Plexin-semaphorin signalling modifies neuromuscular defects in a Drosophila model of peripheral neuropathy

Dominant mutations in GARS, encoding the ubiquitous enzyme glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and Charcot-Marie-Tooth disease type 2D (CMT2D). This genetic disorder exemplifies a recurring paradigm in neurodegeneration, in which mutations in essential genes cause selective degeneration of the nervous system. Recent evidence suggests that the mechanism underlying CMT2D involves extracellular neomorphic binding of mutant GlyRS to neuronally-expressed proteins. Consistent with this, our previous studies indicate a non-cell autonomous mechanism, whereby mutant GlyRS is secreted and interacts with the neuromuscular junction (NMJ). In this Drosophila model for CMT2D, we have previously shown that mutant gars expression decreases viability and larval motor function, and causes a concurrent build-up of mutant GlyRS at the larval neuromuscular presynapse. Here, we report additional phenotypes that closely mimic the axonal branching defects of Drosophila plexin transmembrane receptor mutants, implying interference of plexin signaling in gars mutants. Individual dosage reduction of two Drosophila Plexins, plexin A (plexA) and B (plexB) enhances and represses the viability and larval motor defects caused by mutant GlyRS, respectively. However, we find plexB levels, but not plexA levels, modify mutant GlyRS association with the presynaptic membrane. Furthermore, increasing availability of the plexB ligand, Semaphorin-2a (Sema2a), alleviates the pathology and the build-up of mutant GlyRS, suggesting competition for plexB binding may be occurring between these two ligands. This toxic gain-of-function and subversion of neurodevelopmental processes indicate that signaling pathways governing axonal guidance could be integral to neuropathology and may underlie the non-cell autonomous CMT2D mechanism

Progressive ataxia with oculo-palatal tremor and optic atrophy

The final publication is available at Springer via doi: 10.​1007/​s00415-013-7136-

Predictive Technique Of Security Data Breaches In Ai Powered Mobile Cloud Application Using Deep Random Forest Algorithm

With the rapid integration of artificial intelligence (AI) in mobile cloud applications, ensuring robust security mechanisms is vital to safeguard sensitive user data. The proliferation of AI technologies in mobile cloud applications has brought unprecedented efficiency and convenience, accompanied by an escalating risk of security breaches. As the threat landscape evolves, traditional security measures fall short in providing comprehensive protection. This research recognizes the critical need for a predictive approach to security data breaches in AI-powered mobile cloud applications. Existing security frameworks often lack the adaptability to detect and pre-emptively address emerging threats specific to AI-enhanced mobile cloud environments. This study employs the Deep Random Forest Algorithm, an advanced machine learning technique known for its ability to handle complex and dynamic datasets. The algorithm combines the power of deep learning with the versatility of random forest classifiers to predict security breaches in real-time. The results demonstrate the efficacy of the proposed Deep Random Forest Algorithm in predicting and mitigating security breaches in AI-powered mobile cloud applications. The model exhibits high accuracy and sensitivity, showcasing its potential to enhance the security posture of mobile cloud ecosystems

Hearing Benefit in Middle Ear Reconstructive Surgery: A Comparative Study of the Current Methods

