Miracle-dz/UniFAR-FTUs huggingface dataset:
The notion of “invisibility” in people’s experiences of the symptoms of multiple sclerosis: a systematic meta-synthesis

Abstract Purpose Invisible symptoms have a negative impact on people living with Multiple Sclerosis (MS), related to the very notion that they are “unseen. ” It is important to understand the notion of “invisibility” in MS, as invisible symptoms are particularly distressing, and there is a paucity of research focussing on their invisible nature and its specific impact. We aimed to systematically identify, appraise and synthesise qualitative research regarding the notion of “invisibility” in relation to people’s lived experience of symptoms of MS. Methods and materials Articles meeting inclusion criteria were critically appraised and synthesised using a meta-ethnographic approach. Results 17 articles were identified from six electronic databases. Three third-order themes were presented as a line of argument. “Invisibility” was conceptualised by people with MS as a discrepancy between the internal experience of symptoms and what is observed externally. “Invisibility” of MS symptoms was found to have numerous impacts, including not feeling understood or validated by others, issues around the perceived legitimacy of the illness, and living with needs which are hidden. We found that “invisibility” by its nature offers people a choice of strategies they use to navigate it. This choice introduces a dilemma: disclose the diagnosis to be “seen,” or remain “invisible. ” Conclusions This review revealed the manner in which people with MS are affected by the invisibility of their symptoms and the various adaptations used to navigate these lived experiences. We highlight the need to improve clinician and public understanding, and to better respond to these experiences. Future research focusing on the exploration of people’s experiences of “invisibility” in MS, including the ways in which “invisibility” is managed on a day-to-day basis could raise clinical and public awareness of the impact of “invisibility” and how to provide support for this, thus easing the dilemmas faced by those with MS. IMPLICATIONS FOR REHABILITATION People with Multiple Sclerosis (MS) experience symptoms that are not overtly visible to others, impacting their emotional and social wellbeing negatively. It is important for healthcare professionals to validate MS patients’ experiences around “invisibility” and provide appropriate support. Healthcare professionals should address with MS patients any issues around disclosure of their diagnosis to those around them and support them to navigate these decisions. Raising awareness about the impact of “invisibility” for people with MS may help to lessen patient burden and promote understanding amongst healthcare professionals and the general public.
Characterization of tailoring steps of nargenicin A1 biosynthesis reveals novel analogue with anticancer activities.

Nargenicin A1 is an antibacterial macrolide with effective activity against various gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Due to promising properties of this compound in inhibiting cell proliferation, immunomodulation, and cell protective effect there have been significant interest in this molecule. Recently, the biosynthetic gene cluster (BGC) of nargenicin A1 was reported from Nocardia argentinesis and Nocardia arthritidis. Further, two crucial enzyme involved in the formation of the core decalin moiety and post-modification of the decalin moiety by an ether bridge was characterized. This study reports on the BGC of nargenicin A1 from Nocardia sp. CS682. In addition the direct capture and heterologous expression of nar BGC from Nocardia sp. CS682 in Streptomyces venezuelae led to production of nargenicin A1. Further metabolic profiling of wild type, Nocardia sp. CS682 in optimized media (DD media) resulted on isolation of two acetylated derivatives as 18-O-acetyl nodusmicin and 18-O-acetyl-nargenicin. The post-PKS modification pathway in nargenicin A1 biosynthesis was also deciphered by identifying intermediates and/or in-vitro enzymatic reactions of NgnP1, NgnM, and NgnO3. Different novel analogues of nargenicin, such as Compound 6, Compound 7, 23-Demethyl 8, 13 deoxy-nodusmicin (8), 23-Demethyl 8,13 deoxy nargenicin (9), 8,13 deoxynodusmicin (10) and 8,13 deoxynargenicin (11) were also characterized, which extended our understanding of key post-PKS modification steps during the biosynthesis of nargenicin A1. In addition, the antimicrobial and anticancer activities of selected analogues were also evaluated, whereas it was observed that compound 9 exhibits potent antitumor activity by induction of G2/M cell cycle arrest, apoptosis, and autophagy.
Anti-Müllerian Hormone Concentrations Are Inversely Associated With Subclinical Atherosclerosis in Premenopausal Women

