Reshaping Antibody Diversity

SummarySome species mount a robust antibody response despite having limited genome-encoded combinatorial diversity potential. Cows are unusual in having exceptionally long CDR H3 loops and few V regions, but the mechanism for creating diversity is not understood. Deep sequencing reveals that ultralong CDR H3s contain a remarkable complexity of cysteines, suggesting that disulfide-bonded minidomains may arise during repertoire development. Indeed, crystal structures of two cow antibodies reveal that these CDR H3s form a very unusual architecture composed of a β strand “stalk” that supports a structurally diverse, disulfide-bonded “knob” domain. Diversity arises from somatic hypermutation of an ultralong DH with a severe codon bias toward mutation to cysteine. These unusual antibodies can be elicited to recognize defined antigens through the knob domain. Thus, the bovine immune system produces an antibody repertoire composed of ultralong CDR H3s that fold into a diversity of minidomains generated through combinations of somatically generated disulfides

A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling.

Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes1,2, and regulate cellular functions such as metabolism3-5 and transcription6. An important 'sensor' protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF27,8, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1-NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases

Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-beta-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents

Effect of microwave assisted convective drying on physical properties, bioactive compounds, antioxidant potential and storage stability of red bell pepper

Current study was aimed to optimize the process conditions for microwave assisted convective drying of red bell pepper (RBP) by employing Response Surface Methodology (RSM). Responses analyzed for determining the optimum conditions were total phenolics, vitamin C, antioxidant activity, color change, non-enzymatic browning (NEB), rehydration ratio and firmness. Second order polynomial model was fitted to the experimental results and high values of R2 (>0.8) were noticed in all responses. The optimal drying conditions were determined to be 62.44 °C and 418.84 W. Furthermore, separate experiment was carried out at these derived optimum conditions for ensuring the appropriateness of models. A close similarity among experimental and predicted values indicated the fitness of the model for determining the quality characteristics of RBP. Prolonged storage of RBP, however, led to the reductions of some quality attributes, although remained stable and acceptable at the end of six months storage

Hydrodynamics of bluefin tuna - a review

In the recent years, the study of unconventional fish-like bodies has been growing with the purpose of developing more efficient under-water vehicles; inspiration from nature to emulate these life forms to understand their propulsion system and to attain superior manoeuvring has given birth to the field of aquatic Biomimetics. Because of their remarkable capabilities, fish have shown extraordinary adaptation towards underwater locomotion which naturally has led to the sense of curiosity among engineers. A limited number of works has been published on bluefin tuna which is considered the largest Tuna species and the largest bony fish in ocean, weighing over 540 kilograms with length reaching over 3.05 meters and with a lifespan of 30 years. This fish has evolved overtime in terms of high-speed (reaching 75-100 km/hour), making it one of the fastest fish that swims in pelagic zone of oceans. Their torpedo shaped body is the most hydrodynamically efficient shape possible, making them the ultimate fish. This paper presents an overview of literature studies done exclusively and relevant to bluefin tuna. The review is divided into following sections: (I) Introduction (to swimming classification), (II) Thunniform Locomotion, (III) Undulatory Motion and Propulsion, (IV) Energy Efficiency and Energy Extraction, and (V) Computational Studies. The review highlights that this riveting fish is not only fastest but also, warm-blooded unlike any other fish that dives in pelagic zone and how that contributes to its high-speed. This paper aims to show that thunniform locomotion, with an emphasis on the lunate tail propulsion, is the most efficient locomotion only attained by super-advanced fish, and highlights the propulsive efficiency of thunniform motion which reaches about 70%, and the energy saving techniques adopted by bluefin tuna to make it the most efficient engine created by nature

A Review on Pharmacological Properties of Zingerone (4-(4-Hydroxy-3-methoxyphenyl)-2-butanone)

Humans have been using natural products for medicinal use for ages. Natural products of therapeutic importance are compounds derived from plants, animals, or any microorganism. Ginger is also one of the most commonly used condiments and a natural drug in vogue. It is a traditional medicine, having some active ingredients used for the treatment of numerous diseases. During recent research on ginger, various ingredients like zingerone, shogaol, and paradol have been obtained from it. Zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone) is a nontoxic and inexpensive compound with varied pharmacological activities. It is the least pungent component of Zingiber officinale. Zingerone is absent in fresh ginger but cooking or heating transforms gingerol to zingerone. Zingerone closely related to vanillin from vanilla and eugenol from clove. Zingerone has potent anti-inflammatory, antidiabetic, antilipolytic, antidiarrhoeic, antispasmodic, and so forth properties. Besides, it displays the property of enhancing growth and immune stimulation. It behaves as appetite stimulant, anxiolytic, antithrombotic, radiation protective, and antimicrobial. Also, it inhibits the reactive nitrogen species which are important in causing Alzheimer’s disease and many other disorders. This review is written to shed light on the various pharmacological properties of zingerone and its role in alleviating numerous human and animal diseases

