Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeted Depletion of Primary Cilia in Dopaminoceptive Neurons in a Preclinical Mouse Model of Huntington’s Disease

Multiple pathomechanisms triggered by mutant Huntingtin (mHTT) underlie progressive degeneration of dopaminoceptive striatal neurons in Huntington’s disease (HD). The primary cilium is a membrane compartment that functions as a hub for various pathways that are dysregulated in HD, for example, dopamine (DA) receptor transmission and the mechanistic target of rapamycin (mTOR) pathway. The roles of primary cilia (PC) for the maintenance of striatal neurons and in HD progression remain unknown. Here, we investigated PC defects in vulnerable striatal neurons in a progressive model of HD, the mHTT-expressing knock-in zQ175 mice. We found that PC length is affected in striatal but not in cortical neurons, in association with the accumulation of mHTT. To explore the role of PC, we generated conditional mutant mice lacking IFT88, a component of the anterograde intraflagellar transport-B complex lacking PC in dopaminoceptive neurons. This mutation preserved the expression of the dopamine 1 receptor (D1R), and the survival of striatal neurons, but resulted in a mild increase of DA metabolites in the striatum, suggesting an imbalance of ciliary DA receptor transmission. Conditional loss of PC in zQ175 mice did not trigger astrogliosis, however, mTOR signaling was more active and resulted in a more pronounced accumulation of nuclear inclusions containing mHTT. Further studies will be required of aged mice to determine the role of aberrant ciliary function in more advanced stages of HD.
Rapid Return for School Refusal: A School-Based Approach Applied With Japanese Adolescents

Cognitive behavioral therapy (CBT) is often effective in the treatment of school refusal (SR). Its usefulness is limited, however, if youth displaying SR also refuse to attend treatment sessions. In these cases parents and school staff may consider using school-based interventions that do not rely on face-to-face assessment and treatment with the young person. The current study examined the effectiveness of a school-based intervention applied in Japan to achieve rapid return to school among adolescents displaying SR. Between 2009 and 2015, the parents of 62 adolescents displaying SR were invited to implement a school-based rapid return approach. Thirty-nine parents agreed to implement the approach and 23 decided to wait until their child spontaneously attended school. Of the 39 cases in which the approach was implemented, 28 adolescents (72%) resumed attendance at their original school, 2 (5%) transferred to another school, and 9 (23%) did not resume attendance. In contrast, all 23 non-intervention cases continued to refuse to attend school for 3 months or longer, and none of these adolescents returned to regular school attendance within 9 months. This study tentatively suggests that the rapid return approach may be an effective form of intervention for adolescents displaying SR and simultaneously refusing to attend individual therapy. Because this approach is ethically complex, involving forced school attendance in adolescence, it should only be employed under specific circumstances. These circumstances are discussed.
Time-Dependent Squamous Cell Carcinoma Antigen in Prediction of Relapse and Death of Patients With Cervical Cancer.

OBJECTIVE The aim of the study was to develop a methodology to identify the best use of a longitudinally measured biomarker in relevance to prognosis. MATERIALS AND METHODS Data of squamous cell carcinoma antigen (SCC-Ag) from 770 patients with cervical squamous cell carcinoma (SCC) were used. The pretreatment, nadir, and time-dependent SCC-Ag values were analyzed in relevance to disease relapse and death with univariate and multivariate analysis side by side with a variety of available clinicopathologic factors. The predictive power of the significant variates was evaluated by C-index with 5-fold cross validation. RESULTS The pretreatment, nadir, and time-dependent SCC-Ag were all significant risk factors for both relapse and death in the univariate analysis (p < .05), and the time-dependent SCC-Ag had the highest C-index in both events. The nadir and time-dependent SCC-Ag were both independently significant in response to relapse with International Federation of Gynecology and Obstetrics (FIGO) stage as the covariate, and the latter had a higher C-index (0.745). Only the time-dependent SCC-Ag was independently significant together with FIGO stage in response to death with the C-index at 0.844. CONCLUSIONS Increases in the serum level of SCC-Ag in cervical SCC patients suggest a higher risk of both relapse and death. The best use of serial SCC-Ag measurements is to include the time-dependent value in prognostic assessment with FIGO stage also accounted for. Cervical SCC patients should be followed up on their levels of SCC-Ag, and prognostic evaluation should be updated with recent measurements.
Enjeux liés aux ressources termino-ontologiques en santé. (Issues related to termino-ontological resources in health)

