Miracle-dz/UniFAR-FTUs huggingface dataset:
A Novel Mouse Model of MYO7A USH1B Reveals Auditory and Visual System Haploinsufficiencies

Usher’s syndrome is the most common combined blindness–deafness disorder with USH1B, caused by mutations in MYO7A, resulting in the most severe phenotype. The existence of numerous, naturally occurring shaker1 mice harboring variable MYO7A mutations on different genetic backgrounds has complicated the characterization of MYO7A knockout (KO) and heterozygote mice. We generated a novel MYO7A KO mouse (Myo7a–/–) that is easily genotyped, maintained, and confirmed to be null for MYO7A in both the eye and inner ear. Like USH1B patients, Myo7a–/– mice are profoundly deaf, and display near complete loss of inner and outer cochlear hair cells (HCs). No gross structural changes were observed in vestibular HCs. Myo7a–/– mice exhibited modest declines in retinal function but, unlike patients, no loss of retinal structure. We attribute the latter to differential expression of MYO7A in mouse vs. primate retina. Interestingly, heterozygous Myo7a+/– mice had reduced numbers of cochlear HCs and concomitant reductions in auditory function relative to Myo7a+/+ controls. Notably, this is the first report that loss of a single Myo7a allele significantly alters auditory structure and function and suggests that audiological characterization of USH1B carriers is warranted. Maintenance of vestibular HCs in Myo7a–/– mice suggests that gene replacement could be used to correct the vestibular dysfunction in USH1B patients. While Myo7a–/– mice do not exhibit sufficiently robust retinal phenotypes to be used as a therapeutic outcome measure, they can be used to assess expression of vectored MYO7A on a null background and generate valuable pre-clinical data toward the treatment of USH1B.
Arabidopsis ZUOTIN RELATED FACTOR1 Proteins Are Required for Proper Embryonic and Post-Embryonic Root Development

The H2A/UBIQUITIN-binding proteins AtZRF1a/b have been reported as key regulators involved in multiple processes of Arabidopsis plant growth and development. Yet, the cellular and molecular mechanisms underlying the mutant phenotype remain largely elusive. Here we show that loss-of-function of AtZRF1a/b causes defective root elongation and deformed root apical meristem organization in seedlings. The premature termination of the primary root in the atzrf1a;atzrf1b double mutant is associated with an advanced onset of endoreduplication and subsequent consumption of reservoir stem cells. Cytological analyses using cell type-specific markers and florescent dyes indicate that AtZRF1a/b are involved in maintenance of proper cell layer organization, determinacy of cell identity, and establishment of auxin gradient and maximum at the root tip. During embryogenesis AtZRF1a/b act dominantly in regulating the maintenance of ground tissue initial cells and production of lateral root cap. Lastly, quantitative real-time polymerase chain reaction analysis shows mis-expression of some key genes involved in regulating cell patterning, cell proliferation and/or hormone pathways. Our results provide important insight into AtZRF1a/b function in cell fate determinacy and in establishment and maintenance of proper stem cell reservoir during embryonic and post-embryonic root development.
Health-Related Physical Fitness and Quality of Life in Children and Adolescents With Isolated Left-to-Right Shunt

Objective: Atrial (ASD) and ventricular septal defects (VSD) represent the most common congenital heart defects (CHD) and are considered simple and curable. This study investigates long-term functional outcomes in children with such defects. Patients and Methods : We examined 147 patients (74 girls, 12.1 ± 3.5 years) with isolated shunts (ASD: 54%, VSD: 46%) for their Health-Related Physical Fitness (HRPF) and Health-Related Quality of Life (HRQoL). Native condition was present in 58 patients, interventional closure of the defect was performed in 42 and surgical closure in 47. For comparison, a healthy control group (CG) of 1,724 children (48.9% girls, 12.8 ± 2.8 years) was recruited within two recent school projects. Results: After adjustment for age and sex, children with ASD and VSD presented lower HRPF (z-score healthy peers: 0.02 ± 0.73, ASD: −0.41 ± 0.73, p < 0.001; VSD: −0.61 ± 0.73, p < 0.001) then healthy peers. Transferred into percentiles, VSD were on the 26th and ASD on the 34th percentile of the healthy peers. HRQoL did not differ between peers and CHD with isolated shunts (healthy peers: 76.1 ± 9.7, ASD: 76.2 ± 9.9, p = 0.999; VSD: 78.7 ± 9.7, p = 0.316). Regarding the surgical history of the shunts (native, percutaneously treated, surgically treated), there were also no difference in-between these three states, nor differed HRPF and HRQoL in-between gender. Conclusions: Children with ASD or VSD have impaired HRPF but normal HRQoL. Early childhood sports promotion could be a good measure to counteract these restrictions in HRPF at an early stage.
Management of chronic pain with Jalaprakshalana (water-wash) Shodhita (processed) Bhanga (Cannabis sativa L.) in cancer patients with deprived quality of life: An open-label single arm clinical trial