Anti-Müllerian hormone (AMH), which is secreted by granulosa cells of late preantral and small antral follicles, is a marker of ovarian reserve. The association of ovarian reserve with subclinical atherosclerosis in women of reproductive age is currently unknown. We primary investigated whether AMH levels are associated with markers of subclinical atherosclerosis in healthy, normally menstruating women. In this cross-sectional study, vascular structure and function were assessed by measurement of carotid and femoral intima–media thickness (IMT), flow-mediated dilation, carotid–femoral pulse wave velocity and augmentation index. Lipid profile and serum AMH concentrations were also measured. Seventy premenopausal women, aged 32.7 ± 6.5 years, were included. Mean AMH levels were lower in smokers than in non-smokers and negatively associated with total cholesterol (TC) levels. An inverse association between mean AMH concentrations and femoral and carotid IMT in all segments was observed. No correlation with other markers of subclinical atherosclerosis or established cardiovascular (CV) risk factors was found. After multivariable adjustment, the association between AMH concentrations and combined carotid IMT or carotid bulb IMT remained significant. In conclusion, in healthy, normally ovulating women, AMH concentrations are negatively associated with subclinical atherosclerosis indices and TC levels, independently of established CV risk factors.
Effects of the Conductive Component of Hearing Loss on Speech Discrimination Ability

OBJECTIVES Effects of decreasing auditory activity on speech discrimination ability are not fully understood. To investigate influence of decrease in auditory activity due to conductive and sensorineural components of hearing loss (HL) on speech discrimination ability. MATERIALS and METHODS We retrospectively reviewed medical records of patients with suspected HL at Kitasato University Hospital in 2017 and 2018. Patients were divided according to pure-tone audiometry findings: no HL (N-HL), conductive HL (C-HL), sensorineural HL (S-HL), and mixed HL (M-HL) groups. RESULTS In total, 149 patients (224 ears) were eligible. The maximum speech discrimination score (SDSmax) for all ears significantly negatively correlated with age (r = −0.29, p<0.0001) and bone conduction (BC) threshold (r = −0.55, p<0.0001). For patients aged <50 years in N-HL and C-HL groups, SDSmax was nearly 100%, with no significant difference. SDSmax was significantly lower for older patients (≥50 years) in the M-HL group than in the S-HL group, even though there were no significant differences in age and BC thresholds between groups. CONCLUSION Decrease of auditory activity due to the conductive component of M-HL may worsen speech discrimination ability. Early treatment of M-HL would be desirable for the preservation of auditory function.
The Microbial Community of Tetrodotoxin-Bearing and Non-Tetrodotoxin-Bearing Ribbon Worms (Nemertea) from the Sea of Japan

A potent marine toxin, tetrodotoxin (TTX), found in a great variety of marine and some terrestrial species, leaves intriguing questions about its origin and distribution in marine ecosystems. TTX-producing bacteria were found in the cultivable microflora of many TTX-bearing hosts, thereby providing strong support for the hypothesis that the toxin is of bacterial origin in these species. However, metagenomic studies of TTX-bearing animals addressing the whole microbial composition and estimating the contribution of TTX-producing bacteria to the overall toxicity of the host were not conducted. The present study is the first to characterize and compare the 16S rRNA gene data obtained from four TTX-bearing and four non-TTX-bearing species of marine ribbon worms. The statistical analysis showed that different nemertean species harbor distinct bacterial communities, while members of the same species mostly share more similar microbiomes. The bacterial species historically associated with TTX production were found in all studied samples but predominated in TTX-bearing nemertean species. This suggests that deeper knowledge of the microbiome of TTX-bearing animals is a key to understanding the origin of TTX in marine ecosystems.
Recombination Pattern Characterization via Simulation Using Different Maize Populations

