Miracle-dz/UniFAR-FTUs huggingface dataset:
Interpreting Genetic Variants in Titin in Patients With Muscle Disorders

Importance Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Objective To identify genetic variants in titin in a cohort of patients with muscle disorders. Design, Setting, and Participants In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Main Outcomes and Measures The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. Results Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. Conclusions and Relevance The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.
Visual Complexity Accentuates Picture-Description Deficit in Amnesia

Objective: A recent study indicated that amnesic patients have difficulties not only in describing past and imagined scenarios, but also in describing pictures that are in full view. This finding suggests that impaired memory hampers descriptions of scenarios more broadly. However, no such impairment in picture description in amnesic patients was observed in a related study. One key methodological difference between these studies was the complexity of the pictures to be described, hinting that group differences might be marked only if pictures are sufficiently complex to tax aspects of memory. Method: To test this complexity hypothesis, we examined whether differences in picture description between amnesic patients and controls increase with increasing picture complexity. As in previous studies, we also assessed our participants’ ability to describe imagined scenarios. Results: Amnesic patients reported significantly fewer elements than did controls when describing pictures and imagined scenarios. The group difference in picture description was significantly larger for complex than for simple pictures. Conclusion: Although variations in lesion sites might have accounted for the aforementioned cross-study differences in picture description in amnesic patients, our results suggest that, at least in amnesic patients with extramedial temporal lobe lesions, the complexity of pictures can determine whether or not a (substantial) picture-description deficit is observed. We interpret these findings in terms of a narrative-construction deficit. We hypothesize that, whereas brief narrative can be constructed via nonmemory cognitive processes, the construction of more detailed narrative depends upon intact functioning of a temporary memory system, such as the episodic buffer.
Adult Age Differences in Eye Movements During Reading: The Evidence From Chinese

Abstract Objectives Substantial evidence indicates that older readers of alphabetic languages (e.g., English and German) compensate for age-related reading difficulty by employing a more risky reading strategy in which words are skipped more frequently. The effects of healthy aging on reading behavior for nonalphabetic languages, like Chinese, are largely unknown, although this would reveal the extent to which age-related changes in reading strategy are universal. Accordingly, the present research used measures of eye movements to investigate adult age differences in Chinese reading. Method The eye movements of young (18–30 years) and older (60+ years) Chinese readers were recorded. Results The older adults exhibited typical patterns of age-related reading difficulty. But rather than employing a more risky reading strategy compared with the younger readers, the older adults read more carefully by skipping words infrequently, making shorter forward eye movements, and fixating closer to the beginnings of two-character target words in sentences. Discussion In contrast with the findings for alphabetic languages, older Chinese readers appear to compensate for age-related reading difficulty by employing a more careful reading strategy. Age-related changes in reading strategy therefore appear to be language specific, rather than universal, and may reflect the specific visual and linguistic requirements of the writing system.
Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: Challenges and lessons of the VITAL trial

Invasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator.
Convergence across a continent: adaptive diversification in a recent radiation of Australian lizards

Recent radiations are important to evolutionary biologists, because they provide an opportunity to study the mechanisms that link micro- and macroevolution. The role of ecological speciation during adaptive radiation has been intensively studied, but radiations can arise from a diversity of evolutionary processes; in particular, on large continental landmasses where allopatric speciation might frequently precede ecological differentiation. It is therefore important to establish a phylogenetic and ecological framework for recent continental-scale radiations that are species-rich and ecologically diverse. Here, we use a genomic (approx. 1 200 loci, exon capture) approach to fit branch lengths on a summary-coalescent species tree and generate a time-calibrated phylogeny for a recent and ecologically diverse radiation of Australian scincid lizards; the genus Cryptoblepharus. We then combine the phylogeny with a comprehensive phenotypic dataset for over 800 individuals across the 26 species, and use comparative methods to test whether habitat specialization can explain current patterns of phenotypic variation in ecologically relevant traits. We find significant differences in morphology between species that occur in distinct environments and convergence in ecomorphology with repeated habitat shifts across the continent. These results suggest that isolated analogous habitats have provided parallel ecological opportunity and have repeatedly promoted adaptive diversification. By contrast, speciation processes within the same habitat have resulted in distinct lineages with relatively limited morphological variation. Overall, our study illustrates how alternative diversification processes might have jointly stimulated species proliferation across the continent and generated a remarkably diverse group of Australian lizards.
Characteristics of Good's Syndrome in China: A Systematic Review