Introduction: Pain is a common and complex symptom of cancer having physical, social, spiritual and psychological aspects. Approximately 70%–80% of cancer patients experiences pain, as reported in India. Ayurveda recommends use of Shodhita (Processed) Bhanga (Cannabis) for the management of pain but no research yet carried out on its clinical effectiveness. Objective: To assess the analgesic potential of Jala-Prakshalana (Water-wash) processed Cannabis sativa L. leaves powder in cancer patients with deprived quality of life (QOL) through openlabel single arm clinical trial. Materials and Methods: Waterwash processed Cannabis leaves powder filled in capsule, was administered in 24 cancer patients with deprived QOL presenting complaints of pain, anxiety or depression; for a period of 4 weeks; in a dose of 250 mg thrice a day; along with 50 ml of cow's milk and 4 g of crystal sugar. Primary outcome i.e. pain was measured by Wong-Bakers FACES Pain Scale (FACES), Objective Pain Assessment (OPA) scale and Neuropathic Pain Scale (NPS). Secondary outcome namely anxiety was quantified by Hospital Anxiety and Depression Scale (HADS), QOL by FACT-G scale, performance score by Eastern Cooperative Oncology Group (ECOG) and Karnofsky score. Results: Significant reduction in pain was found on FACES Pain Scale (P < 0.05), OPA (P < 0.05), NPS (P < 0.001), HADS (P < 0.001), FACT-G scale (P < 0.001), performance status score like ECOG (P < 0.05) and Karnofsky score (P < 0.01). Conclusion: Jalaprakshalana Shodhita Bhanga powder in a dose of 250 mg thrice per day; relieves cancerinduced pain, anxiety and depression significantly and does not cause any major adverse effect and withdrawal symptoms during trial period.
The MATH-BTB Protein TaMAB2 Accumulates in Ubiquitin-Containing Foci and Interacts With the Translation Initiation Machinery in Arabidopsis

MATH-BTB proteins are known to act as substrate-specific adaptors of CUL3-based E3 ligases in the ubiquitin proteasome pathway. Their BTB domain binds to CUL3 scaffold proteins and the less conserved MATH domain targets a highly diverse collection of substrate proteins to promote their ubiquitination and subsequent degradation. In plants, a significant expansion of the MATH-BTB family occurred in the grasses. Here, we report analysis of TaMAB2, a MATH-BTB protein transiently expressed at the onset of embryogenesis in wheat. Due to difficulties in studying its role in zygotes and early embryos, we have overexpressed TaMAB2 in Arabidopsis to generate gain-of-function mutants and to elucidate interaction partners and substrates. Overexpression plants showed severe growth defects as well as disorganization of microtubule bundles indicating that TaMAB2 interacts with substrates in Arabidopsis. In tobacco BY-2 cells, TaMAB2 showed a microtubule and ubiquitin-associated cytoplasmic localization pattern in form of foci. Its direct interaction with CUL3 suggests functions in targeting specific substrates for ubiquitin-dependent degradation. Although direct interactions with tubulin could not be confimed, tandem affinity purification of TaMAB2 interactors point towards cytoskeletal proteins including tubulin and actin as well as the translation initiation machinery. The idenification of various subunits of eucaryotic translation initiation factors eIF3 and eIF4 as TaMAB2 interactors indicate regulation of translation initiation as a major function during onset of embryogenesis in plants.
An EEG-/EOG-Based Hybrid Brain-Computer Interface: Application on Controlling an Integrated Wheelchair Robotic Arm System

