Miracle-dz/UniFAR-FTUs huggingface dataset:
A Toxic RNA Catalyzes the Cellular Synthesis of Its Own Inhibitor, Shunting It to Endogenous Decay Pathways

Myotonic dystrophy type 2 (DM2) is a genetically defined muscular dystrophy caused by a toxic expanded repeat of r(CCUG) [heretofore (CCUG)exp], harbored in intron 1 of CHC-Type Zinc Finger Nucleic Acid Binding Protein (CNBP) pre-mRNA. This r(CCUG)exp causes DM2 via a gain-of-function mechanism that results in three hallmarks of its pathology: (i) binding to RNA-binding proteins (RBPs) that aggregate into nuclear foci; (ii) sequestration of muscleblind-like-1 (MBNL1) protein, a regulator of alternative pre-mRNA splicing, leading to splicing defects; and (iii) retention of intron 1 in the CNBP mRNA. Here, we find that CNBP intron retention is caused by the r(CCUG)exp-MBNL1 complex and can be rescued by small molecules. We studied two types of small molecules with different modes of action, ones that simply bind and ones that can be synthesized by a r(CCUG)exp-templated reaction in cells, that is the RNA synthesizes its own drug. Indeed, our studies completed in DM2 patient-derived fibroblasts show that the compounds disrupt the r(CCUG)exp-MBNL1 complex, reduce intron retention, subjecting the liberated intronic r(CCUG)exp to native decay pathways, and rescue other DM2-associated cellular defects. Collectively, this study shows that small molecules can affect RNA biology by shunting toxic transcripts towards native decay pathways. HIGHLIGHTS Intron retention in RNA repeat expansions can be due to repeats binding to proteins Small molecules that bind RNA repeats and inhibit protein binding can trigger decay A toxic RNA repeat can catalyze the synthesis of its own inhibitor on-site On-site drug synthesis most potently affects disease biology eTOC BLURB The most common way to target RNA is to use antisense oligonucleotides to target unstructured RNAs for destruction. Here, we show for the first time that small molecules targeting structured, disease-causing RNAs can shunt them towards native decay pathways by affecting their processing.
High‐pressure freezing followed by freeze substitution of a complex and variable density miniorgan: the wool follicle

Cryofixation by high‐pressure freezing (HPF) followed by freeze substitution (FS) is a preferred method to prepare biological specimens for ultrastructural studies. It has been shown to achieve uniform vitrification and ultrastructure preservation of complex structures in different cell types. One limitation of HPF is the small sample volume of <200 µm thickness and about 2000 µm across. A wool follicle is a rare intact organ in a single sample about 200 µm thick. Within each follicle, specialized cells derived from multiple cell lineages assemble, mature and cornify to make a wool fibre, which contains 95% keratin and associated proteins. In addition to their complex structure, large density changes occur during wool fibre development. Limited water movement and accessibility of fixatives are some issues that negatively affect the preservation of the follicle ultrastructure via conventional chemical processing. Here, we show that HPF‐FS of wool follicles can yield high‐quality tissue preservation for ultrastructural studies using transmission electron microscopy.
Effects of pressure garment on spasticity and function of the arm in the early stages after stroke: a randomized controlled trial

Objective: To investigate the effects of pressure (Lycra) garment on the spasticity and function of the arm in the early stages after stroke. Design: A randomized controlled trial. Setting: Occupational therapy unit of a public hospital. Subjects: A total of 46 adults with stroke. Intervention: After random assignment, for six weeks, both intervention group and control group received a 2 hour/week conventional occupational therapy program, with the intervention group receiving an extra 6 hour/day pressure garment application (long glove). Main Measures: Modified Modified Ashworth Scale, Disabilities of Arm, Shoulder and Hand Outcome Measure, and Jebsen–Taylor Hand Function Test. Eligibility measures: Mini Mental State Examination and Modified Modified Ashworth Scale. Assessments were performed at baseline and six weeks postintervention. Results: There were 21 participants with the mean age of 51.19 (8.28) years in the intervention group and 22 participants with the mean (SD) age of 52.82 (8.71) years in the control group. The intervention group had median (interquartile range (IQR)) post-stroke duration of 1 (1) month, while for the control group, they were 2 (2) months. There was no difference in spasticity, and both perceived and actual arm functions between the groups at six weeks after baseline. Conclusion: Wearing a pressure garment on the arm for 6 hours daily had no effect in controlling spasticity or on improving arm function in the early stages after stroke.
Mitochondrial DNA copy number is associated with all‐cause mortality and cardiovascular events in patients with peripheral arterial disease

