Miracle-dz/UniFAR-FTUs huggingface dataset:
CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short- and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.
Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging

Aging is associated with high prevalence of chronic degenerative diseases that take a large part of the increasing burden of morbidities in a growing demographic of elderly people. Aging is a complex process that involves cell autonomous and cell non-autonomous mechanisms where senescence plays an important role. Senescence is characterized by the loss of proliferative potential, resistance to cell death by apoptosis and expression of a senescence-associated secretory phenotype (SASP). SASP includes pro-inflammatory cytokines and chemokines, tissue-damaging proteases, growth factors; all contributing to tissue microenvironment alteration and loss of tissue homeostasis. Emerging evidence suggests that the changes in the number and composition of extracellular vesicles (EVs) released by senescent cells contribute to the adverse effects of senescence in aging. In addition, age-related alterations in mesenchymal stem/stromal cells (MSCs) have been associated to dysregulated functions. The loss of functional stem cells necessary to maintain tissue homeostasis likely directly contributes to aging. In this review, we will focus on the characteristics and role of EVs isolated from senescent MSCs, the potential effect of MSC-derived EVs in aging and discuss their therapeutic potential to improve age-related diseases.
Effects of Repetition Suppression on Sound Induced Flash Illusion With Aging

The sound-induced flash illusion (SiFI) is a classical auditory-dominated multisensory integration phenomenon in which the observer misperceives the number of visual flashes due to the simultaneous presentation of a different number of auditory beeps. Although the SiFI has been documented to correlate with perceptual sensitivity, to date there is no consensus as to how it corresponds to sensitivity with aging. The present study was based on the SiFI paradigm (Shams et al., 2000), adding repeated auditory stimuli prior to the appearance of audiovisual stimuli to investigate the effects of repetition suppression (RS) on the SiFI with aging. The repeated auditory stimuli consisted of one or two of the same auditory stimuli presented twice in succession, which were then followed by the audiovisual stimuli. By comparing the illusions in old and young adults, we aimed to explore the influence of aging on the RS of auditory stimuli on the SiFI. The results showed that both age groups showed SiFI effects, however, the RS performance of the two age groups had different effects on the fusion and fission illusions. The illusion effect in old adults was weaker than in young adults. Specifically, RS only affected fission illusions in the old adults but both fission and fusion illusions in young adults. Thus, the present study indicated that the decreased perceptual sensitivity based on auditory RS could weaken the SiFI effect in multisensory integration and that old adults are more susceptible to RS, showing that old adults perceived the SiFI effect weakly under auditory RS.
I’ll Be a Caregiver-Employee: Aging of the Workforce and Family-to-Work Conflicts

Background The double role of caregiver-employee (CE) defines those workers who simultaneously serve as an informal, unpaid care provider for sick, disabled, or elderly relatives, and it is a situation that is on the increase in most western countries. Providing informal caregiving can lead to detrimental effects on emotional well-being and several physical and psychological diseases (e.g., caregiver-burden). CEs can suffer double discomfort (at work and at home), but, first of all, they can be exposed to a high level of home-to-work conflict (HWI). In this study, we analyzed the CE phenomenon in a typical Italian public company, where the mean age of workers is particularly high. Methods An online questionnaire related to the perception of HWI, well-being, and discomfort at work (depression, emotional exhaustion, job engagement) in relation to the family load (none, parents with <12 children to care for, caregiver to other adults, or children and older adults to care for/old/children to care for employees) was answered by 1704 administrative workers. Results More than 20% of our sample was included in the elder caregiver condition or in the double role or “sandwiched” condition with older adults and children to care for. The family load changed significantly between the different age groups: for workers aged between 55 and 64 years, the percentage was nearly 27%. CEs had higher levels of HWI and of personal and job discomfort and lower levels of engagement, when compared with non-CEs. Having “only” older adults to care for (the typical CE condition) was associated with having the most negative results. Conclusion This study confirms and underlines the increasing number of CEs in western organizations and their higher levels of HWI, work disengagement, emotional exhaustion, and depression. As the general population and workforce experience increased “graying,” and many more workers become CEs out of necessity, stable caregiver-friendly workplace policies (CFWPs) should be developed.
Left Prefrontal Cortex Supports the Recognition of Meaningful Patterns in Ambiguous Stimuli

