Modular design of synthetic receptors for programmed gene regulation in cell therapies.

Synthetic biology has established powerful tools to precisely control cell function. Engineering these systems to meet clinical requirements has enormous medical implications. Here, we adopted a clinically driven design process to build receptors for the autonomous control of therapeutic cells. We examined the function of key domains involved in regulated intramembrane proteolysis and showed that systematic modular engineering can generate a class of receptors that we call synthetic intramembrane proteolysis receptors (SNIPRs) that have tunable sensing and transcriptional response abilities. We demonstrate the therapeutic potential of the receptor platform by engineering human primary T cells for multi-antigen recognition and production of dosed, bioactive payloads relevant to the treatment of disease. Our design framework enables the development of fully humanized and customizable transcriptional receptors for the programming of therapeutic cells suitable for clinical translation.

A study of neural artistic style transfer models and architectures for Indian art styles.

Neural Style Transfer (NST) has been a widely researched topic as of late enabling new forms of image manipulation. Here we perform an extensive study on NST algorithms and extend the existing methods with custom modifications for application to Indian art styles. In this paper, we aim to provide a comprehensive analysis of various methods ranging from the seminal work of Gatys et al which demonstrated the power of Convolutional Neural Networks (CNNs) in creating artistic imagery by separating and recombining image content and style, to the state of the art image-to-image translation models which use Generative Adversarial Networks (GANs) to learn the mapping between two domain of images. We observe and infer based on the results produced by the models on which one could be a more suitable approach for Indian art styles, especially Tanjore paintings which are unique compared to the Western art styles. We then propose the method which is more suitable for the domain of Indian Art style along with custom architecture which includes an enhancement and evaluation module. We then present evaluation methods, both qualitative and quantitative which includes our proposed metric, to evaluate the results produced by the model.

Contemporary Developments and Emerging Trends in the Application of Spectroscopy Techniques: A Particular Reference to Coconut (Cocos nucifera L.).

The number of food frauds in coconut-based products is increasing due to higher consumer demands for these products. Rising health consciousness, public awareness and increased concerns about food safety and quality have made authorities and various other certifying agencies focus more on the authentication of coconut products. As the conventional techniques for determining the quality attributes of coconut are destructive and time-consuming, non-destructive testing methods which are accurate, rapid, and easy to perform with no detrimental sampling methods are currently gaining importance. Spectroscopic methods such as nuclear magnetic resonance (NMR), infrared (IR)spectroscopy, mid-infrared (MIR)spectroscopy, near-infrared (NIR) spectroscopy, ultraviolet-visible (UV-VIS) spectroscopy, fluorescence spectroscopy, Fourier-transform infrared spectroscopy (FTIR), and Raman spectroscopy (RS) are gaining in importance for determining the oxidative stability of coconut oil, the adulteration of oils, and the detection of harmful additives, pathogens, and toxins in coconut products and are also employed in deducing the interactions in food constituents, and microbial contaminations. The objective of this review is to provide a comprehensive analysis on the various spectroscopic techniques along with different chemometric approaches for the successful authentication and quality determination of coconut products. The manuscript was prepared by analyzing and compiling the articles that were collected from various databases such as PubMed, Google Scholar, Scopus and ScienceDirect. The spectroscopic techniques in combination with chemometrics were shown to be successful in the authentication of coconut products. RS and NMR spectroscopy techniques proved their utility and accuracy in assessing the changes in coconut oil's chemical and viscosity profile. FTIR spectroscopy was successfully utilized to analyze the oxidation levels and determine the authenticity of coconut oils. An FT-NIR-based analysis of various coconut samples confirmed the acceptable levels of accuracy in prediction. These non-destructive methods of spectroscopy offer a broad spectrum of applications in food processing industries to detect adulterants. Moreover, the combined chemometrics and spectroscopy detection method is a versatile and accurate measurement for adulterant identification.

Outbreaks of epizootic ulcerative syndrome in Kerala, India following episodes of flooding.

Large-scale fish mortality was observed in flood-affected fish farms across several parts of Kerala following heavy rainfall in August 2018 and 2019-nearly 53% above the normal monsoon rain that the region receives. The affected fish had severe haemorrhages and ulcers, typical of the highly infectious disease epizootic ulcerative syndrome (EUS) caused by the water mould Aphanomyces invadans. In freshwater, snakeheads Channa spp. and in brackish water mullet (Mugilidae) and pearl spot (Etroplus suratensis) were severely affected. EUS was observed in 4 freshwater fishes for the first time: dotted sawfin barb Pethia punctata (Cyprinidae), Malabar leaffish Pristolepis malabarica (Pristolepididae), mahecola barb Puntius mahecola (Cyprinidae) and giant snakehead Channa pseudomarulius (Channidae). Histology and molecular diagnosis confirmed the cause of mortality to be EUS. Fungal hyphae were also observed in deeply ulcerated fish, revealed by lactophenol cotton blue staining. The severity of the EUS outbreak was linked to the sudden change in water quality associated with the flood, such as lower water temperature, and decreases in pH, total alkalinity and total hardness.