Dysfunctional mitochondria have an influence on inflammation and increased oxidative stress due to an excessive production of reactive oxygen species. The mitochondrial DNA copy number (mtDNA‐CN) is a potential biomarker for mitochondrial dysfunction and has been associated with various diseases. However, results were partially contrasting which might have been caused by methodological difficulties to quantify mtDNA‐CN.
The effect of combined scalp acupuncture and cognitive training in patients with stroke on cognitive and motor functions.

OBJECTIVE To investigate the effect of combined scalp acupuncture and cognitive training on cognitive and motor functioning in patients with stroke during the recovery stage. METHODS Seventy patients with post-stroke cognitive impairment were randomly divided into an experimental group and a control group. Patients in the experimental group additionally received scalp acupuncture and cognitive training, while the control group received sham scalp acupuncture and cognitive training. The cognitive and motor functioning of all patients were assessed using MMSE, LOTCA, and FMA, before and 12 weeks after treatment. In addition, the plasma BDNF and NGF levels were measured from peripheral blood samples using ELISA kits. RESULTS After 12 weeks, the MMSE, LOTCA and FMA scores were significantly higher in the experimental group than in the control group. In the experimental group, there was an improvement in the total MMSE score, orientation, spatial executive function, the total LOTCA score, and the score of command of language orientation post-treatment. Significant improvements of BDNF and NGF were found in the experimental group after treatment, while only significant improvements of NGF was found in the control group after treatment. Both BDNF and NGF in the experiment group were higher than those in the control group at the last day of treatment. CONCLUSIONS Combined scalp acupuncture and cognitive training can efficiently enhance cognitive and motor functions in patients with stroke during the recovery stage, which may be a more effective rehabilitation treatment after stroke than routine therapy and rehabilitation training alone.
Retroperitoneal sarcomas: from diagnosis to treatment. Case series and review of the literature.

BACKGROUND Retroperitoneal sarcoma is a rare malignancy arising from mesenchymal cells, most commonly presented as an abdominal mass and is associated with poor prognosis. The most effective treatment modality for retroperitoneal sarcomas is complete surgical resection, including sometimes adjacent organs infiltrated by the tumor. Radiotherapy is frequently applied and has shown some benefit, while the role of chemotherapy and molecular-targeted agents is still not clear. Local recurrence is common for retroperitoneal sarcomas and still remains the main cause of death. The major factors associated with the overall survival are tumor grade, histological subtype, complete macroscopic excision and multifocality. AIM To report our experience via the presentation of patients with retroperitoneal sarcomas managed in our department during the period 2014-18; and to review the current literature. PATIENTS AND METHODS Eight patients appeared with chronic non-specific complaints including abdominal distension and changes in bowel or bladder habit, while one patient presented with acute abdominal pain due to mass rupture. All of the patients underwent surgical resection of the tumor. RESULTS Among the patients, seven were operated for primary disease and one only for recurrent. The most common histologic type was liposarcoma (well-differentiated, dedifferentiated), found in five patients; followed by leiomyosarcoma found in two cases. Fibrous histiocytoma was found in only one case. The masses were removed with macroscopically clear margins (R0 and R1 resections) in four cases. In five patient cases adjuvant therapy was required. Three patients are still alive and free of disease. CONCLUSIONS Retroperitoneal sarcomas present to be a therapeutic challenge based on their location, their extent at the time of diagnosis and the high risk of local recurrence or distant metastasis. Their management requires a multidisciplinary approach, with the surgical resection remaining the mainstay of curative treatment, combined with surveillance for early detection of recurrence or metastases.
Projecting global mariculture diversity under climate change