Background: Good's syndrome (GS) is a rare disease characterized by thymoma, hypogammaglobulinemia, low or absent B-cells, decreased T-cells, an inverted CD4+/CD8+ T-cell ratio and reduced T-cell mitogen proliferative responses. GS is difficult to diagnose preoperatively due to its rarity and lack of typical symptoms, the characteristics of Chinese GS patients are still lacking. This study aimed to systematically review all the clinical, laboratory, and immunologic findings of reported cases of Chinese patients with GS. Methods: We searched for case reports and articles up to January 2017 using PubMed, China National Knowledge Infrastructure, Wangfang database and China Science and Technology Journal Database with the following words in combinations as key words: “thymoma,” “hypogammaglobulinemia,” and “Good's syndrome. ” The text words and MeSH terms were entered depending on the databases characteristics. The reference lists from retrieved articles were also screened for additional applicable studies. The authors were restricted to Chinese. There was no language restriction. Results: Forty-seven patients were reported in 27 studies. We found that GS has a nationwide distribution and that most cases (83%) have been described on the mainland of China. The initial clinical presentation is varied, ranging from symptoms related to the thymoma to infections resulting from immunodeficiency. Type AB (50%) is the most common histologic type of thymomas in Chinese GS patients according to the World Health Organization classification of thymomas. With respect to infection, sinopulmonary infection (74%) is the most common type, followed by skin infection (10%) and intestinal tract infection (10%). Diarrhea was presented in 36% of patients, and autoimmune manifestations were presented in 36% of patients. Conclusions: GS is a rare association of thymoma and immunodeficiency with a poor prognosis. Astute clinical acumen and increased awareness of the clinical and immunological profile of GS are needed to increase early diagnosis, that would benefit improved therapeutic effects.
Let‐7c restores radiosensitivity and chemosensitivity and impairs stemness in oral cancer cells through inhibiting interleukin‐8

BACKGROUND The let-7 family of microRNAs has been considered as tumor suppressors in various cancers; however, the role of let-7c in oral squamous cell carcinoma has not been determined yet. METHODS In this study, phenotypical behaviors and the radio/chemoresistance were examined subsequent to overexpression of let-7c. In addition, the expression of let-7c in cancer stem cells (CSCs) was evaluated and the effect of let-7c on stemness characteristics was assessed. Also, luciferase activity assays were performed to test whether interleukin (IL)-8 was a putative target of let-7c. RESULTS Our results confirmed that the expression of let-7c in CSCs was reduced, while overexpression of let-7c attenuated the oncogenicity. Moreover, ectopic expression of let-7c in CSCs downregulated the stemness hallmarks and the radio/chemoresistance. Expression and secretion of IL-8 in oral CSCs were both reduced following overexpression of let-7c. Besides, the inhibitory effect of let-7c on various stemness phenotypes was reverted by IL-8, indicating that lower expression of let-7c may confer higher cancer stemness through a failure to downregulate IL-8. CONCLUSION These findings revealed the significance of let-7c in the contribution of oral cancer stemness and radio/chemoresistance. Targeting let-7c and its downstream IL-8 may be beneficial to prevent cancer recurrence and metastasis of oral squamous cell carcinoma.
Behavioral-Social Adjustment of Adolescents with Craniofacial Microsomia

Objective: The objective was to assess differences in psychosocial adjustment between adolescents with and without craniofacial microsomia (CFM). Design: This is a case-control follow-up study in adolescents with and without CFM. Setting: Participants were originally recruited as infants from 26 cities across the United States and Canada. Participants: Participants included 142 adolescents with CFM (cases) and 316 peers without CFM (controls), their caregivers, and their teachers. Main Outcome Measures: Social and behavior measures from the Achenbach System of Empirically Based Assessments (ASEBA), the PedsQL: Core Version, and the Children’s Communication Checklist–2nd edition (CCC-2) were used. Linear regression was used to estimate case-control differences and corresponding standardized effect sizes (ES) and 95% confidence intervals after adjustment for sociodemographic confounds. We also examined case-control differences by facial phenotype and hearing status. Results: The magnitude and direction of case-control differences varied across assessment and respondent, but were generally modest (ES = –0.4 to 0.02, P values ranged from .003 to .85). There was little evidence for variation in case-control differences across different facial phenotypes or as a function of hearing status. Conclusions: Our results suggest that in spite of multiple risk factors, adolescents with CFM exhibit behavior problems no more frequently than their peers without CFM. Future studies of individuals with CFM should focus on resilience and social coping mechanisms, in addition to maladjustment.
Rapamycin treatment dose‐dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC1 and cell‐cycle‐associated CDK1/cyclin axis

