Miracle-dz/UniFAR-FTUs huggingface dataset:
In vitro activity of aryl-thiazole derivatives against Schistosoma mansoni schistosomula and adult worms

Schistosomiasis is caused by a trematode of the genus Schistosoma and affects over 200 million people worldwide. The only drug recommended by the World Health Organization for treatment and control of schistosomiasis is praziquantel. Development of new drugs is therefore of great importance. Thiazoles are regarded as privileged structures with a broad spectrum of activities and are potential sources of new drug prototypes, since they can act through interactions with DNA and inhibition of DNA synthesis. In this context, we report the synthesis of a series of thiazole derivatives and their in vitro schistosomicidal activity by testing eight molecules (NJ03-08; NJ11-12) containing thiazole structures. Parameters such as motility and mortality, egg laying, pairing and parasite viability by ATP quantification, which were influenced by these compounds, were evaluated during the assays. Scanning electron microscopy (SEM) was utilized for evaluation of morphological changes in the tegument. Schistosomula and adult worms were treated in vitro with different concentrations (6.25 to 50 μM) of the thiazoles for up to 5 and 3 days, respectively. After in vitro treatment for five days with 6.25 μM NJ05 or NJ07 separately, we observed a decrease of 30% in schistosomula viability, whilst treatment with NJ05+NJ07 lead to a reduction of 75% in viability measured by ATP quantitation and propidium iodide labeling. Adult worms’ treatment with 50 μM NJ05, NJ07 or NJ05 + NJ07 showed decreased motility to 30–50% compared with controls. Compound NJ05 was more effective than NJ07, and adult worm viability after three days was reduced to 25% in parasites treated with 50 μM NJ05, compared with a viability reduction to 40% with 50 μM NJ07. SEM analysis showed severe alterations in adult worms with formation of bulges and blisters throughout the dorsal region of parasites treated with NJ05 or NJ07. Oviposition was extremely affected by treatment with the NJ series compounds; at concentrations of 25 μM and 50 μM, oviposition reached almost zero with NJ05, NJ07 or NJ05 + NJ07 already at day one. Tested genes involved in egg biosynthesis were all confirmed by qPCR as downregulated in females treated with 25 μM NJ05 for 2 days, with a significant reduction in expression of p14, Tyrosinase 2, p48 and fs800. NJ05, NJ07 or NJ05+NJ07 treatment of HEK293 (human embryonic cell line) and HES (human epithelial cell line) showed EC50 in the range of 18.42 to 145.20 μM. Overall, our results demonstrate that those molecules are suitable targets for further development into new drugs for schistosomiasis treatment, although progress is needed to lessen the cytotoxic effects on human cells. According to the present study, thiazole derivatives have schistosomicidal activities and may be part of a possible new arsenal of compounds against schistosomiasis.
Aspartate aminotransferase-to-platelet ratio index (APRI): A potential marker for diagnosis in patients at risk of severe malaria caused by Plasmodium vivax

Acute infection with Plasmodium vivax, classically associated with benign disease, has been presenting as serious and even fatal disease in recent years. Severe disease is mainly due to biochemical and hematological alterations during the acute phase of infection. In the present cross-sectional study, the aspartate aminotransferase-to-platelet ratio index (APRI) was evaluated as a method for identifying patients at risk of severe vivax malaria. This retrospective study included 130 patients with confirmed P. vivax infection between June 2006 and January 2018. Clinical-epidemiological data were obtained from medical records. Hematological and biochemical parameters were determined using automated equipment. The criteria of severity for infection by Plasmodium falciparum, established by the World Health Organization (WHO), were adapted to classify patients with danger signs of severe vivax malaria. Of the 130 patient’s records evaluated, 19 (14.6%) had one or more signs and symptoms of severe malaria. The mean APRI values among patients with and without severe malaria were 2.11 and 1.09, respectively (p = 0.044). Among those with severe disease, the proportion with an APRI value above 1.50 was 30% compared to the 10% among those without severe disease (p = 0.007). The area under the receiver operating characteristic curve (95% CI), calculated to assess the accuracy of the APRI in discriminating between patients with and without severe disease, was 0.645 (0.494; 0.795). An APRI cutoff of 0.74 resulted in sensitivity of 74.0%, specificity of 56.0%, and accuracy of 65.0%. This study shows that the APRI is elevated in patients with evidence of infection by P. vivax. Based on the good sensitivity found in this study, we conclude that this simple index can serve as a diagnostic biomarker to identify patients at risk of severe disease during the acute phase of P. vivax infection.
Effect of upper body fat distribution on pulmonary functions in medical students