Most existing brain-computer Interfaces (BCIs) are designed to control a single assistive device, such as a wheelchair, a robotic arm or a prosthetic limb. However, many daily tasks require combined functions which can only be realized by integrating multiple robotic devices. Such integration raises the requirement of the control accuracy and is more challenging to achieve a reliable control compared with the single device case. In this study, we propose a novel hybrid BCI with high accuracy based on electroencephalogram (EEG) and electrooculogram (EOG) to control an integrated wheelchair robotic arm system. The user turns the wheelchair left/right by performing left/right hand motor imagery (MI), and generates other commands for the wheelchair and the robotic arm by performing eye blinks and eyebrow raising movements. Twenty-two subjects participated in a MI training session and five of them completed a mobile self-drinking experiment, which was designed purposely with high accuracy requirements. The results demonstrated that the proposed hBCI could provide satisfied control accuracy for a system that consists of multiple robotic devices, and showed the potential of BCI-controlled systems to be applied in complex daily tasks.
Therapeutic Potential of the Hsp90/Cdc37 Interaction in Neurodegenerative Diseases

Alzheimer’s, Huntington’s, and Parkinson’s are devastating neurodegenerative diseases that are prevalent in the aging population. Patient care costs continue to rise each year, because there is currently no cure or disease modifying treatments for these diseases. Numerous efforts have been made to understand the molecular interactions governing the disease development. These efforts have revealed that the phosphorylation of proteins by kinases may play a critical role in the aggregation of disease-associated proteins, which is thought to contribute to neurodegeneration. Interestingly, a molecular chaperone complex consisting of the 90 kDa heat shock protein (Hsp90) and Cell Division Cycle 37 (Cdc37) has been shown to regulate the maturation of many of these kinases as well as regulate some disease-associated proteins directly. Thus, the Hsp90/Cdc37 complex may represent a potential drug target for regulating proteins linked to neurodegenerative diseases, through both direct and indirect interactions. Herein, we discuss the broad understanding of many Hsp90/Cdc37 pathways and how this protein complex may be a useful target to regulate the progression of neurodegenerative disease.
Structure-Based and Molecular Modeling Studies for the Discovery of Cyclic Imides as Reversible Cruzain Inhibitors With Potent Anti-Trypanosoma cruzi Activity

Chagas disease causes ~10,000 deaths each year, mainly in Latin America, where it is endemic. The currently available chemotherapeutic agents are ineffective in the chronic stage of the disease, and the lack of pharmaceutical innovation for Chagas disease highlights the urgent need for the development of new drugs. The enzyme cruzain, the main cysteine protease of Trypanosoma cruzi, has been explored as a validated molecular target for drug discovery. Herein, the design, molecular modeling studies, synthesis, and biological evaluation of cyclic imides as cruzain inhibitors are described. Starting with a micromolar-range cruzain inhibitor (3a, IC50 = 2.2 μM), this molecular optimization strategy resulted in the nanomolar-range inhibitor 10j (IC50 = 0.6 μM), which is highly active against T. cruzi intracellular amastigotes (IC50 = 1.0 μM). Moreover, most compounds were selective toward T. cruzi over human fibroblasts, which were used as host cells, and are less toxic to hepatic cells than the marketed drug benznidazole. This study enabled the discovery of novel chemical diversity and established robust structure-activity relationships to guide the design of optimized cruzain inhibitors as new trypanocidal agents.
The Fruits of Siraitia grosvenorii: A Review of a Chinese Food-Medicine

Siraitia grosvenorii (Swingle) C. Jeffrey, a member of the family Cucurbitaceae, is a unique economic and medicinal plant grown in China. For more than 300 years, S. grosvenorii has been used as a natural sweetener and as a traditional medicine for the treatment of pharyngitis, pharyngeal pain, as well as an anti-tussive remedy in China. It is one of the first approved medicine food homology species in China. It has been widely studied as a natural product with high development potential. Therefore, the present paper provides a review of the botanical characterization, traditional uses and ethnopharmacology, food and nutritional values, chemical constituents, pharmacological effects, toxicology, and development direction for the future of S. grosvenorii. Phytochemical studies have revealed that the chemical composition of this plant mainly includes iridoid and phenylpropanoid glycosides. Several compounds such as triterpenoids, flavonoids, and amino acids have been isolated from the plant. S. grosvenorii and its active constituents possess broad pharmacological properties, such as antioxidant, hypoglycemic, immunologic, anti-tussive and sputum-reducing, hepatoprotective, and antimicrobial activities, etc. By documenting the comprehensive information of S. grosvenorii, we hope to establishes the groundwork for further research on the mechanism of action of S. grosvenorii and its development as a new health food in the future.
Emergence of NDM-1- and CTX-M-3-Producing Raoultella ornithinolytica in Human Gut Microbiota