Previous studies have focused on changes in the geographical distribution of terrestrial biomes and species targeted by marine capture fisheries due to climate change impacts. Given mariculture's substantial contribution to global seafood production and its growing significance in recent decades, it is essential to evaluate the effects of climate change on mariculture and their socio‐economic consequences. Here, we projected climate change impacts on the marine aquaculture diversity for 85 of the currently most commonly farmed fish and invertebrate species in the world's coastal and/or open ocean areas. Results of ensemble projections from three Earth system models and three species distribution models show that climate change may lead to a substantial redistribution of mariculture species richness potential, with an average of 10%–40% decline in the number of species being potentially suitable to be farmed in tropical to subtropical regions. In contrast, mariculture species richness potential is projected to increase by about 40% at higher latitudes under the ‘no mitigation policy’ scenario (RCP 8.5) by the mid‐21st century. In Exclusive Economic Zones where mariculture is currently undertaken, we projected an average future decline of 1.3% and 5% in mariculture species richness potential under RCP 2.6 (‘strong mitigation’) and RCP 8.5 scenarios, respectively, by the 2050s relative to the 2000s. Our findings highlight the opportunities and challenges for climate adaptation in the mariculture sector through the redistribution of farmed species and expansion of mariculture locations. Our results can help inform adaptation planning and governance mechanisms to minimize local environmental impacts and potential conflicts with other marine and coastal sectors in the future.
Excessive excision of correct nucleotides during DNA synthesis explained by replication hurdles

The proofreading exonuclease activity of replicative DNA polymerase excises misincorporated nucleotides during DNA synthesis, but these events are rare. Therefore, we were surprised to find that T7 replisome excised nearly 7% of correctly incorporated nucleotides during leading and lagging strand syntheses. Similar observations with two other DNA polymerases establish its generality. We show that excessive excision of correctly incorporated nucleotides is not due to events such as processive degradation of nascent DNA or spontaneous partitioning of primer‐end to the exonuclease site as a “cost of proofreading”. Instead, we show that replication hurdles, including secondary structures in template, slowed helicase, or uncoupled helicase–polymerase, increase DNA reannealing and polymerase backtracking, and generate frayed primer‐ends that are shuttled to the exonuclease site and excised efficiently. Our studies indicate that active‐site shuttling occurs at a high frequency, and we propose that it serves as a proofreading mechanism to protect primer‐ends from mutagenic extensions.
Adolescent Mothers’ Perceptions of a Mobile Phone-Based Peer Support Intervention

Background Postpartum depression (PPD) is prevalent among adolescent mothers and is associated with negative maternal and infant outcomes. Peer support can improve health outcomes among adult and adolescent populations and involves the provision of informational, emotional, and appraisal support delivered by a peer. Purpose To describe adolescent mothers’ perceptions of a mobile phone-based peer support (MPPS) intervention designed to prevent PPD. Methods This analysis draws on data from the MPPS intervention group of a pilot randomized controlled trial of pregnant adolescents 17 to 24 years old (n = 16). Maternal perceptions of the intervention were measured using the validated Peer Support Evaluation Inventory at 12 weeks postpartum. Results Participants acknowledged receiving supportive actions including emotional (91%), informational (66%), and appraisal (64%) support. Participants perceived positive relationship qualities with their peer mentor such as trustworthiness (94%), acceptance (75%), empathy (81%), and commitment (81%) and felt their peer mentor possessed social competence (91%) and social skills (91%). Overall, 100% of participants were satisfied with their peer support experience and would recommend this type of support to a friend. Conclusion Participants perceived their experience with the MPPS intervention positively, which lends support to MPPS as an acceptable way to provide support to adolescent mothers.
Deep Neural Network-Based Method for Detecting Obstructive Meibomian Gland Dysfunction With in Vivo Laser Confocal Microscopy.