On recense un nombre important de ressources termino-ontologiques (RTOs ) en sante, qui sont non seulement volumineuses mais aussi de differents types (classifications, thesaurus, ontologies…). Ce manuscrit decrit les activites de recherche que j’ai menees depuis ma these pour repondre a certains enjeux lies a l’utilisation des RTOs en sante. Plus precisement, je me suis interessee aux trois problematiques suivantes : l’evaluation de la qualite des RTOs biomedicales, leur interoperabilite semantique et la conception de nouvelles RTOs. J’expose donc tout d’abord mes travaux sur l’evaluation de la qualite des RTOs. Les differentes evaluations que j’ai realisees portaient sur plusieurs criteres de qualite (coherence, concision…) pour verifier la coherence de RTOs ayant des caracteristiques differentes (langages de representation, types de RTO…). Je presente ensuite mes contributions quant a l’interoperabilite semantique entre RTOs. Je decris premierement des travaux qui visaient a aligner deux RTOs decrivant des connaissances similaires dans le contexte de la pharmacovigilance puis deux etudes dont l’objectif etait d’integrer des RTOs diagnostiques utilisees en cancerologie grâce a une RTO de support. Je detaille enfin mes contributions liees a la problematique de conception de RTOs au travers de deux approches : l’acquisition des connaissances a partir de textes lies a la maladie d’Alzheimer et l’integration de differentes RTOs decrivant de maniere parcellaire les connaissances concernant les interactions entre medicaments et aliments. Je termine par des travaux en cours sur la visualisation et l’integration de donnees omiques et cliniques avant d’introduire les perspectives que j’envisage d’explorer dans les annees a venir.
Are lizards sensitive to anomalous seasonal temperatures? Long-term thermobiological variability in a subtropical species

Alterations in thermal niches have been widely associated with the Anthropocene erosion of reptiles’ diversity. They entail potential physiological constraints for organisms’ performance, which can lead to activity restrictions and impact fitness and demography. Reptiles are ectotherms which rely on seasonal periodicity to maximize the performance of biological functions. Despite it, the ecological implications of shifts in local temperatures are barely explored at the seasonal scale. This study aims to assess how changes in air temperature and substrate temperature affect the activity, body temperature (Tb) and thermoregulation patterns of the sand lizard, Liolaemus arambarensis (an endangered, microendemic species from southern Brazil), throughout a four-year period. Field surveys were conducted monthly on a restricted population in a sand-dune habitat. The annual fluctuations of the seasonal temperatures led to significant changes in the activity and Tb of L. arambarensis and shaped thermoregulation trends, suggesting biological plasticity as a key factor in the face of such variability. Lizards tended to maintain seasonal Tb in mild and harsh seasons through increased warming/cooling efforts. Anomalous winter conditions seemed especially critical for individual performance due to their apparent high impact favouring/constraining activity. Activity and thermoregulation were inhibited in frigid winters, probably due to a vulnerable physiology to intense cold spells determined by higher preferred body temperatures than Tb. Our results warn of a complex sensitivity in lizards to anomalous seasonal temperatures, which are potentially enhanced by climate change. The current work highlights the importance of multiannual biomonitoring to disentangle long-term responses in the thermal biology of reptiles and, thereby, to integrate conservation needs in the scope of global change.
Naps reliably estimate nocturnal sleep spindle density in health and schizophrenia

