Miracle-dz/UniFAR-FTUs huggingface dataset:
Noise suppression in stochastic genetic circuits using PID controllers

Inside individual cells, protein population counts are subject to molecular noise due to low copy numbers and the inherent probabilistic nature of biochemical processes. We investigate the effectiveness of proportional, integral and derivative (PID) based feedback controllers to suppress protein count fluctuations originating from two noise sources: bursty expression of the protein, and external disturbance in protein synthesis. Designs of biochemical reactions that function as PID controllers are discussed, with particular focus on individual controllers separately, and the corresponding closed-loop system is analyzed for stochastic controller realizations. Our results show that proportional controllers are effective in buffering protein copy number fluctuations from both noise sources, but this noise suppression comes at the cost of reduced static sensitivity of the output to the input signal. In contrast, integral feedback has no effect on the protein noise level from stochastic expression, but significantly minimizes the impact of external disturbances, particularly when the disturbance comes at low frequencies. Counter-intuitively, integral feedback is found to amplify external disturbances at intermediate frequencies. Next, we discuss the design of a coupled feedforward-feedback biochemical circuit that approximately functions as a derivate controller. Analysis using both analytical methods and Monte Carlo simulations reveals that this derivative controller effectively buffers output fluctuations from bursty stochastic expression, while maintaining the static input-output sensitivity of the open-loop system. In summary, this study provides a systematic stochastic analysis of biochemical controllers, and paves the way for their synthetic design and implementation to minimize deleterious fluctuations in gene product levels.
An evaluation of diagnostic tests in a case series of suspected leptospirosis patients seen in primary care.

AIMS This study describes 47 presentations of suspected leptospirosis in general practice in New Zealand. Our primary aim was to assess the laboratory diagnosis of leptospirosis in these patients, by comparing polymerase chain reaction (PCR) tests, microscopic agglutination test (MAT) and culture results. METHODS Patients suspected of leptospirosis were recruited from general practices in the Waikato (n=17) and Wairoa (n=30) between August 2011 and June 2015. Blood and urine samples were tested for leptospirosis at two diagnostic laboratories and one research laboratory using PCR tests, MAT and culture. RESULTS Forty-seven patients were recruited for this study: 37 during the acute phase of the illness (within 10 days of symptom onset) and 10 after the acute phase. Eleven of the acute phase patients (11/37, 30%) and two of the later phase patients (2/10, 20%) returned positive leptospirosis test results. The 11 acute phase leptospirosis positive patients had the following positive diagnostic tests: PCR and paired MAT (+/- blood culture) (n=3), PCR only (+/- blood culture) (n=4), paired MAT only (n=3) and blood culture only (n=1). Urine PCR (performed only on Wairoa patients) was the only positive test for two of these patients. CONCLUSION About a quarter of farm workers and meat workers presenting to general practice with flu-like symptoms will have leptospirosis, but they will not be diagnosed unless appropriately tested, and then they may only test positive for some of the tests available. To increase the likelihood of making a diagnosis, clinicians should order multiple laboratory tests, including blood and urine PCR and a paired MAT.
On-the-Fly, Sample-Tailored Optimisation of NMR Experiments

NMR experiments, indispensable to chemists in many areas of research, are often run with generic, unoptimized experimental parameters. This approach makes robust and automated acquisition on different samples and instruments extremely challenging. Here, we present NMR-POISE (Parameter Optimization by Iterative Spectral Evaluation), the first demonstration of on-the-fly, sample-tailored, and fully automated optimization of a wide range of NMR experiments. We illustrate how POISE maximizes spectral sensitivity and quality with a diverse set of 1D and 2D examples, ranging from HSQC and NOESY experiments to ultrafast and pure shift techniques. Our Python implementation of POISE has an interface integrated into Bruker's TopSpin software, one of the most widely used platforms for NMR acquisition and automation, allowing NMR optimizations to be run without direct user supervision. We predict that POISE will find widespread usage in academia and industry, where sample-specific and automated experiment optimization is mandatory.
Melatonin Adjusts the Phase of Mouse Circadian Clocks in the Cornea Both Ex Vivo and In Vivo