Background: The prevalence of obesity is increasing, and there is evidence that obesity, in particular abdominal obesity as a marker of insulin resistance, is negatively associated with pulmonary function. The mechanism for this association and the best marker of abdominal adiposity in relation to pulmonary function is not known. Study objectives: We assessed the association between pulmonary function and body mass index (BMI), waist/hip ratio and Body fat percentage as markers of adiposity and body fat distribution. We used Pearson correlation coefficient to analyse the association of pulmonary function (i.e., FEV1 and FVC) [with manoeuvres performed in the sitting position] with overall adiposity markers (i.e., Body fat percentage and BMI) and abdominal adiposity markers (WHR). Methods: One forty male subjects underwent physical examination, computerised pulmonary function tests (spirometry, lung volumes) and various anthropometric measurements (waist-hip ratio, BMI, skin fold thickness) out of which seventy were case and seventy were control. Results: Result showed that expiratory reserve volume and FVC were showed negative correlation with WHR in obese group (p<0.001). There was negative correlation observed between BF% and ERV (-0.49), FVC (-0.05), and MVV (-0.11). There was negative correlation observed between BMI and ERV (-0.46) and MVV (-0.17). WHR also showed negative correlation with ERV (-0.14). Conclusion: ERV and FVC were significantly decreased in subjects with WHR more than 0.93. These results suggest that abdominal adiposity is a better predictor of pulmonary function than Body fat percentage or BMI, and investigators should consider it when investigating the determinants of pulmonary function.
TGDS pathogenic variants cause Catel‐Manzke syndrome without hyperphalangy

Catel‐Manzke syndrome, also known as micrognathia‐digital‐syndrome, is a rare autosomal recessive disorder characterized by the combination of the two cardinal features Pierre‐Robin sequence and bilateral hyperphalangy leading to ulnar clinodactyly (ulnar curvature of the phalanges) and radial deviation (radial angulation at the metacarpophalangeal joint) of the index fingers. Individuals without one of these major hallmarks or with additional hand malformations have been described as atypical or Catel‐Manzke‐like syndrome. Biallelic TGDS pathogenic variants have thus far been detected in eight individuals with typical Catel‐Manzke syndrome and in one fetus with additional features. Here we report on two individuals with TGDS pathogenic variants who presented with mild radial deviation and ulnar clinodactyly of the index fingers but without radiologic signs of hyperphalangy. Furthermore, both individuals have disproportionate short stature, a feature that has not yet been associated with Catel‐Manzke syndrome. Our data broaden the phenotypic spectrum of TGDS‐associated Catel‐Manzke syndrome and expand the indication for diagnostic testing.
Photoperiodic and clock regulation of the vitamin A pathway in the brain mediates seasonal responsiveness in the monarch butterfly