Sleep spindles, defining oscillations of non‐rapid eye movement stage 2 sleep (N2), mediate memory consolidation. Spindle density (spindles/minute) is a stable, heritable feature of the sleep electroencephalogram. In schizophrenia, reduced spindle density correlates with impaired sleep‐dependent memory consolidation and is a promising treatment target. Measuring sleep spindles is also important for basic studies of memory. However, overnight sleep studies are expensive, time consuming and require considerable infrastructure. Here we investigated whether afternoon naps can reliably and accurately estimate nocturnal spindle density in health and schizophrenia. Fourteen schizophrenia patients and eight healthy controls had polysomnography during two overnights and three afternoon naps. Although spindle density was lower during naps than nights, the two measures were highly correlated. For both groups, naps and nights provided highly reliable estimates of spindle density. We conclude that naps provide an accurate, reliable and more scalable alternative to measuring spindle density overnight.
Non-Leishmania Parasite in Fatal Visceral Leishmaniasis–like Disease, Brazil

To the Editor: We read with interest the recent article describing involvement of Crithidia-related parasites in visceral leishmaniasis (VL) in Brazil (1). In 2010, we published a similar study about the identification of Leptomonas sp. , another monoxenous trypanosomatid, among clinical isolates from VL patients in India: of 120 cultured isolates, 111 were typed as L. donovani and 9 as Leptomonas sp. (2). As in the Brazil study, we infected BALB/c mice with 1 Leptomonas isolate; at 45 days postinfection, we found Leptomonas and Leishmania DNA by PCR in the animals’ spleens. Assuming that sterility was preserved during the experiment, we interpreted that original infection in patients resulted from a mixture of the 2 species, Leptomonas overgrew L. donovani in culture because of substantial growth advantage of the former, and a few remaining L. donovani cells in the culture spread in the animals after inoculation because of their higher in vivo fitness. We suspect a similar phenomenon could have occurred in Brazil, and additional analyses are required to support the authors’ conclusions. Given that mice were inoculated with clinical isolates, postanimal typing should have been done. Furthermore, linking genotyping information of cultivated (cloned) strains with a patient phenotype is risky because of the selection biases of in vitro isolation and maintenance. Using a recently developed method for direct sequencing of L. donovani complex parasites in host tissues, we demonstrated that genotypes of parasites in bone marrow samples differed from derived and cultivated isolates. This result most likely was due to polyclonal L. donovani infections and differences in fitness of different genotypes in vitro and in vivo. On the basis of this evidence, we recommend direct parasite sequencing in clinical samples in future work. If impossible, results based on cultured isolates should be interpreted with caution. We recommend a follow-up study to verify the possibility of Crithidia/Leishmania co-infection and the capacity of Crithidia to cause leishmaniasis-like disease as a single infection.
Parallel seed color adaptation during multiple domestication attempts of an ancient new world grain.

Thousands of plants have been selected as crops, yet, only a few are fully domesticated. The lack of adaptation to agro-ecological environments of many crop plants with few characteristic domestication traits potentially has genetic causes. Here, we investigate the incomplete domestication of an ancient grain from the Americas, amaranth. Although three grain amaranth species have been cultivated as crop for millennia, all three lack key domestication traits. We sequenced 121 crop and wild individuals to investigate the genomic signature of repeated incomplete adaptation. Our analysis shows that grain amaranth has been domesticated three times from a single wild ancestor. One trait that has been selected during domestication in all three grain species is the seed color, which changed from dark seeds to white seeds. We were able to map the genetic control of the seed color adaptation to two genomic regions on chromosome 3 and 9, employing three independent mapping populations. Within the locus on chromosome 9, we identify a MYB-like transcription factor gene, a known regulator for seed color variation in other plant species. We identify a soft selective sweep in this genomic region in one of the crops species but not in the other two species. The demographic analysis of wild and domesticated amaranths revealed a population bottleneck predating the domestication of grain amaranth. Our results indicate that a reduced level of ancestral genetic variation did not prevent the selection of traits with a simple genetic architecture but may have limited the adaptation of complex domestication traits.
Endometrioid Tubal Intraepithelial Neoplasia (E-TIN) of the Fallopian Tube: A Case Series