Efficient recombination is critical to both plant breeding and gene cloning. However, almost all traditional recombination studies and genetic improvements require the slow and labor-intensive population construction process, and little is known about the recombination characteristics of populations of different types, generations, and origins. Here, we provide a simple and efficient simulation method for population construction based on doubled haploid (DH) and intermated B73 × Mo17 maize (IBM) populations to predict the recombination pattern. We found that the chromosomes had 0, 1, 2, and 3 recombination events that occurred at rates of 0.16, 0.30, 0.23, and 0.15, respectively, in the DH and the recombination rate of each chromosome in the IBM population ranged from 0 to 12.1 cM per 125 kb. Based on the observed recombination parameters, we estimated the number of recombination events and constructed the linkage maps of the simulated DH and recombination inbred line (RIL) populations. These simulated populations exhibited similar recombination patterns compared with the real populations, suggesting the feasibility of this simulation approach. We then compared the recombination rates of the simulated populations of different types (DH induced or self-crossed), generations, and origins (using the 8, 16, and 32 multiparent advanced generation intercross (MAGIC) populations), and suggested a rapid and cost-effective population construction procedure for breeders and geneticists, while maintaining an optimal recombination rate. This study offers a convenient method for optimizing the population construction process and has broader implications for other crop species, thereby facilitating future population studies and genetic improvement strategies.
Eye movements shape visual learning

Significance In domains as diverse as radiology and airport baggage screening, it has been observed that experts make fewer eye movements than novices. We therefore hypothesized that eye movements influence learning in the context of noisy or complicated stimulus patterns. Observers practiced a task in which noisy visual signals were presented during a saccade. Under these conditions, most observers integrated these signals in a manner that was dictated by the eye movement direction. Surprisingly, observers who exhibited this tendency to integrate during saccades learned, through extensive training, to perform the same integration in the absence of eye movements. These results suggest that eye movements can shape the way in which people learn to extract meaningful information from challenging visual stimuli. Most people easily learn to recognize new faces and places, and with more extensive practice they can become experts at visual tasks as complex as radiological diagnosis and action video games. Such perceptual plasticity has been thoroughly studied in the context of training paradigms that require constant fixation. In contrast, when observers learn under more natural conditions, they make frequent saccadic eye movements. Here we show that such eye movements can play an important role in visual learning. Observers performed a task in which they executed a saccade while discriminating the motion of a cued visual stimulus. Additional stimuli, presented simultaneously with the cued one, permitted an assessment of the perceptual integration of information across visual space. Consistent with previous results on perisaccadic remapping [M. Szinte, D. Jonikaitis, M. Rolfs, P. Cavanagh, H. Deubel, J. Neurophysiol. 116, 1592–1602 (2016)], most observers preferentially integrated information from locations representing the presaccadic and postsaccadic retinal positions of the cue. With extensive training on the saccade task, these observers gradually acquired the ability to perform similar motion integration without making eye movements. Importantly, the newly acquired pattern of spatial integration was determined by the metrics of the saccades made during training. These results suggest that oculomotor influences on visual processing, long thought to subserve the function of perceptual stability, also play a role in visual plasticity.
Connective tissue growth factor (CTGF) regulates the fusion of osteoclast precursors by inhibiting Bcl6 in periodontitis

Connective tissue growth factor (CTGF), an extracellular matrix protein with various biological functions, is known to be upregulated in multiple chronic diseases such as liver fibrosis and congestive heart failure, but the mechanism it undertakes to cause alveolar bone loss in periodontitis remains elusive. The present study therefore investigates the pathways involving CTGF in chronic periodontitis. RNA sequencing revealed a notable increase in the expression of CTGF in chronic periodontitis tissues. Also, TRAP staining, TRAP activity and bone resorption assays showed that osteoclast formation and function is significantly facilitated in CTGF-treated bone marrow-derived macrophages (BMMs). Interestingly, western blotting and immunofluorescence staining results displayed that CTGF had little effect on the osteoclastogenic differentiation mediated by the positive regulators of osteoclastogenesis such as nuclear factor of activated T cells 1 (NFATc1). However, following results showed that both the mRNA and protein expressions of B cell lymphoma 6 (Bcl6), a transcriptional repressor of “osteoclastic” genes, were significantly downregulated by CTGF treatment. Moreover, CTGF upregulated the expressions of v-ATPase V0 subunit d2 (ATP6v0d2) and Dendritic cell-specific transmembrane protein (DC-STAMP) which are osteoclastic genes specifically required for osteoclast cell-cell fusion in pre-osteoclasts. Findings from this study suggest that CTGF promotes the fusion of pre-osteoclasts by downregulating Bcl6 and subsequently increasing the expression of DC-STAMP in periodontitis. Understanding this novel mechanism that leads to increased osteoclastogenesis in periodontitis may be employed for the development of new therapeutic targets for preventing periodontitis-associated alveolar bone resorption.
Burden of Menstrual Pain Measured by Heatmap Visualization of Daily Patient-Reported Data in Japanese Patients Treated with Ethinylestradiol/Drospirenone: A Randomized Controlled Study

