Miracle-dz/UniFAR-FTUs huggingface dataset:
Amyloidogenic cross-seeding of Tau protein: Transient emergence of structural variants of fibrils

Amyloid aggregates of Tau protein have been implicated in etiology of many neurodegenerative disorders including Alzheimer's disease (AD). When amyloid growth is induced by seeding with preformed fibrils assembled from the same protein, structural characteristics of the seed are usually imprinted in daughter generations of fibrils. This so-called conformational memory effect may be compromised when the seeding involves proteins with non-identical sequences leading to the emergence of distinct structural variants of fibrils (amyloid ‘strains’). Here, we investigate cross-seeding of full-length human Tau (FL Tau) with fibrils assembled from K18 and K18ΔK280 fragments of Tau in the presence of poly-L-glutamate (poly-Glu) as an enhancer of Tau aggregation. To study cross-seeding between Tau polypeptides and the role of the conformational memory effect in induction of Tau amyloid polymorphism, kinetic assays, transmission electron microscopy, infrared spectroscopy and limited proteolysis have been employed. The fastest fibrillization was observed for FL Tau monomers seeded with preformed K18 amyloid yielding daughter fibrils with unique trypsin digestion patterns. Morphological features of daughter FL Tau fibrils induced by K18 and K18ΔK280 seeds were reminiscent of the mother fibrils (i.e. straight paired fibrils and paired helical filaments (PHFs), respectively) but disappeared in the following generations which became similar to unpaired FL Tau amyloid fibrils formed de novo. The structural evolution observed in our study was accompanied by disappearance of the unique proteolysis profile originated from K18. Our findings may have implications for understanding molecular mechanisms of the emergence and stability of Tau amyloid strains.
microRNA Profiling in Glaucoma Eyes With Varying Degrees of Optic Neuropathy by Using Next-Generation Sequencing.

Purpose To explore the microRNA (miRNA) profile and its putative role in glaucomatous optic neuropathy by using next-generation sequencing. Methods Aqueous humor (AH) samples were collected from 19 primary open-angle glaucoma (POAG) eyes and 17 cataract eyes before surgery. Next-generation sequencing was performed for RNA samples extracted from 18 AH samples, and the bioinformatics approach was applied for samples with adequate clean data output. The other 18 samples were used for quantitative PCR validation of sequencing results. Results In total, 12 (six POAG and six cataract controls) samples with sufficient clean data output after sequencing were used for further data analysis. Four hundred sixty-six and 480 mature miRNAs were detected in the POAG and cataract control groups, respectively. Among them, 164 miRNAs were detected in all POAG samples, and 96 miRNAs were detected in all cataract control samples. Furthermore, 88 miRNAs were identified as differently expressed between POAG and cataract control eyes. In addition, 16 miRNAs were differently expressed between POAG eyes with severe visual field damage and eyes with moderate visual field damage. This differential expression was predicted to regulate thiamine metabolism, purine metabolism, and transcriptional misregulation. Relative expression patterns of hsa-miR-184, hsa-miR-486-5p, and hsa-miR-93-5p were confirmed by quantitative PCR. Conclusions This study comprehensively demonstrated the miRNA expression profile in the AH of POAG eyes, especially the differential expression of miRNA in eyes with varying degrees of visual field damage, which, together with the underlying miRNA-related pathways, indicate new targets for the pathogenesis and progression of POAG.
The Indirect Effect of Posttraumatic Stress Disorder Symptoms on Current Alcohol Use Through Negative Cognitions in Sexual Minority Men.