Although serous tubal intraepithelial carcinoma has been well described in the distal fallopian tube as precancers of pelvic high-grade serous carcinoma, endometrioid precancers have drawn less attention. Recently, endometrioid precursor lesions have been identified and reported to have a specific immunophenotype (PAX2−, ALDH1+, diffuse nuclear beta-catenin), as well as an association with both uterine and ovarian endometrioid carcinomas. These have been referred to as endometrioid (or type II) secretory cell outgrowths. A subset of endometrioid secretory cell outgrowths show architectural complexity resembling hyperplasia of the endometrium and have been referred to as endometrioid tubal intraepithelial neoplasia. We report 4 cases of endometrioid tubal intraepithelial neoplasia with clinical correlation and morphologic differential diagnosis.
Pharmacokinetics and Acute Toxicity of a Histone Deacetylase Inhibitor, Scriptaid, and Its Neuroprotective Effects in Mice After Intracranial Hemorrhage.

BACKGROUND & OBJECTIVE The pharmacokinetics and acute toxicity of a histone deacetylase inhibitor, Scriptaid, was unknown in mouse. The aim of this study was to determine the pharmacokinetics, acute toxicity, and tissue distribution of Scriptaid, a new histone deacetylase inhibitor, in mice, and its neuroprotective efficacy in a mouse intracranial hemorrhage (ICH) model. METHODS The pharmacokinetics, acute toxicity, and tissue distribution were determined in C57BL/6 male and female mice after the intraperitoneal administration of a single dose. Behavioral tests, as well as investigations of brain atrophy and white matter injury, were used to evaluate the neuroprotective effect of Scriptaid after ICH. Western blotting was used to investigate if Scriptaid could offer anti-inflammatory benefits after ICH. RESULTS No significant differences were observed in body weight or brain histopathology between the group that received Scriptaid at 50 mg/kg and the group that received dimethyl sulfoxide (control). The pharmacokinetics of Scriptaid in mice was nonlinear, and it was cleared rapidly at low doses and slowly at higher doses. Consistent with the pharmacokinetic data, Scriptaid was found to distribute in several tissues, including the spleen and kidneys. In the ICH model, we found that Scriptaid could reduce neurological deficits, brain atrophy, and white matter injury in a dose-dependent manner. Western blotting results demonstrated that Scriptaid could decrease the expression of pro-inflammatory cytokines IL1β and TNFα, as well as iNOS, after ICH. CONCLUSION These findings indicate that Scriptaid is safe and can alleviate brain injury after ICH, thereby providing a foundation for the pharmacological action of Scriptaid in the treatment of brain injury after ICH.
Good Manufacturing Practice Strategy for Antibody–Drug Conjugate Synthesis Using Site-Specific Chemical Conjugation: First-Generation AJICAP

The development of antibody–drug conjugates (ADCs) is in great demand in the oncology field. With the goal of maximizing the therapeutic index, the conjugation technology to produce ADCs has been shifted to a site-specific manner; however, it is still challenging to establish robust and scalable synthetic processes. We have developed a chemical conjugation platform termed AJICAP for site-specific ADC synthesis using IgG Fc-affinity peptides. Here, we report the preparation of site-specific ADCs based on first-generation AJICAP technology for use in good laboratory practice studies. Analysis of the final ADC product was conducted using validated systems and good manufacturing practice. This work may not only prompt further biological studies of AJICAP-ADC but also establish a strategy to provide well-documented manufacturing data to enable new drug application filings (e.g., investigational new drug applications) for site-specific ADCs.
Fingerprinting of anti-alpha enolase antibodies in systemic sclerosis.