Purpose Dysmenorrhea negatively affects women’s quality of life and poses a considerable economic burden. A recent study in Japanese patients with dysmenorrhea (NCT01892904) reported a significant reduction in the number of days with menstrual pain after treatment with a flexible extended regimen of ethinylestradiol (EE)/drospirenone (DRSP) compared with a cyclic regimen. However, individual patients’ menstrual pain patterns and intensities were not indicated. Heatmapping was used to visualize menstrual pain patterns and intensities by re-evaluating the previously published data from NCT01892904. Patients and Methods NCT01892904 was a Phase III, multicenter, randomized, open-label, active-control study of 212 women aged ≥20 years randomized 1:1 to receive flexible extended or 28-day cyclic EE/DRSP treatment. Daily pain levels were recorded in patient diaries, and menstrual pain patterns and intensities were visualized using heatmapping. Patients were stratified by baseline dysmenorrhea scores and primary or secondary dysmenorrhea. Results The heatmap data demonstrated that EE/DRSP reduced the degree of menstrual pain. Regular peaks of menstrual pain were alleviated in the extended regimen group but were still observed in the cyclic regimen group. While a decrease in the days with menstrual pain was observed in patients with higher baseline dysmenorrhea scores (5–6), those with lower baseline scores (3–4) were more likely to experience lower intensities of menstrual pain. Although pain relief was less likely in patients with secondary dysmenorrhea, those who had lower baseline dysmenorrhea scores (3–4) and received the flexible extended regimen experienced a greater reduction in the number of days with menstrual pain than those who received the cyclic regimen. Conclusion Heatmapping effectively visualized the daily burden of menstrual pain in Japanese patients with dysmenorrhea. The analysis using heatmaps suggested that the flexible extended EE/DRSP treatment regimen was more likely to alleviate the regular occurrence of menstrual pain peaks compared with the cyclic regimen.
Effects of Ursolic Acid on the Expression of Th1–Th2-related Cytokines in a Rat Model of Allergic Rhinitis After PM2.5 Exposure

Background Allergic rhinitis (AR) is a global health problem and closely related to environmental factors. Ursolic acid (UA) has potential in the treatment of allergic inflammation. The effects of UA intervention on PM2.5-induced AR remain uncertain. Objective To assess the effects of UA on nasal symptoms and the expression of T-helper (Th)1–Th2-related cytokines in a rat model of AR after fine particulate matter (particulate matter ≤ 2.5 µm [PM2.5]) exposure. Methods A total of 40 healthy female Sprague-Dawley rats were randomly divided into 4 groups: normal control group (NC group), ovalbumin (OVA)- induced AR model (AR group), PM2.5-exposed AR group exposed to 200 g/m3 PM2.5 for 30 days via inhalation (ARE group), and a group with UA intervention to the AR model after PM2.5 exposure (UA group). UA intervention was adopted after PM2.5 exposure in the UA group. Nasal symptoms and levels of Th1–Th2 cytokines in the serum were detected in each individual rat. The pathological changes and expression of Eotaxin in the nasal mucosa of each individual rat were examined by histology. Results PM2.5 significantly increased the number of sneezes and nasal rubs in the rats with AR, and UA alleviated these symptoms. UA decreased interleukin (IL)-4, IL-5, IL-13, Eotaxin-1, and OVA Immunoglobulin E (IgE) protein levels. In the AR group, hematoxylin and eosin staining showed disordered arrangement of the nasal mucosa epithelium, cell shedding, eosinophilic infiltration, swelling of the glands, and submucosal vascular congestion. UA group showed reduced eosinophilic infiltration and orderly arrangement of the mucosal epithelium when compared with the ARE group. Immunohistochemical results showed that the expression of Eotaxin in the UA group was lower than that in the ARE group. Conclusion UA could relieve nasal symptoms caused by PM2.5 exposure, the possible mechanism of which is to inhibit the expression of Th2 cytokines, eosinophilic infiltration, and specific IgE production.
Neuroprotective role of lactate in rat neonatal hypoxia-ischemia