PURPOSE To evaluate the ability of deep learning (DL) models to detect obstructive meibomian gland dysfunction (MGD) using in vivo laser confocal microscopy images. METHODS For this study, we included 137 images from 137 individuals with obstructive MGD (mean age, 49.9 ± 17.7 years; 44 men and 93 women) and 84 images from 84 individuals with normal meibomian glands (mean age, 53.3 ± 19.6 years; 29 men and 55 women). We constructed and trained 9 different network structures and used single and ensemble DL models and calculated the area under the curve, sensitivity, and specificity to compare the diagnostic abilities of the DL. RESULTS For the single DL model (the highest model; DenseNet-201), the area under the curve, sensitivity, and specificity for diagnosing obstructive MGD were 0.966%, 94.2%, and 82.1%, respectively, and for the ensemble DL model (the highest ensemble model; VGG16, DenseNet-169, DenseNet-201, and InceptionV3), 0.981%, 92.1%, and 98.8%, respectively. CONCLUSIONS Our network combining DL and in vivo laser confocal microscopy learned to differentiate between images of healthy meibomian glands and images of obstructive MGD with a high level of accuracy that may allow for automatic obstructive MGD diagnoses in patients in the future.
The association between hypertension and colorectal cancer: a meta-analysis of observational studies

The relationship between hypertension and risk of colorectal cancer (CRC) is unclear. This meta-analysis aims to explore the association between them. Six databases were searched for studies published before August 2019. The pooled relative risk (RR) and 95% confidence intervals (CIs) were calculated to estimate the association between the hypertension and CRC risk. A total of 2841 potentially relevant articles were obtained, and 25 studies with a pooled 1.95 million participants were finally included in the meta-analysis. These results suggested a positive association between hypertension and risk of CRC with a pooled RR of 1.15 (95% CI: 1.08, 1.23). Male patients with hypertension had a 13% (95% CI: 1.06, 1.20) increased risk of CRC. The risk of colon cancer and rectal cancer in male patients was 1.17 (95% CI: 1.01, 1.36) and 1.35 (95% CI: 1.04, 1.74), respectively, while no association between hypertension and the risk of CRC in females was elucidated. This meta-analysis demonstrated that a positive association between hypertension and CRC exists, with male patients having a higher risk of developing CRC than female patients.
Emotion and conflict adaptation: the role of phasic arousal and self-relevance

ABSTRACT Conflict adaptation reflects the increase in cognitive control after previous conflict between task-relevant and task-irrelevant information. Tonic (sustained) arousal elicited by emotional words embedded in a conflict task has previously been shown to increase conflict adaptation. However, the role of phasic (transient) emotional arousal remains unclear. In Experiment 1 (N = 55), we therefore investigated the effect of phasic arousal using a colour flanker task with negative, positive, and neutral words as stimuli. We hypothesised that phasic arousal elicited in this context will increase conflict adaptation in the subsequent trial. Indeed, when the words were positive or negative as compared to neutral, we observed increased conflict adaptation. In Experiment 2 (N = 54), we examined the role of the self-relevance by presenting words with a self-related pronoun (“my”) or sender-related pronoun (“his”/“her”). We expected that emotional words with high self-relevance would lead to stronger effects of emotional arousal on conflict adaptation. Confirming this hypothesis, results showed that emotional words within a self-related context again increased conflict adaptation, whereas this effect was not observed in the sender-related context. Taken together, these results are the first to show that phasic arousal elicited by emotional words increases conflict adaptation, in particular when these words have high self-relevance.
An Independent Validation of the Brighton Spondylodiscitis Score and a Proposal to Modify the Score.

INTRODUCTION The Brighton Spondylodiscitis Score (BSS) aims to identify patients with pyogenic spinal infections (PSIs) requiring surgery; an independent assessment of the BSS is required. METHODS We evaluated 60 patients with PSIs. Using the BSS, we determined whether patients with low, moderate, and high risk (LMHR) had different rates of surgery. We proposed a modified score (MS) using a logistic regression (LOGR). Applying the MS, we determined whether patients with LMHR exhibited different rates of surgery. Another LOGR determined the association of the BSS and the MS with surgery. A C-statistic using the BSS and the MS was generated. RESULTS We studied 60 patients (mean age = 63 years); 37 (62%) were men; 30 (50%) required surgery. Using the BSS, patients with LMHR had similar rates of surgery (P = 0.53). LOGR showed that cervical PSIs had a larger chance of surgery (odds ratio [OR] = 7.3 [1.1 to 51.3]) than other locations. Using the MS, patients with moderate- and high-risk were operated more frequently than low-risk patients (P = 0.04). The BSS did not predict surgery (OR = 1.07; P = 0.31), but the MS did (OR = 1.16; P = 0.02). The C-statistic using the BSS (0.59) improved using the MS (0.69), P = 0.03. DISCUSSION The discriminatory capacity to predict surgery of the BSS augmented using the MS. LEVEL OF EVIDENCE II (Diagnostic study: Transverse study).
Microglia in the hypothalamus respond to tumor‐derived factors and are protective against cachexia during pancreatic cancer