Self-medication theory posits that some trauma survivors use alcohol to cope with posttraumatic stress disorder (PTSD) symptoms, but the role of negative posttraumatic cognitions in this relationship is not well defined. We examined associations among PTSD symptoms, posttraumatic cognitions, and alcohol intoxication frequency in 290 men who have sex with men (MSM), who reported a history of childhood sexual abuse (CSA). Using a bootstrap approach, we examined the indirect effects of PTSD symptoms on alcohol intoxication frequency through posttraumatic cognitions regarding the self, world, and self-blame. In separate regression models, higher levels of PTSD symptoms and posttraumatic cognitions were each associated with more frequent intoxication, accounting for 2.6% and 5.2% of the variance above demographics, respectively. When examined simultaneously, posttraumatic cognitions remained significantly correlated with intoxication frequency whereas PTSD symptoms did not. Men reporting elevated posttraumatic cognitions faced increased odds for current alcohol dependence, odds ratio (OR) = 2.19, 95% CI [1.13, 4.22], compared with men reporting low posttraumatic cognitions, independent of current PTSD diagnosis. A higher level of PTSD symptom severity was indirectly associated with more frequent alcohol intoxication through cognitions about the self and world; the indirect to total effect ratios were 0.74 and 0.35, respectively. Negative posttraumatic cognitions pertaining to individuals' self-perceptions and appraisals of the world as dangerous may play a role in self-medication with alcohol among MSM with a history of CSA. Interventions targeting these cognitions may offer potential for reducing alcohol misuse in this population, with possible broader implications for HIV-infection risk.
Genomic Prediction Using Prior Quantitative Trait Loci Information Reveals a Large Reservoir of Underutilised Blackleg Resistance in Diverse Canola (Brassica napus L.) Lines

Genomic prediction accuracy was moderate to high for blackleg resistance within and low across locations indicating substantial genotype‐by‐environment effects. Known blackleg resistance quantitative trait loci (QTL) regions explained at most 30% of the genetic variance for survival rate and internal infection. Incorporating known QTL regions in the genomic prediction method BayesRC increased prediction accuracy for the traits survival and internal infection. Strict prediction from Winter into Spring lines (and vice versa) had limited prediction accuracy, and combining both sets in one reference population was beneficial only if reference population size was low. Selection for improved blackleg resistance based on genomic breeding values is now feasible and will capture a greater proportion of the genetic variance than marker‐assisted selection on known QTL alone.
Deflazacort versus prednisone/prednisolone for maintaining motor function and delaying loss of ambulation: A post HOC analysis from the ACT DMD trial

Introduction: ACT DMD was a 48‐week trial of ataluren for nonsense mutation Duchenne muscular dystrophy (nmDMD). Patients received corticosteroids for ≥6 months at entry and stable regimens throughout study. This post hoc analysis compares efficacy and safety for deflazacort and prednisone/prednisolone in the placebo arm. Methods: Patients received deflazacort (n = 53) or prednisone/prednisolone (n = 61). Endpoints included change from baseline in 6‐minute walk distance (6MWD), timed function tests, estimated age at loss of ambulation (extrapolated from 6MWD). Results: Mean changes in 6MWD were ‐39.0 m (deflazacort; 95% confidence limit [CL], ‐68.85, ‐9.17) and ‐70.6 m (prednisone/prednisolone; 95% CL, ‐97.16, ‐44.02). Mean changes in 4‐stair climb were 3.79 s (deflazacort; 95% CL, 1.54, 6.03) and 6.67 s (prednisone/prednisolone; 95% CL, 4.69, 8.64). Conclusions: This analysis, limited by its post hoc nature, suggests greater preservation of 6MWD and 4‐stair climb with deflazacort vs. prednisone/prednisolone. A head‐to‐head comparison will better define these differences. Muscle Nerve 58: 639–645, 2018
Gene Birth Contributes to Structural Disorder Encoded by Overlapping Genes