OBJECTIVES Anti-alpha enolase antibodies have been detected in systemic sclerosis (SSc), but little is known on their fine specificity and their predictive value on single disease manifestations. The aim of this work is to perform an epitope mapping of alpha enolase by means of truncated recombinant proteins and to analyse the clinico-serological correlations of anti-alpha enolase antibodies in SSc patients. METHODS Thirty-eight SSc patients were recruited and fully clinically and serologically characterised. Plasmids encoding full length and truncated polypeptides of alpha enolase were generated; the polypeptides were purified under native conditions and used in dot blot to test sera from SSc patients and controls. The densitometric values obtained on all the polypeptides with anti-IgG subclass specific antibodies were analysed by cluster analysis and partial least square regression. RESULTS Anti-alpha enolase antibodies (mostly IgG1 and IgG2) are detected in 47% of SSc patients. IgG1 target the amino terminal region of alpha enolase, while IgG2 are more restricted to the central portion of the molecule. Anti-alpha enolase antibodies are not associated with disease-specific antibodies or with interstitial lung disease and do not identify patients affected by the limited vs. diffuse form. CONCLUSIONS Anti-alpha enolase antibodies are very frequent in SSc but are not associated with clinical or serological features of the disease. Further studies on larger cohorts of patients are necessary to define their possible contribution in defining specific subsets of the disease.
Initial validation of the electronic form of the Michigan Body Map

Background The Michigan Body Map (MBM) was developed to assess pain location in a reliable and valid manner; however, electronic formats have not been validated. This study had two aims: (1) initial validation of the electronic form of the MBM (eMBM) and (2) preliminary test of assessing pain severity within body zones. Methods For the first aim, 68 participants with chronic pain completed paper and electronic forms of the MBM, then underwent scripted interviews to assess preferences among body maps and verbal confirmation of pain locations. For the second aim, a subset of the participants (n=40) completed the Brief Pain Inventory (BPI) pain severity subscale, as well as the eMBM again and endorsed pain severity using additional screens showing body zones that contained areas in which pain was endorsed. Results There were few discrepancies between MBM, eMBM and verbal report (1.9% and 1.6%, respectively), and no difference between forms in perceived ability to indicate areas of pain or ease of completion. Patients accurately indicated their bodily pain on both maps, with 84% and 87% reporting one or no errors on MBM and eMBM, respectively. Participants also reported no preference for which version best-depicted areas of pain or best distinguished left from right. Lastly, the most preferred measure was eMBM with pain severity zones, followed by eMBM without zones, followed by the BPI pain severity subscale. Conclusions These data support the validity of the eMBM for patients with chronic pain. Further, an expanded form of the eMBM that assesses pain severity was preferred by most participants.
CGLFold: a contact-assisted de novo protein structure prediction using global exploration and loop perturbation sampling algorithm

MOTIVATION Regions that connect secondary structure elements in a protein are known as loops, whose slight change will produce dramatic effect on the entire topology. This study investigates whether the accuracy of protein structure prediction can be improved using a loop-specific sampling strategy. RESULTS A novel de novo protein structure prediction method that combines global exploration and loop perturbation is proposed in this study. In the global exploration phase, the fragment recombination and assembly are used to explore the massive conformational space and generate native-like topology. In the loop perturbation phase, a loop-specific local perturbation model is designed to improve the accuracy of the conformation and is solved by differential evolution algorithm. These two phases enable a cooperation between global exploration and local exploitation. The filtered contact information is used to construct the conformation selection model for guiding the sampling. The proposed CGLFold is tested on 145 benchmark proteins, 20 free modeling (FM) targets of CASP13, and 29 FM targets of CASP12. The experimental results show that the loop-specific local perturbation can increase the structure diversity and success rate of conformational update and gradually improve conformation accuracy. CGLFold obtains TM-score > 0.5 models on 95 standard test proteins, 11 FM targets of CASP13 and 9 FM targets of CASP12. AVAILABILITY The source code and executable versions are freely available at https://github.com/iobiozjut/CGLFold. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.