Miracle-dz/UniFAR-FTUs huggingface dataset:
Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding

The inflammasome is a critical molecular complex that activates interleukin-1 driven inflammation in response to pathogen- and danger-associated signals. Germline mutations in the inflammasome sensor NLRP1 cause Mendelian systemic autoimmunity and skin cancer susceptibility, but its endogenous regulation remains less understood. Here we use a proteomics screen to uncover dipeptidyl dipeptidase DPP9 as a novel interacting partner with human NLRP1 and a related inflammasome regulator, CARD8. DPP9 functions as an endogenous inhibitor of NLRP1 inflammasome in diverse primary cell types from human and mice. DPP8/9 inhibition via small molecule drugs and CRISPR/Cas9-mediated genetic deletion specifically activate the human NLRP1 inflammasome, leading to ASC speck formation, pyroptotic cell death, and secretion of cleaved interleukin-1β. Mechanistically, DPP9 interacts with a unique autoproteolytic domain (Function to Find Domain (FIIND)) found in NLRP1 and CARD8. This scaffolding function of DPP9 and its catalytic activity act synergistically to maintain NLRP1 in its inactive state and repress downstream inflammasome activation. We further identified a single patient-derived germline missense mutation in the NLRP1 FIIND domain that abrogates DPP9 binding, leading to inflammasome hyperactivation seen in the Mendelian autoinflammatory disease Autoinflammation with Arthritis and Dyskeratosis. These results unite recent findings on the regulation of murine Nlrp1b by Dpp8/9 and uncover a new regulatory mechanism for the NLRP1 inflammasome in primary human cells. Our results further suggest that DPP9 could be a multifunctional inflammasome regulator involved in human autoinflammatory diseases.
Another longin SNARE for autophagosome-lysosome fusion—how does Ykt6 work?

ABSTRACT Formation of the autolysosome involves SNARE-mediated autophagosome-lysosome fusion, which is mediated by a combination of the Qa SNARE STX17 (syntaxin 17), the Qbc SNARE SNAP29 and the R-SNAREs VAMP7/8. 2 very recent reports have now implicated another R-SNARE with a longin domain, YKT6, in this fusion process. Interestingly, these reports painted two different pictures of YKT6’s involvement. Studies in HeLa cells indicated that YKT6, acting independently of STX17, could form a separate SNARE complex with SNAP29 and another Qa SNARE to mediate autophagosome-lysosome fusion. Conversely, work in Drosophila larvae fat cells showed that while Ykt6 could form a SNARE complex with Snap29 and Syx17/Stx17, it is readily outcompeted by lysosomal Vamp7 in this regard. Moreover, its activity in autophagosome-lysosome fusion is not impaired by mutation of the supposedly critical ionic zero-layer residue from R to Q. In this regard, YKT6 may therefore act in a noncanonical way to regulate fusion. Here, we ponder on the fresh mechanistic perspectives on the final membrane fusion step of macroautophagy/autophagy offered by these new findings. Further, we propose another possible mechanism as to how YKT6 might act, which may provide some reconciliation to the differences observed. Abbreviations: LD: longin domain
Noncoding miRNAs as key controllers of pancreatic β-cell functions

miRNAs, a recently discovered family of small noncoding RNAs, are emerging as major controllers of gene expression and key determinants of pancreatic β-cell function. These 19–22-nucleotide molecules govern gene expression by partially pairing to 3´-untranslated regions of target mRNAs and by inhibiting their translation. The elucidation of the role of miRNAs promises to unravel new aspects of β-cell biology and to clarify the mechanisms leading to defective insulin secretion in diabetes mellitus. This information is expected to favor the design of new approaches for preserving functional β-cells in prediabetic stages and the development of strategies for engineering insulin-secreting cells capable of replacing endogenous β-cells in diabetic patients.
Celecoxib Treatment Improves Neurologic Deficit and Reduces Selective Neuronal Loss and Glial Response in Rats after Transient Middle Cerebral Artery Occlusion

Areas of selective neuronal loss (SNL) represent the first morphologic signs of damage in the penumbra region and are considered putative targets for ischemic stroke therapy. We performed a novel assessment of measuring the effects of the anti-inflammatory agent celecoxib by analyzing simultaneously the different neural populations (neurons, astrocytes, and microglia cells) in SNL and non-SNL areas. Rats were subjected to 1 hour of middle cerebral artery occlusion (MCAO) and treated with celecoxib 1 and 24 hours after ischemia. Infarct volume measurements and triple immunostaining of neurons (neuronal nuclear antigen), microglia (ionized calcium-binding adaptor molecule 1), and astroglia were performed after 12 and 48 hours of reperfusion. Motor response was tested by standard behavioral assays at 3, 12, 24, and 48 hours. Confocal analysis revealed that the percentage of SNL areas, microglia densities, and glial activation increased at 48 hours of reperfusion. Celecoxib treatment improved the neurologic deficit, reduced the infarct volume by 50% after 48 hours of reperfusion, and resulted in a reduced percentage of SNL areas and microglia and astroglia reactivity after 48 hours of reperfusion. This study proves, for the first time, that celecoxib presents postischemic neuroprotective effects in a transient MCAO model, prevents or delays the presence of SNL areas, and reduces glial activation.
Health system measurement: Harnessing machine learning to advance global health

