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Talaromyce marneffei is an important thermally dimorphic pathogen causing disseminated mycoses in immunocompromised individuals in southeast Asia. Previous studies have suggested that NLRP3 inflammasome plays a critical role in antifungal immunity. However, the mechanism underlying the role of NLRP3 inflammasome activation in host defense against T. marneffei remains unclear. We show that T. marneffei yeasts but not conidia induce potent IL-1β production. The IL-1β response to T. marneffei yeasts is differently regulated in different cell types; T. marneffei yeasts alone are able to induce IL-1β production in human PBMCs and monocytes, whereas LPS priming is essential for IL-1β response to yeasts. We also find that Dectin-1/Syk signaling pathway mediates pro-IL-1β production, and NLRP3-ASC-caspase-1 inflammasome is assembled to trigger the processing of pro-IL-1β into IL-1β. In vivo, mice deficient in NLRP3 or caspase-1 exhibit higher mortality rate and fungal load compared to wild-type mice after systemic T. marneffei infection, which correlates with the diminished recruitment of CD4 T cells into granulomas in knockout mice. Thus, our study first demonstrates that NLRP3 inflammasome contributes to host defense against T. marneffei infection.

Alström syndrome (AS) is a monogenic syndromic ciliopathy caused by mutations in the ALMS1 (Alström Syndrome 1) gene. A total of 21 subjects with AS from 20 unrelated Chinese families were recruited. Our cohort consists of 9 females and 12 males, between 5 months and 20 years old. The first symptom(s) appeared between 3 and 24 months. They were recorded to be either visual impairments (83%) or dilated cardiomyopathy (17%). Median time from symptom onset to seeking medical attention was 6 months (3–36 months) and the median time needed to reach the final molecular diagnosis is 54 months (6–240 months). System involvement at the time of the survey was as follows: visual symptoms (100%), hearing Impairment (67%), endocrine symptoms (43%), neurological symptoms (19%), hepatic symptoms (14%), and renal Involvement (14%). These findings are comparable to data reported in the literature. However, the proportion of subjects with cognitive impairment (33%) and behavioral problems (19%) were higher. Thirty‐three unique mutations were identified in the ALMS1 gene, of which 18 are novel mutations classified as pathogenic/likely pathogenic according to the American College of Medical Genetics (ACMG) guideline. Four recurrent mutations were identified in the cohort, in particular; c.2084C>A, p. (Ser695Ter), is suggestive to be a founder mutation in people of Chinese ancestry. The participation of AS subjects of differing ethnicities is essential to improve the algorithm in facial recognition/phenotyping, as well as to understand the mutation spectrum beyond than just those of European ancestry. [ABSTRACT FROM AUTHOR]

We present a comprehensive study of the structural and electronic properties of ultrathin films containing graphene layers synthesized by chemical vapor deposition based surface segregation on polycrystalline Ni foils then transferred onto insulating SiO2/Si substrates. Films of size up to several mm’s have been synthesized. Structural characterizations by atomic force microscopy, scanning tunneling microscopy, cross-sectional transmission electron microscopy (XTEM), and Raman spectroscopy confirm that such large-scale graphitic thin films (GTF) contain both thick graphite regions and thin regions of few-layer graphene. The films also contain many wrinkles, with sharply-bent tips and dislocations revealed by XTEM, yielding insights on the growth and buckling processes of the GTF. Measurements on mm-scale back-gated transistor devices fabricated from the transferred GTF show ambipolar field effect with resistance modulation ∼50% and carrier mobilities reaching ∼2000 cm2/V s. We also demonstrate quantum transport of carriers with phase coherence length over 0.2 μm from the observation of two-dimensional weak localization in low temperature magnetotransport measurements. Our results show that despite the nonuniformity and surface roughness, such large-scale, flexible thin films can have electronic properties promising for device applications. [ABSTRACT FROM AUTHOR]

Several studies are conducted to explain the synthesis and the structural and electronic properties of the various ultrathin graphitic thin films formed by the chemical vapor deposition method. The films are shown to exhibit excellent electronic properties and hence can be easily used for various device applications.

Summary: Objective: Early onset drug‐resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure‐free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug‐resistant epilepsy and evaluate whether the findings can provide information on patient management. Methods: We include patients with drug‐resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first‐tier analysis of the exome data, we aimed to identify disease‐causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome‐wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: We recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: SCN8A, SCN1A, MECP2, CDKL5, DEPDC5, and CHD2. The CDKL5 variant was found to be mosaic. One variant of unknown significance (VUS) in KCNT1 was found in a patient with compatible clinical features. Of note, a reported pathogenic SCN5A mutation known to contribute to Brugada syndrome, was also found in the patient with an SCN1A mutation. Significance: Our study suggests that singleton WES is an effective diagnostic tool for drug‐resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy. [ABSTRACT FROM AUTHOR]

Background: Rapid whole-exome sequencing (rWES) offers the potential for early diagnosis-predicated precision medicine. Previous evidence focused predominantly on infants from the intensive care unit (ICU). This study sought to examine the diagnostic and clinical utility, and the economic impact on clinical management of rWES in patients beyond infancy and ICU setting., Methods: rWES was performed on a prospective cohort of patients with suspected monogenic disorder referred from territory-wide paediatric ICUs and non-ICUs in Hong Kong urging for rapid genetic diagnosis. All eligible families were invited. We aimed to achieve a rapid turnaround time (TAT) of 14 days. Clinical utility and costs associated with clinical management were assessed in diagnosed cases. Actual quantitative changes in healthcare utilisation were compared with a counterfactual diagnostic trajectory and/or with matched historical control whenever possible., Findings: rWES were offered to 102 families and 32/102 (31%) patients received a molecular diagnosis, with a median TAT of 11 days. Clinical management changed in 28 of 32 diagnosed patients (88%), including but not limited to modifications in treatment, avoidance of surgeries, and informing decisions on redirection of care. Cost analysis was performed in eight patients. rWES was estimated to reduce hospital length of stay by 566 days and decrease healthcare costs by HKD$8,044,250 (GBP£796,460) for these eight patients. The net cost-savings after inclusion of rWES costs were estimated to be HKD$5,325,187 (GBP£527,246)., Interpretation: This study replicates the diagnostic capacity and rapid TAT of rWES in predominantly Chinese patients, and demonstrates diagnosis-predicated precision medicine and net healthcare savings. Findings were corroborated by evidence from multinational cohorts, combined as part of a meta-analysis. rWES merits consideration as a first-tier diagnostic tool for patients with urgent needs in the clinical setting., Funding: Health and Medical Research Fund, HKU Seed Fund for Basic Research, The Society for the Relief of Disabled Children, and Edward and Yolanda Wong Fund., Competing Interests: The authors declare that they have no competing interests., (© 2020 The Authors. Published by Elsevier Ltd.)

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)