Raoultella ornithinolytica is an opportunistic pathogen of the Enterobacteriaceae family and has been implicated in nosocomial infections in recent years. The aim of this study was to characterize a carbapenemase-producing R. ornithinolytica isolate and three extended-spectrum β-lactamase (ESBL)-producing R. ornithinolytica isolates from stool samples of adults in a rural area of Shandong Province, China. The species were identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and 16S rDNA sequence analysis. Antimicrobial susceptibility test showed that all four isolates were multidrug-resistant (MDR). The whole genome sequence (WGS) of these isolates was determined using an Illumina HiSeq platform, which revealed MDR-related genes. The S1 nuclease-pulsed-field gel electrophoresis (S1-PFGE) was used to characterize the plasmids carried by the R. ornithinolytica isolates. The blaNDM-1 and blaCTX-M-3 genes were probed using Southern blotting, which confirmed the location of both genes on the same plasmid with molecular weight of 336.5–398.4 kb. The transferability of blaNDM-1 and blaCTX-M was also confirmed by conjugation assays. Finally, BLAST analysis of both genes showed that mobile genetic elements were associated with the spread of drug resistance genes. Taken together, we report the presence of conjugative blaNDM-1 and blaCTX-M plasmids in R. ornithinolytica isolates from healthy humans, which indicate the possibility of inter-species transfer of drug resistance genes. To the best of our knowledge, this is the first study to isolate and characterize carbapenemase-producing R. ornithinolytica and ESBL-producing R. ornithinolytica isolates from healthy human hosts.
A Pilot Study of an In-Home Multicomponent Exergame Training for Older Adults: Feasibility, Usability and Pre-Post Evaluation

Aging is associated with sensory, motor and cognitive impairments that may lead to reduced daily life functioning including gait disturbances, falls, injuries and mobility restrictions. A strong need exists for implementing effective evidence-based interventions for healthy aging. Therefore, the aim of this study was to (i) evaluate the feasibility and usability of an in-home multicomponent exergame training and (ii) explore its effects on physical functions, cognition and cortical activity. Twenty-one healthy and independently living older adults were included (11 female, 74.4 ± 7.0 years, range: 65–92 years) and performed 24 trainings sessions (each 40 min) over eight weeks. The first part was conducted in a living lab (home-like laboratory environment), the second part at participants’ home. The multicomponent exergame included Tai Chi-inspired exercises, dance movements and step-based cognitive games to train strength, balance and cognition. Attendance and attrition rates were calculated and safety during training was evaluated to determine feasibility. Participants rated the usability of the exergame (System Usability Scale) and reported on their game experience (Game Experience Questionnaire). Physical and cognitive functions and cortical activity (resting state electroencephalopathy) were assessed pre and post intervention. Results showed a high training attendance rate for the living lab and the home-based setting (91.7 and 91.0%, respectively) with a rather high attrition rate (28.6%, six drop-outs). Half of the drop-out reasons were related to personal or health issues. System usability was rated acceptable with a mean score of 70.6/100. Affective game experience was rated favorable. Significant improvements were found for minimal toe clearance, short-term attentional span, and information processing speed (p < 0.05). No significant pre-post differences were found for cortical activity. To summarize, the exergame is generally feasible and usable for healthy older adults applied in an in-home setting and provides an overall positive emotional game experience. Nevertheless, flawless technical functionality should be a mandatory consideration. Additionally, the training might have potential positive influence on specific functions in older adults. However, the efficacy has to be evaluated in a future randomized controlled trial assessing the behavioral and neuroplastic changes in a larger population after a longer training period.
Characterization of the Dynamic Behavior of Neutrophils Following Influenza Vaccination