INTRODUCTION: Discharging ear and deafness are perpetual source of misery to humankind. Chronic suppurative otitis media is found to be the single major cause of conductive deafness manifesting in 66.3% of cases. The other causes being trauma, otosclerosis, congenital malformations, neoplastic causes etc. Auditory sensation is one of the vital sensations for existence. Deafness upsets the tranquility of life. When such a great vital sensation is lost, life naturally loses its charm. In last 50 years, various researches have been carried out for repair of ossicular chain defects alone or those associated with tympanic membrane perforations. A number of materials have been used with varying results. Right from Hall and Rytzer of 1957 till today, several pioneers have revolutionized the outlook of ossiculoplasty. Several materials have been used for ossiculoplasty. Some of the materials are autograft/homograft ossicles, autograft/homograft cartilage, teflon, hydroxyapatite, titanium, gold, bioglass etc. The goal of otologists performing middle ear surgery to correct conductive hearing loss is to improve hearing as well as to provide a functional benefit to the patient. Unilateral conductive hearing loss is associated with various disabilities including difficulty in sound localization and in hearing and understanding speech. Traditionally, otologists have reported the results of middle ear surgery as the closure of the air - bone gap or the reduction in air conduction thresholds. The closure of the air-bone gap refers to improvement of the air conduction thresholds (involving conductive and sensorineural components) to the level of the bone conduction thresholds (sensorineural component). While these provide a measure of the technical success of the operation, they may not always translate into real life benefit for the patient. Hence standardization of results of treatment should be by a method based on subjective perception which benefits patients in real life. Other methods have been used to evaluate the effectiveness of middle ear surgery including questionnaires that evaluate a patient's subjective benefit from surgery. Using questionnaires to evaluate benefit is complicated by the fact that both surgeons and patients want to believe that the operation has succeeded. The two most common methods found in the otologic literature to evaluate benefit from middle ear surgery are the Belfast 15/30 dB rule of thumb and the Glasgow benefit plot. These methods facilitates the assessment of subjective benefit as well as objective achievement, we have employed these two most common methods to estimate patient benefit from middle ear surgery in our study. AIMS AND OBJECTIVES: 1. To compare two methods of predicting the level of hearing benefit following middle ear surgery, namely Glasgow benefit plot and Belfast 15/30 dB rule of Thumb. 2. To correlate hearing benefit as measured by using the above methods with patients' self assessment of his/her hearing status 3. To analyze the differences in hearing improvement by various ossiculoplasties like incus interposition, tragal/ conchal cartilage and autograft malleus. 4. To compare the success rates with surgery on dry and wet ears. 5. To compare success rates with cavity mastoidectomy cases versus those without cavity. MATERIALS AND METHODS: Sixty patients undergoing middle ear surgery were selected at random with no age or sex bias. Only patients with conductive hearing loss were selected. The minimum age was 11 years and maximum age was 48 years. Those cases requiring myringoplasty were excluded from the study. Any allergic or septic focus was ruled out preoperatively. Cases with bilateral ear disease were also taken up and revision cases were also subjected to surgery on 7 occassions. Both wet and dry ears were taken up. Patients were admitted one day before the surgery. Mastoid shaving and local preparation were done in the ward. All cases were operated under general anaesthesia. The types of surgery included in the study were mastoid exploration, tympanoplasty and ossiculoplasty. Apart from a detailed case history, patients were assessed clinically with the help of otoscopy, tuning fork tests, pure tone audiometry, free field hearing tests, X-ray Mastoids and CT Temporal bone were done where applicable. A detailed questionnaire was used (separately to be filled in by the patient and the close first relative of the patient) pre and post operatively, to assess the level of hearing. Patients were followed post operatively for 3 & 6 months. RESULTS AND OBSERVATIONS: There were 38 males and 22 females. Age range was from 11-48 years. The younger patients were more aware of their hearing loss and consisted of 76.6 % of all the patients. The commonest disease was CSOM - tubotympanic (14 cases) and atticoantral (46 cases). Group 1 : Unilateral hearing impairment, asymmetric threshold 12 patients were included in this group. All had pure tone average above 30 dB in one ear; all had interaural difference of more than 10 dB. Preoperative self assessment of hearing loss by patients : Patients presented with varying degrees of subjective hearing impairment, such as diminished hearing from a distance, in group conversation, on telephone, discharge and diminished hearing. Post operatively: Hearing from operated and non-operated ear was same in 6 patients (3 patients had inter aural difference of 12, 12 & 18 dB but claimed symmetric hearing). Group 2 : Bilateral hearing impairment, asymmetric threshold. 40 patients were included in this group and 37 patients had pure tone averages above 30 dB in both ears. 29 patients had inter aural difference of more than 10dB. Patients claimed significant benefit post operatively. Hearing from operated and non-operated ear was same in 33 patients. The prediction by both methods in this group was 100%. 19 patients fell in category 'c' and claimed significant benefit. Group 3 : Bilateral hearing impairment - symmetric threshold 8 patients were included in this group. Pure tone average was less than 30 dB in six cases and interaural difference within 10 dB in 2 cases and 12,12,15,16,25,28,26 dB in 6 patients. They had significant benefit following surgery and claimed that the operated ear was the better hearing ear. As per audiometry, 2 patients fell in category 'c' and claimed significant benefit. As per subjective benefit all these patients claimed significant benefit. Comparing the same with 15/30 dB rule of thumb as per audiometry, the overall positive predictive value was 80% and as per subjective benefit 84%. Applying Z test for significance of difference between the predictive values by pure Tone Audiometry and subjective benefit in both the methods, the difference is not significant since Z is <1.96 at 95% confidence interval. 10 out of 12 patients (83%) in Group I had no difficulty in localizing sound, as only one ear is actually sufficient to localize sound. According to Browning GG (1993), minor head movement can achieve the necessary variation in speech perception level. In Group 3, 8 patients had bilateral symmetric hearing loss as per pure tone audiometry. Pure tone averages in the 0.5,1,2 kHz were same in both ears. This correlates with observations of G.G.Browning (1993), audiometric tests do not measure all aspects of hearing; hence the ear being operated upon should be as per patient's choice. CONCLUSION: 1. The overall success rate of ossiculoplasty in the present study is 80%. 2. In this study its found that Glasgow benefit plot is more sophisticated, graphical, providing a good visual impression whereas Belfast Rule of thumb is easy and simple to use, but, it suffers from the disadvantages of 'all or none phenomenon' with no place for marginal benefit. 3. Hearing improvement with Incus transposition is better followed by tragal and conchal cartilage ossiculoplasty, Homograft Malleus (in descending order). 4. Hearing improvement is better when minimal ossicular disruption is present. (All present > Incus absent > M-I-> M-I-S-) 5. Hearing improvement is better when cholesteatoma is absent (when compared to cholesteatoma cases). 6. Hearing improvement is better with dry ears. 7. Hearing improvement is better when cavity mastoidectomy was not done (when compared to cavity mastoidectomy cases.) 8. Fresh cases do better than revision cases. 9. Cases without granulations do better than those with granulations