Processing of ambiguous visual stimuli has been associated with an increased activation of the left lateral prefrontal cortex (PFC) in neuroimaging studies. Nevertheless, the functional role of prefrontal activity in this process is not fully understood. In this experiment we asked participants to evaluate ambiguous inkblots from the Rorschach test, while stimulating the left lateral PFC using excitatory anodal transcranial direct current stimulation (tDCS). In addition, visual insight ability was assessed as a control measure requiring visual and conceptual restructuring and convergent thinking rather than divergent idea generation employed to interpret the equivocal Rorschach inkblots. Using a randomized double-blind design, we demonstrated that anodal tDCS increased the number of meaningful patterns recognized in the inkblots but had no significant effect on visual insight. These findings support the role of left lateral PFC in the processing of ambiguous visual information and object recognition. More generally, we discuss that the PFC may be involved in the mechanisms supporting the activation of stored visual and semantic representations in order to compensate for less informative bottom-up inputs and thus facilitate flexible cognition and idea generation.
FAIM Opposes Aggregation of Mutant SOD1 That Typifies Some Forms of Familial Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative illness that is unremittingly fatal and for which no effective treatment exists. All forms of ALS are characterized by protein aggregation. In familial forms of ALS, specific and heritable aggregation-prone proteins have been identified, such as mutant superoxide dismutase (SOD1). It has been suggested that a factor capable of preventing mutant SOD1 protein aggregation and/or disassembling mutant SOD1 protein aggregates would ameliorate SOD1-associated forms of familial ALS. Here we identify Fas Apoptosis Inhibitory Molecule (FAIM), a highly evolutionarily conserved 20 kDa protein, as an agent with this activity. We show FAIM counteracts intracellular accumulation of mutant SOD1 protein aggregates, which is increased in the absence of FAIM, as determined by pulse-shape analysis and filter trap assays. In a cell-free system, FAIM inhibits aggregation of mutant SOD1, and further disassembles and solubilizes established mutant SOD1 protein aggregates, as determined by thioflavin T (ThT), filter trap, and sedimentation assays. In sum, we report here a previously unknown activity of FAIM that opposes ALS disease-related protein aggregation and promotes proteostasis of an aggregation-prone ALS protein.
Whole-Transcriptome Analysis Unveils the Synchronized Activities of Genes for Fructans in Developing Tubers of the Jerusalem Artichoke

Helianthus tuberosus L. , known as the Jerusalem artichoke, is a hexaploid plant species, adapted to low-nutrient soils, that accumulates high levels of inulin in its tubers. Inulin is a fructose-based polysaccharide used either as dietary fiber or for the production of bioethanol. Key enzymes involved in inulin biosynthesis are well known. However, the gene networks underpinning tuber development and inulin accumulation in H. tuberous remain elusive. To fill this gap, we selected 6,365 expressed sequence tags (ESTs) from an H. tuberosus library to set up a microarray platform and record their expression across three tuber developmental stages, when rhizomes start enlarging (T0), at maximum tuber elongation rate (T3), and at tuber physiological maturity (Tm), in “VR” and “K8-HS142”clones. The former was selected as an early tuberizing and the latter as a late-tuberizing clone. We quantified inulin and starch levels, and qRT-PCR confirmed the expression of critical genes accounting for inulin biosynthesis. The microarray analysis revealed that the differences in morphological and physiological traits between tubers of the two clones are genetically determined since T0 and that is relatively low the number of differentially expressed ESTs across the stages shared between the clones (93). The expression of ESTs for sucrose:sucrose 1-fructosyltransferase (1-SST) and fructan:fructan 1-fructosyltransferase (1-FFT), the two critical genes for fructans polymerization, resulted to be temporarily synchronized and mirror the progress of inulin accumulation and stretching. The expression of ESTs for starch biosynthesis was insignificant throughout the developmental stages of the clones in line with the negligible level of starch into their mature tubers, where inulin was the dominant polysaccharide. Overall, our study disclosed candidate genes underpinning the development and storage of carbohydrates in the tubers of two H. tuberosus clones. A model according to which the steady-state levels of 1-SST and 1-FFT transcripts are developmentally controlled and might represent a limiting factor for inulin accumulation has been provided. Our finding may have significant repercussions for breeding clones with improved levels of inulin for food and chemical industry.
A 5 Year Retrospective Study of 131I Therapy for Thyroid Cancer Practice in King Abdulaziz University Hospital