Significance Seasonality is a widespread adaptation in nature, which is driven by changes in day length (i.e., photoperiod) in organisms living at temperate latitudes. In insects, despite decades of research, the molecular and genetic mechanisms by which photoperiodic changes are sensed and translated into seasonal changes in developmental, physiological, and behavioral processes have remained elusive. The present study supports a role for circadian clock genes in sensing photoperiodic signals and genetically demonstrates that the vitamin A in the insect brain, which is photoperiod- and clock-regulated, is necessary for regulating seasonal responses. These findings also establish the monarch butterfly as one of the few animal models in which to genetically dissect the molecular mechanisms that underlie photoperiodic responsiveness. Seasonal adaptation to changes in light:dark regimes (i.e., photoperiod) allows organisms living at temperate latitudes to anticipate environmental changes. In nearly all animals studied so far, the circadian system has been implicated in measurement and response to the photoperiod. In insects, genetic evidence further supports the involvement of several clock genes in photoperiodic responses. Yet, the key molecular pathways linking clock genes or the circadian clock to insect photoperiodic responses remain largely unknown. Here, we show that inactivating the clock in the North American monarch butterfly using loss-of-function mutants for the circadian activators CLOCK and BMAL1 and the circadian repressor CRYPTOCHROME 2 abolishes photoperiodic responses in reproductive output. Transcriptomic approaches in the brain of monarchs raised in long and short photoperiods, summer monarchs, and fall migrants revealed a molecular signature of seasonal-specific rhythmic gene expression that included several genes belonging to the vitamin A pathway. We found that the rhythmic expression of these genes was abolished in clock-deficient mutants, suggesting that the vitamin A pathway operates downstream of the circadian clock. Importantly, we showed that a CRISPR/Cas9-mediated loss-of-function mutation in the gene encoding the pathway’s rate-limiting enzyme, ninaB1, abolished photoperiod responsiveness independently of visual function in the compound eye and without affecting circadian rhythms. Together, these results provide genetic evidence that the clock-controlled vitamin A pathway mediates photoperiod responsiveness in an insect. Given previously reported seasonal changes associated with this pathway in the mammalian brain, our findings suggest an evolutionarily conserved function of vitamin A in animal photoperiodism.
Giant cell arteritis-related aortitis with positive or negative temporal artery biopsy: a French multicentre study

Objective: To compare the clinical presentation and outcome of giant cell arteritis (GCA)-related aortitis according to the results of temporal artery biopsy (TAB). Method: Patients with GCA-related aortitis diagnosed between 2000 and 2017, who underwent TAB, were retrospectively included from a French multicentre database. They all met at least three American College of Rheumatology criteria for the diagnosis of GCA. Aortitis was defined by aortic wall thickening > 2 mm on computed tomography scan and/or an aortic aneurysm, associated with an inflammatory syndrome. Patients were divided into two groups [positive and negative TAB (TAB+, TAB−)], which were compared regarding aortic imaging characteristics and aortic events, at aortitis diagnosis and during follow-up. Results: We included 56 patients with TAB+ (70%) and 24 with TAB− (30%). At aortitis diagnosis, patients with TAB− were significantly younger than those with TAB+ (67.7 ± 9 vs 72.3 ± 7 years, p = 0.022). Initial clinical signs of GCA, inflammatory parameters, and glucocorticoid therapy were similar in both groups. Coronary artery disease and/or lower limb peripheral arterial disease was more frequent in TAB− patients (25% vs 5.3%, p = 0.018). Aortic wall thickness and type of aortic involvement were not significantly different between groups. Diffuse arterial involvement from the aortic arch was more frequent in TAB− patients (29.1 vs 8.9%, p = 0.03). There were no differences between the groups regarding overall, aneurism-free, relapse-free, and aortic event-free survival. Conclusion: Among patients with GCA-related aortitis, those with TAB− are characterized by younger age and increased frequency of diffuse arterial involvement from the aortic arch compared to those with TAB+, without significant differences in terms of prognosis.
Vitamin D Status and Thyroid Autoantibodies in Autoimmune Thyroiditis