Background Further improvements in population health in low- and middle-income countries demand high-quality care to address an increasingly complex burden of disease. Health facility surveys provide an important but costly source of information on readiness to provide care. To improve the efficiency of health system measurement, we applied unsupervised machine learning methods to assess the performance of the service readiness index (SRI) defined by the World Health Organization and compared it to empirically derived indices. Methods We drew data from nationally representative Service Provision Assessment surveys conducted in 10 countries between 2007 and 2015. We extracted 649 items in domains such as infrastructure, medication, and management to calculate an index using all available information and classified facilities into quintiles. We compared three approaches against the full item set: the SRI, a new index based on sequential backward selection, and an enriched SRI that added empirically selected items to the SRI. We evaluated index performance with a cross-validated kappa statistic comparing classification using the candidate index against the 649-item index. Results 9238 facilities were assessed. The 49-item SRI performed poorly against the index using all 649 items, with a kappa value of 0.35. New empirically derived indices with 50 and 100 items captured much more information, with cross-validated kappa statistics of 0.71 and 0.80, respectively. Items varied across the indices and in sensitivity analyses. A 100-item enriched SRI reliably captured the information from the full index: 83% of the facilities were classified into correct quintiles of service readiness based on the full index. Conclusion A facility readiness measure developed by global health experts performed poorly in capturing the totality of readiness information collected during facility surveys. Using a machine learning approach with sequential selection and cross-validation to identify the most informative items dramatically improved performance. Such approaches can make assessment of health facility readiness more efficient. Further improvements in measurement will require identification of external criteria—such as patient outcomes—to guide and validate measure development.
RAB30 regulates PI4KB (phosphatidylinositol 4-kinase beta)-dependent autophagy against group A Streptococcus

ABSTRACT Macroautophagy/autophagy plays an important role in the immune response to invasion by intracellular pathogens such as group A Streptococcus (GAS; Streptococcus pyogenes). We previously identified RAB30, a Golgi-resident GTPase, as a novel anti-bacterial autophagic regulator in the formation of GAS-containing autophagosome-like vacuoles (GcAVs); however, the precise mechanism underlying this process remains elusive. Here, we elucidate a novel property of RAB30: the ability to recruit PI4KB (phosphatidylinositol 4-kinase beta) to the Golgi apparatus and GcAVs. We found that trans-Golgi network (TGN) vesicles were incorporated into GcAVs via RAB30 to promote GcAV formation. Moreover, depletion of phosphatidylinositol-4-phosphate (PtdIns4P), a phosphatidylinositol enriched in the TGN, by wortmannin and phenylarsine oxide, followed by subsequent repletion with exogenous PtdIns4P revealed that PtdIns4P is crucial for GcAV formation. Furthermore, we identify an interaction between RAB30 and PI4KB, in which the knockdown of RAB30 decreased the localization of PI4KB to the TGN and GcAVs. Finally, PI4KB knockout suppressed autophagy by inhibiting GcAV formation, resulting in the increased survival of GAS. Our results demonstrate a novel autophagosomal formation mechanism involving coordinative functions of RAB30 and PI4KB distinct from those utilized in canonical autophagy. Abbreviations: GAS: group A Streptococcus; GcAVs: GAS-containing autophagosome-like vacuoles; PI4KB: phosphatidylinositol 4-kinase beta; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns4P: phosphatidylinositol-4-phosphate; PtdIns5P: phosphatidylinositol-5-phosphate; SLO: streptolysin O; TGN: trans-Golgi network; TGOLN2: trans-golgi network protein 2; PH: plekstrin homology; OSBP: oxysterol binding protein
The impact of a rehabilitation and recovery service on patient groups residing in high support community residences