Although translational research into autosomal dominant polycystic kidney disease (ADPKD) and its pathogenesis has made considerable progress, there is presently lack of standardized animal model for preclinical trials. In this study, we developed an orthologous mouse model of human ADPKD by cross‐mating Pkd2 conditional‐knockout mice (Pkd2f3) to Cre transgenic mice in which Cre is driven by a spectrum of kidney‐related promoters. By systematically characterizing the mouse model, we found that Pkd2f3/f3 mice with a Cre transgene driven by the mouse villin‐1 promoter (Vil‐Cre;Pkd2f3/f3) develop overt cysts in the kidney, liver and pancreas and die of end‐stage renal disease (ESRD) at 4–6 months of age. To determine whether these Vil‐Cre;Pkd2f3/f3 mice were suitable for preclinical trials, we treated the mice with the high‐dose mammalian target of rapamycin (mTOR) inhibitor rapamycin. High‐dose rapamycin significantly increased the lifespan, lowered the cystic index and kidney/body weight ratio and improved renal function in Vil‐Cre;Pkd2f3/f3 mice in a time‐ and dose‐dependent manner. In addition, we further found that rapamycin arrested aberrant epithelial‐cell proliferation in the ADPKD kidney by down‐regulating the cell‐cycle‐associated cyclin‐dependent kinase 1 (CDK1) and cyclins, namely cyclin A, cyclin B, cyclin D1 and cyclin E, demonstrating a direct link between mTOR signalling changes and the polycystin‐2 dysfunction in cystogenesis. Our newly developed ADPKD model provides a practical platform for translating in vivo preclinical results into ADPKD therapies. The newly defined molecular mechanism by which rapamycin suppresses proliferation via inhibiting abnormally elevated CDK1 and cyclins offers clues to new molecular targets for ADPKD treatment.
Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation

Significance After opening in response to a specific stimulus, some potassium channels undergo C-type inactivation. Crystal structures of KcsA have revealed that the selectivity filter constricts under conditions associated with C-type inactivation. Functional studies based on semisynthetic KcsA channels with either D-ala77 or amide-to-ester backbone substitutions provide important observations arguing against the constricted conformation of the selectivity filter as the molecular basis of C-type inactivation. In this study, molecular dynamics simulations based on atomic models of the KcsA channel are performed to clarify the impact of these chemical modifications on the conformation of the selectivity filter. The results support the notion that the constricted conformation of the selectivity filter, indeed, corresponds to the functional C-type inactivated state of the KcsA channel. In many K+ channels, prolonged activating stimuli lead to a time-dependent reduction in ion conduction, a phenomenon known as C-type inactivation. X-ray structures of the KcsA channel suggest that this inactivated state corresponds to a “constricted” conformation of the selectivity filter. However, the functional significance of the constricted conformation has become a matter of debate. Functional and structural studies based on chemically modified semisynthetic KcsA channels along the selectivity filter led to the conclusion that the constricted conformation does not correspond to the C-type inactivated state. The main results supporting this view include the observation that C-type inactivation is not suppressed by a substitution of D-alanine at Gly77, even though this modification is believed to lock the selectivity filter into its conductive conformation, whereas it is suppressed following amide-to-ester backbone substitutions at Gly77 and Tyr78, even though these structure-conserving modifications are not believed to prevent the selectivity filter from adopting the constricted conformation. However, several untested assumptions about the structural and functional impact of these chemical modifications underlie these arguments. To make progress, molecular dynamics simulations based on atomic models of the KcsA channel were performed. The computational results support the notion that the constricted conformation of the selectivity filter corresponds to the functional C-type inactivated state of the KcsA. Importantly, MD simulations reveal that the semisynthetic KcsAD-ala77 channel can adopt an asymmetrical constricted-like nonconductive conformation and that the amide-to-ester backbone substitutions at Gly77 and Tyr78 perturb the hydrogen bonding involving the buried water molecules stabilizing the constricted conformation.
Light pollution is associated with earlier tree budburst across the United Kingdom