The presence of an endogenous circadian clock within most mammalian cells is associated with the amazing observation that within a given tissue, these clocks are largely in synchrony with each other. Different tissues use a variety of systemic or environmental cues to precisely coordinate the phase of these clocks. The cornea is a unique tissue in that it is largely isolated from the direct blood supply that most tissues experience, it is transparent to visible light, and it is exposed directly to environmental light and temperature. Melatonin is a hormone that has been implicated in regulation of the cornea’s circadian clocks. Here, we analyze the ability of rhythmic melatonin to entrain corneas ex vivo, and analyze the phase of corneal circadian clocks in vivo both in light: dark cycles and in constant darkness. We find that the presence of a retina from a melatonin-proficient mouse strain, C3Sn, can photoentrain the circadian clocks of a co-cultured mouse cornea, but a retina from a melatonin-deficient strain, C57Bl/6, cannot. Furthermore, pharmacologic blockade of melatonin or use of a retina with advanced retinal degeneration, Pde6brd1, blocks the photoentraining effect. Corneal circadian clocks in vivo adopt an advanced phase in C3Sn mice compared with C57Bl/6, but the circadian clocks in the liver are unaffected. This observation is not attributable to a shorter endogenous period of the cornea or behavior between the strains. Some transcripts of circadian genes in the corneas of C3Sn mice also show an advanced phase of expression in a light: dark cycle, while the transcript of Per2 exhibits a light-dependent transient induction at the onset of darkness. We conclude that melatonin acts as a phase modifying factor in a rhythmic manner for the circadian clocks of the cornea.
LncRNA NEAT1 regulated diabetic retinal epithelial-mesenchymal transition through regulating miR-204/SOX4 axis

Aim Epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells is the key of the development of diabetic retinopathy (DR), and lncRNA NEAT1 could accelerate EMT in diabetic nephropathy. Meanwhile, as a diabetes susceptibility gene, whether sex-determining region Y-related (SRY) high-mobility group box 4 (SOX4) has relationship with lncRNA NEAT1 in DR remains unclear. Methods Firstly, NEAT1, SOX4 and miR-204 were evaluated by qRT-PCR (quantitative reverse-transcriptase PCR) under high glucose condition. Then, cell viability, proliferation, migration and invasion were respectively detected by MTT, BrdU staining, wound healing and transwell assay after NEAT1 knockdown or miR-204 overexpression. Also, the EMT-related proteins were examined by western blot and cell immunofluorescence assay. In order to confirm the relationship between miR-204 and NEAT1 or SOX4, dual luciferase reporter gene assay was conducted. At the same time, the protein levels of SOX4 and EMT-related proteins were investigated by immunohistochemistry in vivo. Results High glucose upregulated NEAT1 and SOX4 and downregulated miR-204 in ARPE19 cells. NEAT1 knockdown or miR-204 overexpression inhibited the proliferation and EMT progression of ARPE19 cells induced by high glucose. NEAT1 was identified as a molecular sponge of miR-204 to increase the level of SOX4. The effect of NEAT1 knockdown on the progression of EMT under high glucose condition in ARPE19 cells could be reversed by miR-204 inhibitor. Also, NEAT1 knockdown inhibited retinal EMT in diabetic mice. Conclusion NEAT1 regulated the development of EMT in DR through miR-204/SOX4 pathway, which could provide reference for clinical prevention and treatment.
DEveloping Tests for Endometrial Cancer deTection (DETECT): protocol for a diagnostic accuracy study of urine and vaginal samples for the detection of endometrial cancer by cytology in women with postmenopausal bleeding