Abstract A lack of vitamin D seems to be related to autoimmune diseases including autoimmune thyroiditis (AIT). This study intends to determine the correlation between improvement of 25-hydroxyvitamin D [25(OH)D] levels and AIT in patients from an outpatient endocrine clinic in Frankfurt, Germany. This study included 933 patients with thyroid peroxidase antibodies (anti-TPO-Ab) ≥34 kIU/l, including most patients with clear AIT due to a concurrent sonographic evidence of reduced echogenicity. We performed clinical evaluation and laboratory analysis at five points in time within two years retrospectively. Due to a high dropout rate within the observation period, we excluded the last two time points from analysis. Data from 933 AIT patients revealed 89% having vitamin D deficiency or insufficiency [25(OH)D <75 nmol/l] with a median 25(OH)D level of 39.7 nmol/l. At baseline, a weak inverse correlation between 25(OH)D and anti-TPO-Ab was observed during winter (rs=–0.09, p=0.048*), but not during summer time (p>0.2). We discovered 58 patients having initially a 25(OH)D level < 75 nmol/l (median: 40.2 nmol/l), which improved over time to a 25(OH)D level ≥ 75 nmol/l (median: 83.2 nmol/l, p<0.0005***). Simultaneously, the median anti-TPO-Ab level showed a significant decrease of 25% from 245.8 to 181.3 kIU/l (p=0.036*). A significant reduction of the median anti-TPO-Ab level of 9% was also observed in the control group, which consisted of patients having constantly a 25(OH)D level <75 nmol/l. The result may suggest that in particular patients with 25(OH)D levels < 75 nmol/l benefit from an increase of 25(OH)D levels ≥ 75 nmol/l. Further prospective randomized controlled clinical trials are needed to finally evaluate if vitamin D has immunmodulatory effects in AIT.
Letter to the Editor: “Predicting the Debonding of CAD/CAM Composite Resin Crowns with AI”

We appreciate the innovative work of using CNN (convolutional neural network; Krizhevsky et al. 2012) to predict the debonding possibility of composite resin crowns by Yamaguchi et al. (2019). However, we found a fundamental defect in the experiment setting, which made the validity of the method unreliable. As the study described, 8,640 images collected from 24 patients were randomly divided into training and test data sets, which means that both data sets most likely contained images generated from all 24 patients. A serious information leakage from test data set to training data set was therefore caused. As is known to all, in reality, dentists will never know anything about the patient’s future treatment outcome when making predictions independently, yet in this study, CNN had already learned all 24 patients’ outcomes before being tested, which was obviously inappropriate. From the point of machine learning, this information leakage would lead to an unreasonably high evaluation outcome of this model, since a bias/variance dilemma was hidden unintentionally (Geman et al. 2014). Hence, we think that dividing the 24 patients randomly, instead of 8640 images, into training and test data sets is more reasonable and consistent with clinical practice. Specifically, 6,480 images from 18 patients selected randomly are marked as the training data set, and images from the remaining 6 patients are subsequently marked as the test data set. If it was just a misinterpretation of the division method, we believe that the division process should be stated more clearly, since the correct description of it is critical to the understanding of this study.
Heparin chromatography as an in vitro predictor for antibody clearance rate through pinocytosis

ABSTRACT The pharmacokinetic (PK) properties of therapeutic antibodies directly affect efficacy, dose and dose intervals, application route and tissue penetration. In indications where health-care providers and patients can choose between several efficacious and safe therapeutic options, convenience (determined by dosing interval or route of application), which is mainly driven by PK properties, can affect drug selection. Therapeutic antibodies can have greatly different PK even if they have identical Fc domains and show no target-mediated drug disposition. Biophysical properties like surface charge or hydrophobicity, and binding to surrogates for high abundant off-targets (e.g., baculovirus particles, Chinese hamster ovary cell membrane proteins) were proposed to be responsible for these differences. Here, we used heparin chromatography to separate a polyclonal mix of endogenous human IgGs (IVIG) into fractions that differ in their PK properties. Heparin was chosen as a surrogate for highly negatively charged glycocalyx components on endothelial cells, which are among the main contributors to nonspecific clearance. By directly correlating heparin retention time with clearance, we identified heparin chromatography as a tool to assess differences in unspecific cell–surface interaction and the likelihood for increased pinocytotic uptake and degradation. Building on these results, we combined predictors for FcRn-mediated recycling and cell–surface interaction. The combination of heparin and FcRn chromatography allow identification of antibodies with abnormal PK by mimicking the major root causes for fast, non-target-mediated, clearance of therapeutic, Fc-containing proteins.
A Role for Plant KASH Proteins in Regulating Stomatal Dynamics1[OPEN]