The same nucleotide sequence can encode multiple protein products in different reading frames, and these regions encode higher levels of intrinsic structural disorder than non-overlapping genes. Willis and Masel find that. The same nucleotide sequence can encode two protein products in different reading frames. Overlapping gene regions encode higher levels of intrinsic structural disorder (ISD) than nonoverlapping genes (39% vs. 25% in our viral dataset). This might be because of the intrinsic properties of the genetic code, because one member per pair was recently born de novo in a process that favors high ISD, or because high ISD relieves increased evolutionary constraint imposed by dual-coding. Here, we quantify the relative contributions of these three alternative hypotheses. We estimate that the recency of de novo gene birth explains 32% or more of the elevation in ISD in overlapping regions of viral genes. While the two reading frames within a same-strand overlapping gene pair have markedly different ISD tendencies that must be controlled for, their effects cancel out to make no net contribution to ISD. The remaining elevation of ISD in the older members of overlapping gene pairs, presumed due to the need to alleviate evolutionary constraint, was already present prior to the origin of the overlap. Same-strand overlapping gene birth events can occur in two different frames, favoring high ISD either in the ancestral gene or in the novel gene; surprisingly, most de novo gene birth events contained completely within the body of an ancestral gene favor high ISD in the ancestral gene (23 phylogenetically independent events vs. 1). This can be explained by mutation bias favoring the frame with more start codons and fewer stop codons.
Syndemics and HIV-related sexual risk among men who have sex with men in India: influences of stigma and resilience

Abstract Using syndemics theory as a framework, we explored the experience of men who have sex with men in India in relation to four syndemic conditions (depression, alcohol use, internalised homonegativity and violence victimisation) and to understand their resilience resources. Five focus groups were conducted among a purposive sample of diverse men along with seven key informant interviews with HIV service providers. Participants’ narratives suggested various pathways by which syndemic conditions interact with one another to sequentially or concurrently increase HIV risk. Experiences of discrimination and violence from a range of perpetrators (family, ruffians and police) contributed to internalised homonegativity and/or depression, which in turn led some men to use alcohol as a coping strategy. Stigma related to same-sex sexuality, gender non-conformity and sex work contributed to the production of one or more syndemic conditions. While rejection by family and male regular partners contributed to depression/alcohol use, support from family, regular partners and peers served as resources of resilience. In India, HIV prevention and health promotion efforts among men who have sex with men could be strengthened by multi-level multi-component interventions to reduce intersectional/intersecting stigma, address syndemic conditions and foster resilience – especially by promoting family acceptance and peer support.
Sinomenine attenuates cancer-induced bone pain via suppressing microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades in rat models

Cancer-induced bone pain is one of the most severe types of pathological pain, which often occurs in patients with advanced prostate, breast, and lung cancer. It is of great significance to improve the therapies of cancer-induced bone pain due to the opioids’ side effects including addiction, sedation, pruritus, and vomiting. Sinomenine, a traditional Chinese medicine, showed obvious analgesic effects on a rat model of chronic inflammatory pain, but has never been proven to treat cancer-induced bone pain. In the present study, we investigated the analgesic effect of sinomenine after tumor cell implantation and specific cellular mechanisms in cancer-induced bone pain. Our results indicated that single administration of sinomenine significantly and dose-dependently alleviated mechanical allodynia in rats with cancer-induced bone pain and the effect lasted for 4 h. After tumor cell implantation, the protein levels of phosphorylated-Janus family tyrosine kinase 2 (p-JAK2), phosphorylated-signal transducers and activators of transcription 3 (p-STAT3), phosphorylated-Ca2+/calmodulin-dependent protein kinase II (p-CAMKII), and phosphorylated-cyclic adenosine monophosphate response element-binding protein (p-CREB) were persistently up-regulated in the spinal cord horn. Chronic intraperitoneal treatment with sinomenine markedly suppressed the activation of microglia and effectively inhibited the expression of JAK2/STAT3 and CAMKII/CREB signaling pathways. We are the first to reveal that up-regulation of microglial JAK2/STAT3 pathway are involved in the development and maintenance of cancer-induced bone pain. Moreover, our investigation provides the first evidence that sinomenine alleviates cancer-induced bone pain by inhibiting microglial JAK2/STAT3 and neuronal CAMKII/CREB cascades.
The Efficacy and Toxicity of Lobaplatin-contained Chemotherapy in Extensive-stage Small-cell Lung Cancer