Introduction Postmenopausal bleeding (PMB), the red flag symptom for endometrial cancer, triggers urgent investigation by transvaginal ultrasound scan, hysteroscopy and/or endometrial biopsy. These investigations are costly, invasive and often painful or distressing for women. In a pilot study, we found that voided urine and non-invasive vaginal samples from women with endometrial cancer contain malignant cells that can be identified by cytology. The aim of the DEveloping Tests for Endometrial Cancer deTection (DETECT) Study is to determine the diagnostic test accuracy of urine and vaginal cytology for endometrial cancer detection in women with PMB. Methods and analysis This is a multicentre diagnostic accuracy study of women referred to secondary care with PMB. Eligible women will be asked to provide a self-collected voided urine sample and a vaginal sample collected with a Delphi screener before routine clinical procedures. Pairs of specialist cytologists, blinded to participant cancer status, will assess and classify samples independently, with differences settled by consensus review or involving a third cytologist. Results will be compared with clinical outcomes from standard diagnostic tests. A sample size of 2000 women will have 80% power to establish a sensitivity of vaginal samples for endometrial cancer detection by cytology of ≥85%±7%, assuming 5% endometrial cancer prevalence. The primary objective is to determine the diagnostic accuracy of urogenital samples for endometrial cancer detection by cytology. Secondary objectives include the acceptability of urine and vaginal sampling to women. Ethics and dissemination This study has been approved by the North West–Greater Manchester West Research Ethics Committee (16/NW/0660) and the Health Research Authority. Results will be disseminated through publication in peer-reviewed scientific journals, presentation at conferences and via charity websites. Trial registration number ISRCTN58863784.
Emotions in Deaf and Hard-of-Hearing and Typically Hearing Children

Abstract For deaf and hard-of-hearing (DHH) children living in an environment where their access to linguistic input and social interactions is compromised, learning emotions could be difficult, which may further affect social functioning. To understand the role of emotion in DHH children’s social life, this study investigated emotional functioning (i.e., emotion recognition, empathy, emotion expression), and its relation with social functioning (i.e., social competence and externalizing behaviors), in 55 DHH children and 74 children with typical hearing (aged 3–10 years; Mage = 6.04). Parental reports on children’s emotional and social functioning and factors related to DHH children’s hearing were collected. Results showed similar levels of emotional and social functioning in children with and without hearing loss. Use of auditory intervention and speech perception did not correlate with any measures in DHH children. In both groups, higher levels of empathy related to higher social competence and fewer externalizing behaviors; emotion recognition and positive emotion expression were unrelated to either aspect of social functioning. Higher levels of negative emotion expression related to lower social competence in both groups, but to more externalizing behaviors in DHH children only. DHH children in less linguistically accessible environments may not have adequate knowledge for appropriately expressing negative emotions socially.
FREQUENT LEPTOSPIRA SPP. DETECTION BUT ABSENCE OF TULA ORTHOHANTAVIRUS IN MICROTUS SPP. VOLES, NORTHWESTERN SPAIN

Abstract: The common vole (Microtus arvalis) is a major agricultural pest in Europe and is a reservoir for several zoonotic agents, such as Leptospira spp. and Tula orthohantavirus (TULV). However, little is known about the occurrence of those pathogens in voles from Spain, where the species has largely expanded its distribution range in the past decades, causing agricultural pests and zoonotic diseases. For a molecular survey, 580 common voles and six Lusitanian pine voles (Microtus lusitanicus) were collected in 26 localities from four provinces of northwestern Spain. We assessed the presence of Leptospira spp. DNA in kidney tissue by PCR targeting the lipL32 gene, detecting a prevalence of 7.9% (95% confidence interval, 5.9–10.4) for common voles and of 33.3% (95% confidence interval, 4.3–77.7) for Lusitanian pine voles. We identified Leptospira kirschneri in 24 animals and Leptospira borgpetersenii in two animals, using secY gene–specific PCR. We analyzed environmental and demographic factors (such as age class, weight, and sex) and population dynamics data for their potential effect on the Leptospira spp. prevalence in those voles. The Leptospira spp. DNA detection rate in common voles increased significantly with maximum air temperature, vole weight, and amount of accumulated rainfall during the 90 d before capture and within the peak phase of the population cycle. We assessed the presence of TULV in lung tissue of 389 voles by reverse-transcription PCR, with no positive results. The absence of TULV might be explained by the evolutionary isolation of the common vole in Spain. The detection of two Leptospira genomospecies underlines the necessity for further typing efforts to understand the epidemiology of leptospiral infection in the common vole and the potential risk for human health in Spain.
Emerging roles of long non-coding RNAs in spinal cord injury