TRESK is a key regulator of nocturnal suprachiasmatic nucleus dynamics and light adaptive responses

The suprachiasmatic nucleus (SCN) is a complex structure dependent upon multiple mechanisms to ensure rhythmic electrical activity that varies between day and night, to determine circadian adaptation and behaviours. SCN neurons are exposed to glutamate from multiple sources including from the retino-hypothalamic tract and from astrocytes. However, the mechanism preventing inappropriate post-synaptic glutamatergic effects is unexplored and unknown. Unexpectedly we discovered that TRESK, a calcium regulated two-pore potassium channel, plays a crucial role in this system. We propose that glutamate activates TRESK through NMDA and AMPA mediated calcium influx and calcineurin activation to then oppose further membrane depolarisation and rising intracellular calcium. Hence, in the absence of TRESK, glutamatergic activity is unregulated leading to membrane depolarisation, increased nocturnal SCN firing, inverted basal calcium levels and impaired sensitivity in light induced phase delays. Our data reveals TRESK plays an essential part in SCN regulatory mechanisms and light induced adaptive behaviours

Minimally Invasive In Vivo Real-Time Identification of Human Astrocytoma with Sulforhodamine 101

Abstract and poster under embargo until May 31, 2019

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies

A new paradigm for healthcare system using emerging technologies

There are many diseases threatening humans around the globe. Many of them are from the past centuries, and a few are newly discovered. This study has mainly focused on trending technologies such as Artificial Intelligence, Machine Learning, Big Data, Internet of Things that are used to predict diseases in the health sector. This study has collected data from the previously published articles from the reputed publishers using a systematic review approach, and these data were analyzed separately for each technology mentioned above. Studies confirmed that most of the research focused on IoT in the health sector. Furthermore, all the above technologies provide higher accuracy in predicting diseases. But, IoT provides higher accuracy than other emerging technologies for predicting most diseases. A few constraints of the study were the size of the dataset and missing quality qualities. In the end, it is recommended to study the security issues in IoT in the healthcare sector to predict and diagnose diseases