To assess the efficacy and toxicity of Lobaplatin (LBP) -contained chemotherapy on extensive stage small-cell lung cancer (ES-SCLC), we conducted a prospective, single-arm, and multicenter Phase IV clinical trial on Lobaplatin (ChiCTR-ONC-13003471), and used the patient clinical data obtained from our cancer center to perform the analysis. Previously untreated patients with ES-SCLC were given LBP intravenously (IV) at 30 mg/m2 on day 1 and etoposide IV at 100 mg/m2 on day 1, 2, and 3. The treatment was cycled every 21 days, lasting for four to six cycles. The patients with second-line treatment or above were also included in the study, and they were treated with LBP-contained regimen: a single dose of LBP at 50 mg/m2 on day 1 through IV; combined application, LBP30 mg/m2 IV on day 1. From May 2015 to August 2016, 36 patients were enrolled in the study at our cancer center. For the 30 first-line patients, the median overall survival (OS) and the median progression-free survival (PFS) was 13.0 months (ranging from 11.2 to 14.7 months) and 4.7 months (ranging from 1.6 to 7.7 months) respectively, with overall response rate of 57 % and disease control rate of 85.7%. For the 6 patients with second-line treatment or above, one patient got a partial response (PR) and four patients got a stable disease (SD). The most frequent drug-related adverse effects were leukopenia and neutropenia, and no grade 3/4 hepatotoxicity or nephrotoxicity was observed. These results indicated that LBP-contained chemotherapy was effective and tolerable for extensive stage SCLC in terms of response and survival. However, due to the small sample size of this study, we need to wait for the OS data of phase Ⅲ clinical trial and the final data of this multicenter Phase IV study to draw the conclusion.
Pancreatic Pseudocysts and Parenchymal Necrosis in Patients With Autoimmune Pancreatitis: A Systematic Review

Objective To investigate the prevalence and natural history of pancreatic pseudocysts (PCs) and parenchymal necrosis in autoimmune pancreatitis (AIP). Method A search using PubMed, Embase, Scopus, and Cochrane was performed. Search terms were AIP, PC, acute fluid collection, and pancreatic necrosis. Results Fifteen studies with 17 patients were included. In 8 of 17 patients, PC was noted concurrently with the AIP diagnosis, whereas in the other half, PC appeared months or years after. In 10 of 17 cases, PC appeared as solitary. The location was variable. Pseudocysts were small (<3 cm) in 4 cases and large (>3 cm) in 13 cases. A normal pancreatic duct was observed in 6 of 17 cases, whereas 9 of 17 had pancreatic duct stenosis. Steroids were given to 4 of 4 small and 10 of 13 large PC. All small PC resolved with steroids, whereas only 4 of 10 large PC treated had some response. Most (9/13) of large PC underwent endoscopic or surgical procedures. None of the 17 cases developed necrosis. Conclusions Pseudocysts in AIP are rare. Pancreatic pseudocyst can present in variable number, size, and location. Small PC resolved with steroids. Large PC had poor response to steroids requiring invasive interventions. Necrosis in AIP has not been reported.
Typicality-based semantic treatment for anomia results in multiple levels of generalisation

ABSTRACT This study investigated the effects of typicality-based semantic feature analysis (SFA) treatment on generalisation across three levels: untrained related items, semantic/phonological processing tasks, and measures of global language function. Using a single-subject design with group-level analyses, 27 persons with aphasia (PWA) received typicality-based SFA to improve their naming of atypical and/or typical exemplars. Progress on trained, untrained, and monitored items was measured weekly. Pre- and post-treatment assessments were administered to evaluate semantic/phonological processing and overall language ability. Ten PWA served as controls. For the treatment participants, the likelihood of naming trained items accurately was significantly higher than for monitored items over time. When features of atypical items were trained, the likelihood of naming untrained typical items accurately was significantly higher than for untrained atypical items over time. Significant gains were observed on semantic/phonological processing tasks and standardised assessments after therapy. Different patterns of near and far transfer were seen across treatment response groups. Performance was also compared between responders and controls. Responders demonstrated significantly more improvement on a semantic processing task than controls, but no other significant change score differences were found between groups. In addition to positive treatment effects, typicality-based SFA naming therapy resulted in generalisation across multiple levels.
Deep Profiling of the CD8+ T-cell Compartment Identifies Activated Cell Subsets and Multifunctional Responses Associated With Control of Cytomegalovirus Viremia