Neutrophils are amongst the first cells to respond to inflammation and infection. Although they play a key role in limiting the dissemination of pathogens, the study of their dynamic behavior in immune organs remains elusive. In this work, we characterized in vivo the dynamic behavior of neutrophils in the mouse popliteal lymph node (PLN) after influenza vaccination with UV-inactivated virus. To achieve this, we used an image-based systems biology approach to detect the motility patterns of neutrophils and to associate them to distinct actions. We described a prominent and rapid recruitment of neutrophils to the PLN following vaccination, which was dependent on the secretion of the chemokine CXCL1 and the alarmin molecule IL-1α. In addition, we observed that the initial recruitment occurred mainly via high endothelial venules located in the paracortical and interfollicular regions of the PLN. The analysis of the spatial-temporal patterns of neutrophil migration demonstrated that, in the initial stage, the majority of neutrophils displayed a patrolling behavior, followed by the formation of swarms in the subcapsular sinus of the PLN, which were associated with macrophages in this compartment. Finally, we observed using multiple imaging techniques, that neutrophils phagocytize and transport influenza virus particles. These processes might have important implications in the capacity of these cells to present viral antigens.
A Strigolactone Signal Inhibits Secondary Lateral Root Development in Rice

Strigolactones (SLs) and their derivatives are plant hormones that have recently been identified as regulators of primary lateral root (LR) development. However, whether SLs mediate secondary LR production in rice (Oryza sativa L.), and how SLs and auxin interact in this process, remain unclear. In this study, the SL-deficient (dwarf10) and SL-insensitive (dwarf3) rice mutants and lines overexpressing OsPIN2 (OE) were used to investigate secondary LR development. The effects of exogenous GR24 (a synthetic SL analogue), 1-naphthylacetic acid (NAA; an exogenous auxin), 1-naphthylphthalamic acid (NPA; a polar auxin transport inhibitor), and abamine (a synthetic SL inhibitor) on rice secondary LR development were investigated. Rice d mutants with impaired SL biosynthesis and signaling exhibited increased secondary LR production compared with wild-type (WT) plants. Application of GR24 decreased the numbers of secondary LRs in dwarf10 (d10) plants but not in dwarf3 (d3), plants. These results indicate that SLs negatively regulate rice secondary LR production. Higher expression of DR5::GUS and more secondary LR primordia were found in the d mutants than in the WT plants. Exogenous NAA application increased expression of DR5::GUS in the WT, but had no effect on secondary LR formation. No secondary LRs were recorded in the OE lines, although DR5::GUS levels were higher than in the WT plants. However, on application of NPA, the numbers of secondary LRs were reduced in d10 and d3 mutants. Application of NAA increased the number of secondary LRs in the d mutants. GR24 eliminated the effect of NAA on secondary LR development in the d10, but not in the d3, mutants. These results demonstrate the importance of auxin in secondary LR formation, and that this process is inhibited by SLs via the D3 response pathway, but the interaction between auxin and SLs is complex.
The Relationship between Size of Adenocarcinoma of Colon and Lymph Node Involvement

Background and Objectives: Involvement of lymph nodes is an important prognostic factor in the most cancers, including colorectal cancer. In the recent years, invasion to blood and lymphatic vessels has been shown to predict involvement of lymph nodes and the number of involved nodes has been less studied issue. The aim of this study was determination of the relationship between the size of colorectal adenocarcinoma and lymph node involvement. Materials & Methods: In this cross-sectional study, 116 patients were enrolled with colorectal cancer from Rasoul-e-Akram and Mehr Hospitals in 2002-2008. Data analysis was performed by SPSS15 software. Results were expressed as frequency, percent, and mean ±SD. We used Chi2, student ttest and correlation tests for statistical analysis. Results: 54.3% of patients were male and 45.7% were female. Mean age of them was 59.4± 12.9 years. Mean of tumor size (longest diameter) was 5.4± 2.2 (range: 1.5 to 12) cm. Mean number of involved lymph nodes was 4.9± 3.5(range: 1-14). There was no correlation between number of lymph node involvement and tumor size. There was no correlation between lymph node involvement and tumor and age group, sex, location and depth of tumor. Poorly differentiated tumor significantly correlated to lymph node involvement (P=0.001). Conclusion: There is no correlation between tumor size and number of involved lymph node in colorectal cancer. However, poor histopathologic grade is associated with lymph node involvement.
Evaluation of Wear of Milling Cutters for Drilling of Nail Holes Used for Osteosynthesis of Long Bones of Lower Limbs

Abstract This paper deals with wear of intramedullary milling cutters for the drilling of nail holes used for osteosynthesis of lower limbs long bones. After the physician’s complaints about the increasing resistance and total change of its properties that are caused by the reuse the instrument, we have designed a suitable methodology to verify and quantify this problem. The experiment was carried out on three types of milling cutters, differing in their diameter. Using statistical tests, we compared pressure force and torque before and after wear.