BODIPY Fluorophores for Membrane Potential Imaging.

Fluorophores based on the BODIPY scaffold are prized for their tunable excitation and emission profiles, mild syntheses, and biological compatibility. Improving the water-solubility of BODIPY dyes remains an outstanding challenge. The development of water-soluble BODIPY dyes usually involves direct modification of the BODIPY fluorophore core with ionizable groups or substitution at the boron center. While these strategies are effective for the generation of water-soluble fluorophores, they are challenging to implement when developing BODIPY-based indicators: direct modification of BODIPY core can disrupt the electronics of the dye, complicating the design of functional indicators; and substitution at the boron center often renders the resultant BODIPY incompatible with the chemical transformations required to generate fluorescent sensors. In this study, we show that BODIPYs bearing a sulfonated aromatic group at the meso position provide a general solution for water-soluble BODIPYs. We outline the route to a suite of 5 new sulfonated BODIPYs with 2,6-disubstitution patterns spanning a range of electron-donating and -withdrawing propensities. To highlight the utility of these new, sulfonated BODIPYs, we further functionalize them to access 13 new, BODIPY-based, voltage-sensitive fluorophores (VF). The most sensitive of these BODIPY VF dyes displays a 48% ΔF/F per 100 mV in mammalian cells. Two additional BODIPY VFs show good voltage sensitivity (≥24% ΔF/F) and excellent brightness in cells. These compounds can report on action potential dynamics in both mammalian neurons and human stem cell-derived cardiomyocytes. Accessing a range of substituents in the context of a water-soluble BODIPY fluorophore provides opportunities to tune the electronic properties of water-soluble BODIPY dyes for functional indicators.

Shape-Controlled Synthesis of Palladium Nanostructures from Flowers to Thorns: Electrocatalytic Oxidation of Ethanol.

The study focuses on facile shape-controlled deposition of rose, splintery, chrysanthemum flower, and thorn-like structures of palladium on indium-tin-oxide substrates. The hierarchical variation in morphologies from roses to thorns is attributed to a rational choice of the applied potential. This study involved investigating the influence of the precursor concentration, nature of the electrolyte, and deposition time on the morphological patterns. The shape-dependent electrocatalytic performance of these structures for oxidation of ethanol is demonstrated using cyclic voltammetry and electrochemical impedance spectroscopy. The onset potential, active surface area, mass activity, and exchange current density are investigated, and the results indicate that the catalytic activity of thorn-like morphologies is superior to that of the other shapes. The structural growth mechanism of the thorns deduced via scanning electron microscopy reveals the progression from spheres to thorns via cotton wools. The directional growth patterns via transmission electron microscopy indicate that the nanospikes of each thorn exhibit growth with the main branch of the (200) plane and the side branches along the (111) direction.

Ohmic heating as a pre-treatment in solvent extraction of rice bran.

Rice bran, which is one of the major by products of paddy contain high quality proteins and edible oil apart from fibre, ash and NFE (nitrogen free extract). The existing solvent extraction method employs n-hexane as the most viable solvent for the extraction of oil from rice bran. But the high cost and scarce availability of n-hexane resulted in uneconomical extraction of rice bran oil. In this study, rice bran was ohmically heated for different time periods(1, 2 and 3 min) with different current values (5, 15 and 20 A) and with different concentration of sodium chloride (1 M, 0.1 M and 0.01 M) as conducting medium. The ohmically heated rice bran was subjected to extraction studies. Ohmic heating of rice bran of paddy varieties Red Triveni and Basmati reduced the extraction time by nearly 75 % and 70 % respectively and gave a maximum quantity of oil extracted when compared to bran, which was not ohmically heated. From the experiments with varying concentrations, residence time of ohmic heating and currents, it was found that ohmically heating the rice bran with 1 M sodium chloride solution and with a current value of 20 A for 3 min gave maximum oil extraction with minimum extraction time.

"Comparison of activated Platelet Rich Fibrin and Platelet Rich Fibrin in osseous regeneration of freshly extracted socket- A double blinded randomized clinical study".

INTRODUCTION: Dental extraction is a common oral surgery procedure, but it can lead to unpredictable changes in alveolar bone structure, which can complicate future rehabilitation with prostheses. Socket preservation aims to reduce bone and soft tissue loss after extraction and involves various techniques using different materials. Autogenous bone is considered the gold standard for grafts, while autologous platelet concentrates like platelet-rich fibrin (PRF) have been used for tissue healing. This study aims to radiographically assess the bone remodeling of freshly extracted socket filled with Activated Platelet Rich Fibrin (APRF) and PRF. MATERIALS AND METHODS: A randomized controlled study was conducted on 60 patients undergoing tooth extraction as atraumatic as possible. Patients were divided into two groups: one receiving APRF with 10% Calcium Chloride as activating agent and the other PRF. Radiographic assessments were done using Kelley et al. scoring criteria at various time intervals, and statistical analyses were performed to evaluate the results. RESULTS: In this study we found increased bone density in extracted socket filled with APRF at any given time interval compared to PRF which is statistically significant. The maxilla demonstrated better bone formation compared to the mandible. Gender, age, and site also influenced bone formation, with females showing differences in lamina dura and overall density. DISCUSSION: PRF is rich in growth factors, promoting osteoblast formation and angiogenesis. Activation with calcium chloride accelerates clot formation and the release of growth factors. This study's radiographic data suggests that APRF may be more effective than PRF in promoting socket preservation and bone formation.