Spinal cord injury (SCI) is the most serious complication of spinal injury and often leads to severe dysfunction of the limb below the injured segment. SCI causes not only serious physical and psychological harm to the patients, but imposes an enormous economic burden on the whole society. Great efforts have been made to improve the functional outcomes of patients with SCI; however, therapeutic advances have far been limited. Long non-coding RNA (lncRNA) is an important regulator of gene expression and has recently been characterized as a key regulator of central nervous system stabilization. Emerging evidence suggested that lncRNAs are significantly dysregulated and play a key role in the development of SCI. Our review summarizes current researches regarding the roles of deregulated lncRNAs in modulating apoptosis, inflammatory response, neuronal behavior in SCI. These studies suggest that specific regulation of lncRNA or its downstream targets may provide a new therapeutic approach for this desperate disease.
Acute health care among Indigenous patients in Canada: a scoping review

ABSTRACT A recent report by the Chief Public Health Officer of Canada demonstrates the inferior health status of Indigenous Peoples in Canada when compared to non-Indigenous populations. This scoping review maps out the available literature concerning acute health care for Indigenous Peoples in Canada in order to better understand the health care issues they face. All existing articles concerning health care provided to Indigenous Peoples in Canada in acute settings were included in this review. The targeted studied outcomes were access to care, health care satisfaction, hospital visit rates, mortality, quality of care, length of stay and cost per hospitalisation. 114 articles were identified. The most studied outcomes were hospitalisation rates (58.8%), length of stay (28.0%), mortality (25.4%) and quality of care (24.6%) Frequently studied topics included pulmonary disease, injuries, cardiovascular disease and mental illness. Indigenous Peoples presented lower levels of satisfaction and access to care although they tend to be over-represented in hospitalisation rates for acute care. Greater inclusion of Indigenous Peoples in the health care system and in the training of health care providers is necessary to ensure a better quality of care that is culturally safe for Indigenous Peoples.
18F-FDG PET/CT and 68Ga-FAPI-4 PET/CT Findings of Bilateral Knee Osteoarthritis in a Patient With Uveal Malignant Melanoma.

ABSTRACT We present the findings of 68Ga-FAPI-4 PET/CT and 18F-FDG PET/CT of a metastatic malignant melanoma patient with osteoarthritis. A 65-year-old woman with a history of metastatic uveal malignant melanoma was referred to 18F-FDG PET/CT for restaging after enucleation and chemotherapy. 18F-FDG PET/CT imaging showed high radiotracer uptake in liver metastases; additionally mild uptake due to osteoarthritis was observed in both knees. However, although 68Ga-FAPI-4 showed lower uptake in liver lesions, it showed a more prominent uptake in both knee joints compared with 18F-FDG.
Objective and Subjective Outcomes in Patients with Hearing Aids: A Cross-Sectional, Comparative, Associational Study

Introduction: Outcome assessment for hearing aids (HAs) is an essential part of HA fitting and validation. There is no consensus about the best or standard approach for evaluating HA outcomes. And, the relationship between objective and subjective measures is ambiguous. This study aimed to determine the outcomes after HA fitting, explore correlations between subjective benefit and acoustic gain improvement as well as objective audiologic tests, and investigate several variables that may improve patients’ perceived benefits. Methods: Eighty adults with bilateral symmetrical hearing loss using HAs for at least 1 month were included in this study. All subjects completed the pure tone average (PTA) threshold and word recognition score (WRS) tests in unaided and aided conditions. We also administered the Chinese version of International Outcome Inventory for Hearing Aids (IOI-HA), to measure participants’ subjective benefits. Objective HA benefit (acoustic gain improvement) was defined as the difference in thresholds or scores between aided and unaided conditions indicated with ΔPTA and ΔWRS. Thus, patients’ baseline hearing levels were taken into account. Correlations were assessed among objective audiologic tests (PTA and WRS), acoustic gain improvement (ΔPTA and ΔWRS), multiple potential factors, and IOI-HA overall scores. Results: PTA decreased significantly, but WRS did not increase when aided listening was compared to unaided listening. Negative correlations between PTAs and IOI-HA scores were significant but weak (r = −0.370 and r = −0.393, all p < 0.05). Significant weak positive correlations were found between WRSs and IOI-HA (r = 0.386 and r = 0.309, all p < 0.05). However, there was no correlation among ΔPTA, ΔWRS, and IOI-HA (r = 0.056 and r = −0.086, all p > 0.05). Moreover, 2 nonaudiological factors (age and daily use time) were significantly correlated with IOI-HA (r = −0.269 and r = 0.242, all p < 0.05). Conclusions: Correlations among objective audiologic tests, acoustic gain, and subjective patient-reported outcomes were weak or absent. Subjective questionnaires and objective tests do not reflect the same hearing capability. Therefore, it is advisable to evaluate both objective and subjective outcomes when analyzing HA benefits on a regular basis and pay equal attention to nonaudiological and audiological factors.
Prevalence and prognostic impact of apical sparing contractility pattern in patients with aortic stenosis referred for transcatheter aortic valve implantation.