The ecological impact of night-time lighting is of concern because of its well-demonstrated effects on animal behaviour. However, the potential of light pollution to change plant phenology and its corresponding knock-on effects on associated herbivores are less clear. Here, we test if artificial lighting can advance the timing of budburst in trees. We took a UK-wide 13 year dataset of spatially referenced budburst data from four deciduous tree species and matched it with both satellite imagery of night-time lighting and average spring temperature. We find that budburst occurs up to 7.5 days earlier in brighter areas, with the relationship being more pronounced for later-budding species. Excluding large urban areas from the analysis showed an even more pronounced advance of budburst, confirming that the urban ‘heat-island’ effect is not the sole cause of earlier urban budburst. Similarly, the advance in budburst across all sites is too large to be explained by increases in temperature alone. This dramatic advance of budburst illustrates the need for further experimental investigation into the impact of artificial night-time lighting on plant phenology and subsequent species interactions. As light pollution is a growing global phenomenon, the findings of this study are likely to be applicable to a wide range of species interactions across the world.
Insight into plant cell wall chemistry and structure by combination of multiphoton microscopy with Raman imaging

Spontaneous Raman scattering microspectroscopy, second harmonic generation (SHG) and 2‐photon excited fluorescence (2PF) were used in combination to characterize the morphology together with the chemical composition of the cell wall in native plant tissues. As the data obtained with unstained sections of Sorghum bicolor root and leaf tissues illustrate, nonresonant as well as pre‐resonant Raman microscopy in combination with hyperspectral analysis reveals details about the distribution and composition of the major cell wall constituents. Multivariate analysis of the Raman data allows separation of different tissue regions, specifically the endodermis, xylem and lumen. The orientation of cellulose microfibrils is obtained from polarization‐resolved SHG signals. Furthermore, 2‐photon autofluorescence images can be used to image lignification. The combined compositional, morphological and orientational information in the proposed coupling of SHG, Raman imaging and 2PF presents an extension of existing vibrational microspectroscopic imaging and multiphoton microscopic approaches not only for plant tissues.
T1N0 oesophageal cancer: patterns of care and outcomes over 25 years†

OBJECTIVES Historically, surgical resection has been the mainstay of treatment for T1N0 oesophageal cancer (OC). More recently, oesophageal sparing endoscopic techniques have shown value for local control in a large institutional series. However, the effect of their utilization upon survival rates in large population series is largely unknown. METHODS The surveillance, epidemiology, and end results (SEER) database was queried for T1N0M0-OC patients (1988-2013). Patients with multiple treatment types were excluded. Time periods were divided by 5-year increments. Overall survival and cancer-specific survival (CSS) were compared in the group as a whole and in propensity-matched subgroups. Independent predictors of cancer-specific mortality were studied by the Cox proportional hazard models. RESULTS We identified 5497 patients with cT1N0M0 OC. Treatment modalities used were changed significantly over time. The ratio of oesophagectomy when compared with local therapy decreased from 15:1 in 1998-92 to 1.4:1 in 2008-13. The proportion of patients treated with radiation slightly increased (35% vs 41%) between 1988-92 and 2008-13. In the propensity-matched groups, 5-year CSS was similar in patients treated with oesophagectomy and local therapy (81% vs 89%; P = 0.257) (n = 216 in each group), whereas oesophagectomy had superior 5-year CSS compared with radiation alone (73% vs 38%; P < 0.001) (n = 497 in each group). In multivariable analysis, significant predictors of cancer-specific mortality included age [hazard ratio (HR) 1.022], tumour size (HR 1.005), radiation therapy (HR 3.67), tumour Grade III/IV (HR 1.25) and early time period of diagnosis (HR 1.75). CONCLUSIONS Oesophageal sparing endoscopic techniques have been increasingly utilized in the treatment of cT1N0-OC but without compromising CSS. Local therapy, either endoscopic techniques or surgery, remains superior to radiation therapy.