Magnetic resonance urography in the evaluation of obstructive uropathy

Purpose: The purpose of this study was to study the utility of magnetic resonance urography (MRU) in the evaluation of obstructive urological diseases in comparison to intravenous urography (IVU). Materials and Methods: The study was carried out over a period of 2 years. A total of 55 patients were included in this study with ages between 14 and 70 years (average age 37 years). The patients were selected on the basis of ultrasonographic findings of hydronephrosis. The patients were subjected to IVU followed by static and dynamic MRU. The results obtained were compared and the inferences drawn thereof. Results and Conclusions: MRU has high sensitivity in the diagnosis of urinary tract obstruction, detecting the level of obstruction and acts as an aid in the diagnosis of obstructive uropathy, thus showing promising results. MRU is safer than IVU due to avoidance of iodinated contrast material and could also be done without using contrast material so having less contrast related events

Patch testing – Revisited

Patch test is used worldwide for diagnosis of contact dermatitis. Patch test was introduced in late nineteenth century and since then has improved considerably. The methodology is simple but it requires adequate training for the results to be correctly interpreted and used. Despite having been used for over a century, it needs improvement from time to time

A hybrid mental health prediction model using Support Vector Machine, Multilayer Perceptron, and Random Forest algorithms

The prevalence and burden of mental health disorders are on the rise in conflict zones, and if left untreated, they can lead to considerable lifetime disability. Following the repeal of Article 370, political unrest spread quickly, forcing the Indian government to impose safety precautions such as lockdowns and communication ban. Consequently, the region of Kashmir experienced a marked rise in anxiety as a result of these lifestyle changes. Machine learning has proven useful in the early diagnosis and prognosis of certain diseases. Therefore, this study aims to classify anxiety problems early by utilising a pre-clinical mental health dataset collected after the abrogation of article 370 in Kashmir. The first part of the paper aims at developing and implementing a prediction model based on classification into one of the five pre-clinical anxiety stages, i.e., Stage 1: minimal anxiety, Stage 2: mild anxiety, Stage 3: moderate anxiety, Stage 4: severe anxiety, and Stage 5: very severe anxiety. The second part offers recommendations for those suffering from anxiety disorders. Feature selection and prediction are used to predict the correct stage of anxiety for best possible medical intervention. Three different algorithms: Support Vector Machine(SVM), Multilayer Perceptron (MLP), and Random Forest (RF), are employed for predicting anxiety stages. Among them, random forest (RF) achieved 98.13% accuracy. A forecasted likelihood condition was assessed to provide a suitable recommendation. Further, accuracy and kappa statistics are used to assess the performance of the suggested model, which offers a significant addition to predicting anxiety early, and exhibits high prediction and recommendation accuracy. This study aims to assist mental health professionals and experts in making quick and accurate choices

Hydrothermally Synthesized Fluorine Added O₃-NaFe_1-xMg_xO₂ Cathodes for Sodium Ion Batteries

The development and study of Na ion batteries are expanding. This study employs the hydrothermal technique to produce single-phase, well-crystallized, fluorine-added O3-type NaFe1-xMgxO2. Using XRD, FESEM, and HRTEM, the sample’s phase structure and morphological information were characterized. Initially, without adding fluorine the electrode suffers from poor stability at high voltage ranges and also during long-term cycling. So, fluorine was added to the structure and the electrochemical performance of the material was greatly increased. The electrochemical performance of O3-type positive electrode materials for rechargeable Na ion batteries is evaluated. The capacity of fluorine-added O3-type NaFe1-xMgxO2 is approximately 163 mAh g−1 (50 mA g−1). Adding fluorine to the host structure increases the stability of the electrode, leading to improved electrochemical performance during long-term cycling. The electrochemical results indicate that fluorine-added O3-type NaFe1-xMgxO2 cathode material for cost-effective and environmentally friendly sodium-ion batteries is promising. Fluorine-based electrodes will be a future for Na ion energy storage device