INTRODUCTION Prolonged afterload increase in aortic stenosis (AS) may alter left ventricular (LV) contractility, irrespective of LV ejection fraction (LVEF). The prevalence and morbimortality associated with the apical sparing strain pattern (ASP), a typical finding of cardiac amyloidosis (CA), are not fully understood in patients with AS. We assessed the prevalence of the ASP in patients with severe AS and its clinical impact after transcatheter aortic valve implantation (TAVI). METHODS Eighty-nine consecutive patients with severe AS and LV hypertrophy referred for TAVI were included. Baseline clinical and echocardiographic data were assessed, including the ASP in bull's eye plots (ASPB), relative apical longitudinal strain (RALS) and EF to global longitudinal strain (EF/GLS) ratio. We analysed all-cause mortality; a composite of all-cause mortality, stroke, and heart failure hospitalizations; and the rate of pacemaker implantation, after TAVI. RESULTS Mean age was 82 ± 6 years and mean LVEF was 57 ± 10%. ASPB and RALS >1 were present in 43.8% and 24.7% of patients, respectively. Over a median follow-up of 13 months (IQR 6-32), ASPB was associated with higher rates of all-cause mortality (log-rank P=0.001) and was an independent predictor of all-cause mortality in multivariate analysis. Combination of the ASPB and GLS or EF/GLS ratio improved the risk stratification. Patients with RALS >1 were more likely to have new BBB and an indication for pacemaker implantation (P=0.048). CONCLUSION The ASP, as assessed by the ASPB and RALS, was frequent in patients with AS regardless of the diagnosis of CA. The ASPB may refine risk stratification in patients referred for TAVI.
Surgical revascularization in stable coronary artery disease with ventricular dysfunction: a single-center cohort study.

PURPOSE Stress-gated myocardial perfusion scintigraphy (MPS) is used for prognosis in stable coronary artery disease (CAD). We sought to assess coronary artery bypass grafting (CABG) outcomes in stable coronary artery disease patients who had myocardial perfusion scintigraphy and left ventricular (LV) dysfunction. METHODS Stable CAD patients who underwent CABG (2012-2019) and had stress-gated MPS were identified retrospectively. Based on the post-stress LV ejection fraction, a total of 130 patients were divided into a control group (51%) and LV dysfunction group (49%). RESULTS Patients with left ventricular dysfunction had significantly more mean summed stress score (22.1 ± 9 Vs. 12.5 ± 8; P ≤ 0.001) and summed resting score (14.6 ± 8 Vs. 3.7 ± 4; P ≤ 0.001) compared to the control group respectively. They also had a greater risk for developing low cardiac output syndrome after surgery (OR: 2.9, 95% CI 1.1-6.6, P=0.033). At 4.7 years, freedom from cardiac death was not statistically significant between the left ventricular dysfunction and control groups, respectively (90.2% vs. 95.6%; P=0.157). Cardiac death was not influenced by either ventricular dysfunction at the time of surgery (HR: 2.6, 95% CI 0.64-10.6, P=0.182) nor by having percent ischemic myocardium > 10% (HR: 0.86, 95% CI 0.23-3.24, P=0.826). CONCLUSION Significant myocardial ischemia and ventricular dysfunction before complete surgical revascularization did not influence the risk of cardiac-related deaths on long-term follow-up. This might be related to the improved survival after CABG in patients with myocardial ischemia and left ventricular dysfunction.