Protein complexes at the nuclear envelope—known to connect the nucleus to the cytoskeleton—affect stomatal opening and closing in response to a variety of signals. Stomatal movement, which regulates gas exchange in plants, is controlled by a variety of environmental factors, including biotic and abiotic stresses. The stress hormone abscisic acid (ABA) initiates a signaling cascade, which leads to increased H2O2 and Ca2+ levels and F-actin reorganization, but the mechanism of, and connection between, these events is unclear. SINE1, an outer nuclear envelope component of a plant Linker of Nucleoskeleton and Cytoskeleton complex, associates with F-actin and is, along with its putative paralog SINE2, expressed in guard cells. Here, we have determined that Arabidopsis (Arabidopsis thaliana) SINE1 and SINE2 play an important role in stomatal opening and closing. Loss of SINE1 or SINE2 results in ABA hyposensitivity and impaired stomatal dynamics but does not affect stomatal closure induced by the bacterial elicitor flg22. The ABA-induced stomatal closure phenotype is, in part, attributed to impairments in Ca2+ and F-actin regulation. Together, the data suggest that SINE1 and SINE2 act downstream of ABA but upstream of Ca2+ and F-actin. While there is a large degree of functional overlap between the two proteins, there are also critical differences. Our study makes an unanticipated connection between stomatal regulation and nuclear envelope-associated proteins, and adds two new players to the increasingly complex system of guard cell regulation.
Multi-Organ NMR Metabolomics to Assess In Vivo Overall Metabolic Impact of Cisplatin in Mice

This work describes, to our knowledge, the first NMR metabolomics analysis of mice kidney, liver, and breast tissue in response to cisplatin exposure, in search of early metabolic signatures of cisplatin biotoxicity. Balb/c mice were exposed to a single 3.5 mg/kg dose of cisplatin and then euthanized; organs (kidney, liver, breast tissue) were collected at 1, 12, and 48 h. Polar tissue extracts were analyzed by NMR spectroscopy, and the resulting spectra were studied by multivariate and univariate analyses. The results enabled the identification of the most significant deviant metabolite levels at each time point, and for each tissue type, and showed that the largest metabolic impact occurs for kidney, as early as 1 h post-injection. Kidney tissue showed a marked depletion in several amino acids, comprised in an overall 13-metabolites signature. The highest number of changes in all tissues was noted at 12 h, although many of those recovered to control levels at 48 h, with the exception of some persistently deviant tissue-specific metabolites, thus enabling the identification of relatively longer-term effects of cDDP. This work reports, for the first time, early (1–48 h) concomitant effects of cDDP in kidney, liver, and breast tissue metabolism, thus contributing to the understanding of multi-organ cDDP biotoxicity.
Estimating the intervention effect in calibration substudies

Exposure assessment is often subject to measurement errors. We consider here the analysis of studies aimed at reducing exposure to potential health hazards, in which exposure is the outcome variable. In these studies, the intervention effect may be estimated using either biomarkers or self‐report data, but it is not common to combine these measures of exposure. Bias in the self‐reported measures of exposure is a well‐known fact; however, only few studies attempt to correct it. Recently, Keogh et al addressed this problem, presenting a model for measurement error in this setting and investigating how self‐report and biomarker data can be combined. Keogh et al find the maximum likelihood estimate for the intervention effect in their model via direct numerical maximization of the likelihood. Here, we exploit an alternative presentation of the model that leads us to a closed formula for the MLE and also for its variance, when the number of biomarker replicates is the same for all subjects in the substudy. The variance formula enables efficient design of such intervention studies. When the number of biomarker replicates is not constant, our approach can be used along with the EM‐algorithm to quickly compute the MLE. We compare the MLE to Buonaccorsi's method (Buonaccorsi, 1996) and find that they have similar efficiency when most subjects have biomarker data, but that the MLE has clear advantages when only a small fraction of subjects has biomarker data. This conclusion extends the findings of Keogh et al (2016) and has practical importance for efficiently designing studies.