, and further work is needed to understand the impact of mental health microaggressions on people affected by mental health problems.
Irregular sleep and event schedules are associated with poorer self-reported well-being in US college students.

STUDY OBJECTIVES Sleep regularity, in addition to duration and timing, is predictive of daily variations in well-being. One possible contributor to changes in these sleep dimensions are early morning scheduled events. We applied a composite metric - the Composite Phase Deviation (CPD) - to assess mistiming and irregularity of both sleep and event schedules to examine their relationship with self-reported well-being in US college students. METHODS Daily well-being, actigraphy, and timing of sleep and first scheduled events (academic/exercise/other) were collected for ~30 days from 223 US college students (37% females) between 2013 and 2016. Participants rated well-being daily upon awakening on five scales: Sleepy-Alert, Sad-Happy, Sluggish-Energetic, Sick-Healthy, and Stressed-Calm. A longitudinal growth model with time-varying covariates was used to assess relationships between sleep variables (i.e., CPDSleep, sleep duration, and midsleep time) and daily and average well-being. Cluster analysis was used to examine relationships between CPD for sleep vs. event schedules. RESULTS CPD for sleep was a significant predictor of average well-being (e.g., Stressed-Calm: b=-6.3, p<0.01), whereas sleep duration was a significant predictor of daily well-being (Stressed-Calm, b=1.0, p<0.001). While cluster analysis revealed no systematic relationship between CPD for sleep vs. event schedules (i.e., more mistimed/irregular events were not associated with more mistimed/irregular sleep), they interacted upon well-being: the poorest well-being was reported by students for whom both sleep and event schedules were mistimed and irregular. CONCLUSION Sleep regularity and duration may be risk factors for lower well-being in college students. Stabilizing sleep and/or event schedules may help improve well-being.
Analysis of passive tibio-femoral joint movement of Beagle dogs during flexion in cadaveric hind limbs without muscle

The aim of this study was to evaluate the normal range of motion of the canine tibiofemoral joint and the movement of the tibia relative to the femur, especially the internal/external rotation under flexion. Right stifle joints were harvested from eight skeletally mature Beagle dogs, which were euthanized for reasons unrelated to this study. All muscle tissue was removed from the limbs prior to testing. Flexion and extension tests were conducted using a robotic manipulator with six degrees-of-freedom. Cranial/caudal and medial/lateral displacement and varus/valgus and internal/external rotation were measured at various degrees of flexion. We observed that the tibia rotated internally at an increasing flexion angle with mean peak internal and external rotations of 20.0 ± 13.8° and 4.5 ± 3.6°, respectively. The tibia also tended to displace cranially at an increasing flexion angle, with a mean peak cranial displacement of 8.9 ± 4.4 mm; there was minimal medial displacement when increasing the flexion angle. Valgus rotation also tended to occur at an increasing flexion angle. During the flexion of the canine stifle joint, approximately 20° of internal tibial rotation occurred around the longitudinal axis, along with a rollback motion involving the cranial displacement of the tibia.
Randomized study of pazopanib + lapatinib vs. lapatinib alone in patients with HER2-positive advanced or metastatic breast cancer

1016 Background: Preclinical evidence indicates a direct molecular link between HER2 amplification and up-regulation of VEGF in HER2+ breast cancer. Concurrent over-expression of HER2 and VEGF is associated with a poorer clinical outcome than over-expression of either alone. Together these data provide the rationale for clinical translation of simultaneous blockade of both pathways. Pazopanib (P) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit. Lapatinib (L) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER2 (ErbB2). This study (VEG20007) evaluates the efficacy and safety of dual pathway inhibition in patients (pts) with HER2+ adv/met breast cancer. Methods: Eligible pts received no prior chemotherapy or HER2-directed therapy for adv/met disease and had measurable disease per RECIST. Pts were randomized to receive P 400 mg/d + L 1,000 mg/d or L alone (1,500 mg/d) for 12 weeks. Following disease assessment at week (wk) 12, pts with an objective response could continue on stud.