Microglia in the mediobasal hypothalamus (MBH) respond to inflammatory stimuli and metabolic perturbations to mediate body composition. This concept is well studied in the context of high fat diet induced obesity (HFDO), yet has not been investigated in the context of cachexia, a devastating metabolic syndrome characterized by anorexia, fatigue, and muscle catabolism. We show that microglia accumulate specifically in the MBH early in pancreatic ductal adenocarcinoma (PDAC)‐associated cachexia and assume an activated morphology. Furthermore, we observe astrogliosis in the MBH and hippocampus concurrent with cachexia initiation. We next show that circulating immune cells resembling macrophages infiltrate the MBH. PDAC‐derived factors induced microglia to express a transcriptional profile in vitro that was distinct from that induced by lipopolysaccharide (LPS). Microglia depletion through CSF1‐R antagonism resulted in accelerated cachexia onset and increased anorexia, fatigue, and muscle catabolism during PDAC. This corresponded with increased hypothalamic–pituitary–adrenal (HPA) axis activation. CSF1‐R antagonism had little effect on inflammatory response in the circulation, liver, or tumor. These findings demonstrate that microglia are protective against PDAC cachexia and provide mechanistic insight into this function.
The role of prenatal diagnosis following preimplantation genetic testing for single‐gene conditions: A historical overview of evolving technologies and clinical practice

Preimplantation genetic testing for monogenic conditions (PGT‐M) has become a valued reproductive option for couples at risk of having a child with a single gene condition. In line with developments in molecular genetics, there has been an overall trend toward laboratory techniques with higher accuracy in comparison to earlier PGT‐M techniques. The recommendation for confirmatory prenatal diagnostic testing has remained a standard component of PGT‐M counseling, reflecting the inherent difficulties of testing the limited number of cells obtained from embryo biopsy, as well as recognition of the biological and human factors that may lead to misdiagnosis in a PGT‐M cycle. Reported misdiagnosis rates are less than 1 in 200 pregnancies following PGT‐M, although updated data regarding newer methods of PGT‐M are required. There is limited evidence available regarding clinician and patient behavior in pregnancies resulting from PGT‐M cycles. It remains essential that clinicians involved in the care of patients undergoing PGT‐M provide appropriate counseling regarding the risks of misdiagnosis and the importance of confirmatory prenatal diagnosis. The nature of PGT‐M test design lends itself to cell‐free DNA‐based noninvasive prenatal testing for monogenic conditions (NIPT‐M), which is likely to become a popular method in the near future.
Laparoscopic Versus Robotic-assisted Suturing Performance Among Novice Surgeons: A Blinded, Cross-Over Study

Robotic-assisted laparoscopy (RAL) presents several advantages over 3-dimensional conventional laparoscopy (3D-CL) that may facilitate laparoscopic suturing especially with novice surgeons. This study compares novice surgeons’ suturing performance by 3D-CL and RAL using Objective Structured Assessment of Technical Skill (OSATS), an objective, validated scoring tool. Twenty-two surgeons with no robotic experience completed a standardized suturing task in an experimental setup by both 3D-CL and RAL in a randomized, cross-over design. Two experienced surgeons blindly assessed their performance using OSATS. Median (interquartile range) OSATS scores for 3D-CL and RAL were, respectively, 22.8 (17.4 to 25.8) versus 25.0 (21.9 to 26.5), P=0.032. There was no association between laparoscopic experience and robotic-assisted suturing performance. Thus, this study is, to our knowledge, the first to compare novice surgeons’ suturing performance by 3D-CL and RAL using an objective, validated scoring tool and to show better suturing performance when assisted by the robot regardless of experience level.