Abstract Objectives: To describe the characteristics of the patient groups with severe and enduring mental illness residing in high support community residences in Dublin North East Mental Health Service and the impact of a rehabilitation and recovery service on their outcomes since the instigation of that service. Method: Data was collected retrospectively on current and past residents from case notes and staff interviews. Data included demographics, psychiatric history and results of rehabilitation interventions. The results were compiled and analysed using descriptive statistics. Results: Fifty patients were identified. The majority were male (62%) with a diagnosis of paranoid schizophrenia (66%). The levels of co-morbid alcohol and drug misuse were 48% and 36% respectively. Histories of verbal/physical aggression were found in 70% and noncompliance in 60%. Two thirds of patients had a past history of being detained under the Mental Treatment Act (1945). Ninety-four per cent were unemployed at admission to the residence and following rehabilitation intervention 60% were linked with vocational training programmes and 10% with community employment schemes. ‘New long-stay’ and ‘old long-stay’ patients showed a trend towards poorer outcomes, whereas patients who had previously lived in the community showed a trend towards progressing to lower levels of support. Conclusions: Positive outcomes were achieved following active rehabilitation interventions, but there remained a cohort of patients whose needs could not be met in a supported community rehabilitation residential programme. This highlights the need to ensure that a range of rehabilitation services from inpatient to supported community placement are provided to meet the needs of patients with severe and enduring mental illness with complex needs.
PHPT Masquerading as Rickets in Children and Presenting with Rare Skeletal Manifestations: Report of Three Cases and Review of Literature

Primary hyperparathyroidism (PHPT) is an uncommon condition in children and adolescents. However, rapid growth spurt during puberty may result in unmasking and development of certain skeletal manifestations of PHPT. We present three cases of PHPT associated with rare skeletal manifestations of rickets. All three patients had radiological evidence of rickets with primary hyperparathyroidism. All the three patients had single gland adenoma. Literature is sparse regarding reversal of features of rickets following parathyroidectomy. In all three patients of our series, there was a complete resolution of bone/joint pain. However, in two children only the genu valgum persisted but their growth was normal and they had no proximal muscle weakness. In another child multiple corrective surgeries were done to correct the deformities.
Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide

Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14–15 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome‐wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late‐stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagy‐lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM.
PET/MRI in Breast Cancer

Positron emission tomography / magnetic resonance imaging (PET/MRI) is an emerging imaging technology that allows for the acquisition of multiple MRI parameters simultaneously with PET data. In this review, we address the technical requirements of PET/MRI including protocols and tracers, the potential of integrated localized breast PET/MRI exams, and possible applications of whole‐body PET/MRI in breast cancer patients. Currently, PET/MRI can be performed on sequential and integrated PET/MRI scanners but, as not all practices can access these dedicated machines, several studies look at PET and MRI exams that are performed separately on separate scanners within a short time frame. This practice likely provides similar clinical data, although exact colocalization for iso‐voxel analysis, currently performed only in research, is not possible. In PET/MRI, the MRI sequences are flexible and can be customized according to the aim of the exam. The most commonly used radiotracer is 18F‐FDG; however, tracers that image hypoxia and drug targets such as estrogen receptors and HER2 are in development and may increase the utility of PET/MRI. For dedicated breast PET/MRI, a potential advantage over standard breast MRI alone may be the complementary sensitivities of MRI for extent of disease within the breast and PET for axillary and internal mammary nodal metastases. Moreover, layers of multiparametric MRI and PET metrics derived from the index lesion are being investigated as predictors of response to neoadjuvant therapy. These data may eventually be able to be quantified and mined in a way that furthers radiomics and also precision medicine. Finally, in whole‐body imaging of breast cancer patients, single‐institution studies have found that PET/MRI detects more metastases than PET at about half the radiation dose, although a survival benefit has not been shown. For now, whole‐body PET/MRI in breast cancer patients may be most relevant for young patients who may undergo serial surveillance exams.
Porosity analysis of mineral trioxide aggregate Fillapex and BioRoot cements for use in endodontics using microcomputed tomography

Aim: The purpose of this study is to compare the porosity of two sealant cements, mineral trioxide aggregate (MTA) Fillapex® and BioRoot® root canal sealer (RCS). These samples were analyzed using microcomputed tomography. Materials and Methods: Sixteen samples were used in the study that were divided according to the composition of the materials used. MTA Fillapex® (n = 8) and BioRoot® RCS (n = 8) were the samples prepared according to the manufacturer's instructions. They were placed in silicone molds of 5 ± 0.1 mm in height and an internal diameter of 5 ± 0.1 mm; 24 h after its preparation, the samples were scanned through a microcomputed tomography, and the porosity results were analyzed statistically by independent t-tests. Results: It is evident that MTA Fillapex® has better porosity properties than BioRoot® RCS. The results of the study quantify a smaller number of pores per surface, a smaller volume in each pore per mm3, and a lower total porosity present in samples of MTA Fillapex® unlike BioRoot® RCS samples which is larger in both. Conclusions: The results obtained in computerized microtomography endodontic biomaterial samples concluded that MTA Fillapex® has a lower porosity than BioRoot® RCS.
A framework for multiscale bioengineering simulation

__________________________ *Corresponding Author : Janaina de Andréa Dernowsek Email Address: afalcao@ic.unicamp. br A framework for multiscale bioengineering simulation Janaina de Andréa Dernowsek, Pedro Yoshito Noritomi, Daniel Takanori Kemmoku, Maria Bolina Kersanach, Sirley Rocha Brandão, Henrique Idogava , Monize Caiado Decarli, Fabio Albuquerque Vilalba, Julia Adami Nogueira, Rodrigo Bonacin, Rodrigo Alvarenga Rezende, Jorge Vicente Lopes da Silva
Sonographic Measurement of Optic Nerve Sheath Diameter: How Steep is the Learning Curve for a Novice Operator?