Since 1940s, intake of Iodine 131 is a deeprooted postoperative therapy for malignant thyroid. However, clinical practice does differ significantly between hospitals. This paper presents a retrospective study of a clinical practice for patients diagnosed with thyroid cancer at King Abdulaziz University Hospital (KAUH). The aim of this study was to benchmark KAUH practice patterns against international guidelines. A total of 100 patients with thyroid cancer were included, 70% females and 30% males with median age of 42.5 and 43.5 years respectively. Cases were patients, diagnosed with thyroid cancer and treated with radioactive iodine at KAUH in Saudi Arabia between 2005 and 2011. Some additional patient’s data were excluded from the study because of missing information or lost to follow-up. Medical records included patient’s gender, age, clinical diagnoses, iodine dose, and the recurrence. Where, thirty-three percent (33%) of the patients had papillary carcinoma, (3%) had follicular carcinoma and (1%) had Hurtle cell tumors. All patients had their total/partial thyroidectomy at KAUH. Dose administered ranged from (50 to 300) mCi with the 61% receiving a dose of 100mCi. A statistical test, Chisquare test, were used to allow us to test for deviations of observed frequencies from expected frequencies. The medical record showed that 3% of the patient had died and 4% had a recurrence that was successfully treated by the time of the study. Moreover, the 5-year survival rates for patients with thyroid cancers was 93%. The thyroid cancer incidence and the I-131 practice in KAUH is consistent with international data and standards.
Identification of Core Gene Expression Signature and Key Pathways in Colorectal Cancer

Objective Colorectal cancer (CRC) is considered the most prevalent malignant tumor that contributes to high cancer-related mortality. However, the signaling pathways involved in CRC and CRC-driven genes are largely unknown. We sought to discover a novel biomarker in CRC. Materials and Methods All clinical CRC samples (n = 20) were from Renmin Hospital of Wuhan University. We first selected MAD2L1 by integrated bioinformatics analysis of a GSE dataset. Next, the expression of MAD2L1 in tissues and cell lines was verified by quantitative real-time PCR. The effects of MAD2L1 on cell growth, proliferation, the cell cycle, and apoptosis were examined by in vitro assays. Results We identified 683 shared DEGs (420 upregulated and 263 downregulated), and the top twenty genes (CDK1, CCNA2, TOP2A, PLK1, MAD2L1, AURKA, BUB1B, UBE2C, TPX2, RRM2, KIF11, NCAPG, MELK, NUSAP1, MCM4, RFC4, PTTG1, CHEK1, CEP55, DTL) were selected by integrated analysis. These hub genes were significantly overexpressed in CRC samples and were positively correlated. Our data revealed that the expression of MAD2L1 in CRC tissues is higher than that in normal tissues. MAD2L1 knockdown significantly suppressed CRC cell growth by impairing cell cycle progression and inducing cell apoptosis. Conclusion MAD2L1, as a novel oncogenic gene, plays a role in regulating cancer cell growth and apoptosis and could be used as a new biomarker for diagnosis and therapy in CRC.
Adolescent Suicide Ideation, Depression and Self-Esteem: Relationships to a New Measure of Gender Role Conflict

Among 15–24 year olds in Ireland, completed suicide was responsible for 4.1 times more male deaths than female deaths in 2014 (World Health Organization [WHO], 2017). Few international research studies have investigated the relationship between masculinity [as assessed by a measure of gender role conflict (GRC)] and suicide ideation, and none have done so with Irish adolescents. Therefore, the purpose of the current study was to investigate the relationships between a new measure of GRC developed specifically for use with Irish adolescents (I-GRCS-A; O’Beaglaoich et al., 2016), and depression, self-esteem, and negative/protective suicide ideation. A sample of 176 adolescent boys (M = 16.9, SD = 0.94) from a non-clinical population participated in the study. Regression analyses and tests of mediation revealed that depression significantly mediated the relationship between GRC and negative suicide ideation, whilst self-esteem and depression significantly mediated the relationship between GRC and positive suicide ideation. Implications and limitations of the current study are outlined and directions for future research are discussed.
Infectious Wildlife Diseases in Austria—A Literature Review From 1980 Until 2017