Hypoxic-ischemic (HI) encephalopathy remains a major cause of perinatal mortality and chronic disability in newborns worldwide (1–6 for 1000 births). The only current clinical treatment is hypothermia, which is efficient for less than 60% of babies. Mainly considered as a waste product in the past, lactate, in addition to glucose, is increasingly admitted as a supplementary fuel for neurons and, more recently, as a signaling molecule in the brain. Our aim was to investigate the neuroprotective effect of lactate in a neonatal (seven day old) rat model of hypoxia-ischemia. Pups received intra-peritoneal injection(s) of lactate (40 μmol). Size and apparent diffusion coefficients of brain lesions were assessed by magnetic resonance diffusion-weighted imaging. Oxiblot analyses and long-term behavioral studies were also conducted. A single lactate injection induced a 30% reduction in brain lesion volume, indicating a rapid and efficient neuroprotective effect. When oxamate, a lactate dehydrogenase inhibitor, was co-injected with lactate, the neuroprotection was completely abolished, highlighting the role of lactate metabolism in this protection. After three lactate injections (one per day), pups presented the smallest brain lesion volume and a complete recovery of neurological reflexes, sensorimotor capacities and long-term memory, demonstrating that lactate administration is a promising therapy for neonatal HI insult.
HPV genotypic spectrum in Jilin province, China, where non-vaccine-covered HPV53 and 51 are prevalent, exhibits a bimodal age-specific pattern

Background Human papillomavirus (HPV), the most common sexually transmitted disease, is involved in a series of other diseases. The persistent infection of high-risk HPVs (HR-HPVs) is considered to be the causative agent of cervical cancer, and it is related to noncervical cancers. The present study aims to estimate the HPV prevalence and genotype distribution in Jilin province, China, to guide HPV-related cervical cancer screening and HPV vaccination. Methods From October 2017 to September 2019, 21,282 samples (634 male and 20,648 female) were collected for HPV infection detection using an HPV genotyping panel. The age-related HPV prevalence and morbidity of HPV-based disease and HPV prevalence associated with specific diseases were analyzed. Results A total of 7095 (34.4%) positive for HPV infection of 20648 women, and 164 (25.8%) positive of 634 men. The HPV prevalence among women exhibited a bimodal pattern, with a peak in young group and a second peak in old group, with increased severity of cervical lesions. HPV16 (7.8%), HPV52 (5.8%), HPV58 (5.0%), HPV53 (3.4%), and HPV51 (3.0%) were the most prevalent genotypes among women, and HPV6 (6.0%), HPV11 (5.7%), HPV16 (3.6%), HPV18 (2.7%), and HPV51 (3.0%) were prevalent among men. Non-vaccine-covered HPV53 and 51 were found in 6.3% of HPV infection and 8.9% of cervical cancer in Jilin province. Furthermore, 45.5% of females and 28.6% of males with genital warts were infected with HR-HPV genotypes. Conclusion The HPV genotypic spectrum in Jilin province, where non-vaccine-covered HPV53 and 51 were prevalent, exhibited an age- and cervical lesion-specific pattern, which provides guidance for HPV vaccination and cervical cancer screening. HPV infection in men and benign hyper-proliferative lesions should not be neglected.