Background: Transbulbar sonography for measuring optic nerve sheath diameter (ONSD) is noninvasive bedside technique for detection of raised intracranial pressure. This study aims to evaluate the number of sonographic evaluations required for a novice operator to learn proper measurement of ONSD after a formal training and supervised scanning session. Methods: Three novice operators and one expert operator measured ONSD of 27 healthy volunteers using linear array transducer HFL38x (frequency range of 6–13 MHz) (MicroMaxx®; SonoSite, USA). In each eye, ONSD was measured three times by each observer and mean value was determined. Correlation coefficient was calculated between the novice and the experienced operator and in between the novice operators. Number of scans, after which the significant correlation developed between novice and the experienced operator and between the novice operators, was analyzed. Results: Cronbach's alpha was tested to evaluate the reliability of the values obtained from intra- and interobservations. For all 27 cases, the value of Cronbach's alpha was high: 0.80–0.99 for the right eye and 0.69-0.97 for the left eye. The mean interobserver variations were plotted on a graph which fluctuated largely in the first 17 cases but oscillated around 0.5–0.30 in the last 10 cases. Conclusion: Learning curve for novice operators to measure ONSD is steep and they can be taught to measure ONSD in healthy volunteers by sonography in supervised clinical session with an acceptable clinical precision and accuracy comparable to an experienced operator.
Did you choose appropriate tracer for retrograde tracing of retinal ganglion cells? The differences between cholera toxin subunit B and Fluorogold

Cholera toxin subunit B (CTB) and Fluorogold(FG) are two widely utilized retrograde tracers to assess the number and function of retinal ganglion cells (RGCs). However, the relative advantages and disadvantages of these tracers remain unclear, which may lead to their inappropriate application. In this study, we compared these tracers by separately injecting the tracer into the superior Colliculi (SC) in rats, one or 2 weeks later, the rats were sacrificed, and their retinas, brains, and optic nerves were collected. From the first to second week, FG displayed a greater number of labeled RGCs and a larger diffusion area in the SC than CTB; The number of CTB labeled RGCs and the diffusion area of CTB in the SC increased significantly, but there was no distinction between FG; Furthermore, CTB exhibited more labeled RGC neurites and longer neurites than FG, but no difference was evident between the same trace; The optic nerves labeled using CTB were much clearer than those labeled using FG. In conclusion, both CTB and FG can be used for the retrograde labeling of RGCs in rats at 1 or 2 weeks. FG achieves retrograde labeling of a greater number of RGCs than CTB, whereas CTB better delineates the morphology of RGCs. Furthermore, CTB seems more suitable for retrograde labeling of some small, non-image forming nuclei in the brain to which certain RGC subtypes project their axons.
The efficacy of accommodative versus monofocal intraocular lenses for cataract patients

Introduction: We performed a systematic review and meta-analysis to evaluate whether accommodative intraocular lenses (AC-IOLs) are superior for cataract patients compared with monofocal IOLs (MF-IOLs). Methods: Pubmed, Embase, Cochrane library, CNKI, and Wanfang databases were searched through in August 2018 for AC-IOLs versus MF-IOLs in cataract patients. Studies were pooled under either fixed-effects model or random-effects model to calculate the relative risk (RR), weighted mean difference (WMD), or standard mean difference (SMD) and their corresponding 95% confidence interval (CI). Distance-corrected near visual acuity (DCNVA) was chosen as the primary outcome. The secondary outcomes were corrected distant visual acuity (CDVA), pilocarpine-induced IOL shift, contrast sensitivity, and spectacle independence. Results: Seventeen studies, involving a total of 1764 eyes, were included. Our results revealed that AC-IOLs improved DCNVA (SMD = −1.84, 95% CI = −2.56 to −1.11) and were associated with significantly greater anterior lens shift than MF-IOLs (WMD = −0.30, 95% CI = −0.37 to −0.23). Furthermore, spectacle independence was significantly better with AC-IOLs than with MF-IOLs (RR = 3.07, 95% CI = 1.06–8.89). However, there was no significant difference in CDVA and contrast sensitivity between the 2 groups. Conclusion: Our study confirmed that AC-IOLs can provide cataract patients with DCNVA and result in more high levels of spectacle independence than MF-IOLs. Further studies with larger data set and well-designed models are required to validate our findings.