This literature review examines infectious wildlife disease research in Austria. We analyzed 226 research papers, published between 1980 and 2017. We determined that wildlife disease papers increased significantly from 0.8 ± 0.8 publications per year in the first decade (1980–1989) when compared to 2008–2017 with an average of 12.9 ± 4.1 publications per year. We illustrate information about the most investigated diseases and highlight the lack of research into certain wildlife pathogens. A special emphasis was given to diseases with zoonotic potential. The review showed that research focused on a few select species like the red fox (Vulpes vulpes), red deer (Cervus elaphus), and wild boar (Sus scrofa), all game species. Moreover, diseases affecting livestock and human health were seen more often. The review also found that only a low number of publications actually stated disease prevalence and confidence interval data. The reported diseases identified were classified according to their notifiable status and the distribution at the wildlife–human and wildlife–livestock interface. Furthermore, we try to argue why research into some diseases is prioritized, and why other diseases are underrepresented in current Austrian research. While spatiotemporal indicators could not be assessed due to the variability in methodologies and objectives of various studies, the information provided by this review offers the first comprehensive evaluation of the status of infectious wildlife disease research in Austria. Therefore, this study could assist investigators to identify further areas of priorities for research and conservation efforts and for wildlife management professionals to inform policy and funding strategies. With this review, we want to encourage research in the field of wildlife diseases in Austria to enhance current knowledge in the prevention of further loss in biodiversity and to find new measures to promote “One Health” on a global scale.
Audio in VR: Effects of a Soundscape and Movement-Triggered Step Sounds on Presence

For effective virtual realities, “presence,” the feeling of “being there” in a virtual environment (VR), is deemed an essential prerequisite. Several studies have assessed the effect of the (non-)availability of auditory stimulation on presence, but due to differences in study design (e.g., virtual realities used, types of sounds included, rendering technologies employed), generalizing the results and estimating the effect of the auditory component is difficult. In two experiments, the influence of an ambient nature soundscape and movement-triggered step sounds were investigated regarding their effects on presence. In each experiment, approximately forty participants walked on a treadmill, thereby strolling through a virtual park environment reproduced via a stereoscopic head-mounted display (HMD), while the acoustical environment was delivered via noise-canceling headphones. In Experiment 1, conditions with the ambient soundscape and the step sounds either present or absent were combined in a 2 × 2 within-subjects design, supplemented with an additional “no-headphones” control condition. For the synchronous playback of step sounds, the probability of a step being taken was estimated by an algorithm using the HMD's sensor data. The results of Experiment 1 show that questionnaire-based measures of presence and realism were influenced by the soundscape but not by the reproduction of steps, which might be confounded with the fact that the perceived synchronicity of the sensor-triggered step sounds was rated rather low. Therefore, in Experiment 2, the step-reproduction algorithm was improved and judged to be more synchronous by participants. Consequently, large and statistically significant effects of both kinds of audio manipulations on perceived presence and realism were observed, with the effect of the soundscape being larger than that of including footstep sounds, possibly due to the remaining imperfections in the reproduction of steps. Including an appropriate soundscape or self-triggered footsteps had differential effects on subscales of presence, in that both affected overall presence and realism, while involvement was improved and distraction reduced by the ambient soundscape only.
Molecular Characterization of Visceral Leishmaniasis in Asymptomatic Dogs in North Khorasan, Northeastern Iran

Background: Leishmania infantum parasites are the main causative agents of visceral leishmaniasis that threaten a wide range of humans and canines in Iran. Objectives: Our aim was to survey Leishmania parasite species and simultaneous comparison of canine organs in endemic areas for the diagnosis of visceral leishmaniasis using the ITS-rDNA gene, sequencing, and phylogenetic analysis. Methods: In this study, sampling was done with vacuum tubes containing EDTA from blood and sterile swabs from the snout and conjunctiva of asymptomatic sheepdogs (n = 37) using a non-invasive method in north Khorasan, northeastern Iran, from 28 July to 4 August 2018. The DNA of collected samples was extracted, amplified, and sequenced by targeting the ITS-rDNA gene. To demonstrate the taxonomic status of Leishmania spp. , sequences were subjected to phylogenetic analysis based on the maximum likelihood method. Results: We obtained 37 samples from asymptomatic dogs of which, 10 dogs were definitely diagnosed with L. infantum and one dog infected with L. tropica. The blood (n = 8) and right conjunctiva (n = 6) samples were the most infected samples. The highest number of infections in dogs was in the age group of 5 - 10 years indicating that this group is more sensitive to visceral leishmaniasis in this region. Conclusions: The current findings indicate that non-invasive sampling and molecular methods are reliable and suitable in the detection of visceral leishmaniasis. This is the first report of the visceral involvement of a shepherd dog with L. tropica in northeastern Iran. The remarkable occurrence of visceral leishmaniasis (29.7%) in asymptomatic sheepdogs reflects a health alert to conduct the surveillance and monitoring of susceptible individuals/reservoirs in the region.