Background. Human cytomegalovirus (HCMV) is a common opportunistic pathogen in transplant recipients. Patterns of viremia and reactivation are influenced by the host immune response, including CD8+ T cells. However, the cellular deficits or phenotypic differences that account for differential outcomes during HCMV viremia are incompletely understood. Methods. Peripheral blood mononuclear cells were collected from 20 transplant recipients (10 viremia controllers and 10 noncontrollers) at onset of HCMV viremia and 4 weeks postonset. We used mass cytometry to perform in-depth characterization of cell surface and intracellular CD8+ T cell markers and to compare frequencies of these cells between groups. Results. Deep profiling identified 2 central memory T cell subsets at onset and 5 terminally differentiated memory T (TEMRA) cell subsets at 4 weeks that were associated with control of HCMV viremia, in addition to 6 TEMRA subsets at onset and 4 weeks associated with relapsing or remitting HCMV viremia. In general, CD8+ T-cell clusters associated with poorly controlled HCMV viremia lacked markers of activation or terminal differentiation including CD38, CD69, CD25, CD57, and HLA-DR. We also measured the production of 8 HCMV-specific effector molecules (TNF&agr;, IFN&ggr;, interleukin 2, granzyme B, perforin, macrophage inflammatory protein 1&bgr;, interleukin 10, and CD107a) in CD8+ T cells. Viremia controllers had greater diversity of HCMV-specific multifunctional responses at both time points, including significantly higher frequencies of HCMV-specific TNF&agr;+IFN&ggr;+ CD8+ T cells at onset. These multifunctional cells had a phenotype consistent with activated TEM/TEMRA cells. Conclusions. Uncontrolled CMV viremia is associated with specific clusters of memory T-cell subsets and lower frequencies of HCMV-specific multifunctional CD8+ T cells.
Corrigendum: Ending the Reading Wars: Reading Acquisition From Novice to Expert

Original article: Castles, A. , Rastle, K. , & Nation, K. (2018). Ending the reading wars: Reading acquisition from novice to expert. Psychological Science in the Public Interest, 19, 5-51. doi: 10.1177/1529100618772271 On page 23, in the left column, at the beginning of the first full paragraph, four sentences were inadvertently omitted during the editing process. Those sentences are as follows: This characterization changes substantially in cases of words with more than one morpheme. Morphemes are the minimum meaning-bearing units in English (e.g., darkness consists of the morphemes {dark}+{-ness}). For these words, there are underlying regularities between spelling and meaning. These regular patterns emerge because stems occur and reoccur in words with similar meanings (e.g., clean, unclean, cleaner, cleanliness), and affixes alter the meanings of stems in highly predictable ways (e.g., unhook, unlock, unscrew; Rastle, Davis, Marslen-Wilson, & Tyler, 2000). This error has been corrected.
Pushing Hard: The Mandate to Improve Care of Pediatric Cardiopulmonary Arrest.

Each year, an average of 16,000 children require cardiopulmonary resuscitation (CPR) for cardiopulmonary arrest in the United States, and their survival is largely dependent on the provision of optimal and timely resuscitation in concordance with current professional guidelines.1,2 As a profession, emergency department (ED) providers regularly perform inadequate resuscitation for children with cardiopulmonary arrest, and the quality of CPR provided for these patients is not in accordance with accepted standards of care.1 Even with demonstrated familiarity with current American Heart Association (AHA) guidelines for chest compression (CC) rate and hands-off-time (HOT) for compressions, rapid post-training deterioration of CPR performance among pediatric health care professionals is well-described.3 This article is protected by copyright. All rights reserved.