Emotional Eating and Cardiovascular Risk Factors in the Police Force: The Carolina Blue Project.

There is an association between emotional eating and cardiovascular disease (CVD) risk factors; however, little is known about this association in the police force. This study explores the associations between emotional eating and CVD risk factors in law enforcement officers in North Carolina. Four hundred and five officers completed The Emotional Eating Scale, and 221 of them completed the assessment for CVD-related markers. Descriptive statistics, Pearson's correlation, and multiple linear regression analyses were performed. Emotional eating in response to anger was significantly positively associated with body weight (ß = 1.51, t = 2.07, p = 0.04), diastolic blood pressure (ß = 0.83, t = 2.18, p = 0.03), and mean arterial pressure (ß = 0.84, t = 2.19, p = 0.03) after adjusting for age and use of blood pressure medicine. Emotional eating in response to depression was significantly positively associated with triglycerides (ß = 5.28, t = 2.49, p = 0.02), while the emotional eating in response to anxiety was significantly negatively associated with triglycerides (ß = -11.42, t = -2.64, p = 0.01), after adjusting for age and use of cholesterol medicine. Our findings offer new insights to address emotional eating and lower CVD risk in law enforcement officers.

Diversity in the C3b [corrected] contact residues and tertiary structures of the staphylococcal complement inhibitor (SCIN) protein family.

To survive in immune-competent hosts, the pathogen Staphylococcus aureus expresses and secretes a sophisticated array of proteins that inhibit the complement system. Among these are the staphylococcal complement inhibitors (SCIN), which are composed of three active proteins (SCIN-A, -B, and -C) and one purportedly inactive member (SCIN-D or ORF-D). Because previous work has focused almost exclusively on SCIN-A, we sought to provide initial structure/function information on additional SCIN proteins. To this end we determined crystal structures of an active, N-terminal truncation mutant of SCIN-B (denoted SCIN-B18-85) both free and bound to the C3c fragment of complement component C3 at 1.5 and 3.4 Å resolution, respectively. Comparison of the C3c/SCIN-B18-85 structure with that of C3c/SCIN-A revealed that both proteins target the same functional hotspot on the C3b/C3c surface yet harbor diversity in both the type of residues and interactions formed at their C3b/C3c interfaces. Most importantly, these structures allowed identification of Arg44 and Tyr51 as residues key for SCIN-B binding to C3b and subsequent inhibition of the AP C3 convertase. In addition, we also solved several crystal structures of SCIN-D to 1.3 Å limiting resolution. This revealed an unexpected structural deviation in the N-terminal α helix relative to SCIN-A and SCIN-B. Comparative analysis of both electrostatic potentials and surface complementarity suggest a physical explanation for the inability of SCIN-D to bind C3b/C3c. Together, these studies provide a more thorough understanding of immune evasion by S. aureus and enhance potential use of SCIN proteins as templates for design of complement targeted therapeutics.

Effects of Periodontitis on Major Organ Systems.

This review focuses on the fact that oral disorders are not merely localized to the mouth; in a broader sense, they also have a more significant impact on systemic health. In this review, we tried to bring to the notice various complications of periodontitis on the body's major organ systems. It has also been suggested that there is a potential connection between periodontitis and certain systemic disorders. Reviewing this fascinating topic is necessary. The objective is to create a thorough body of knowledge on the subject that is simple to access, alert medical professionals to the connection between dental health and systemic health, and highlight the necessity of a more thorough incorporation of medical and dental training. Periodontitis is a probable risk factor for various problems connected to the cardiovascular, pulmonary, endocrine, musculoskeletal, central nervous, and reproductive systems. It is a continual likely source of infection. Oral health affects overall health, and if extensive healthcare is ever accomplished, dental health should never be considered a distinct, remote, and lower significant part of health wholly disconnected from quality of life. One should never underestimate oral disorders as being acute and always curable. People should take utmost care and take the condition seriously to prevent significant complications.

Novel Chemotherapy Modalities for Different Cancers.

Even though many of the approved drugs still have high systemic toxicity due to a lack of tumor selectivity and present pharmacokinetic drawbacks, like low water solubility, that negatively influence the drug circulation time and bioavailability, the anti-cancer study has produced commendable results in recent years. The stability tests carried out under stressful exposure to high temperatures, hydrolytic media, or light sources during their development or under moderate settings have shown the vulnerability of anti-cancer medications to various factors. Because of this, the development of degradation products is considered hospital waste in pharmaceutical formulations and the environment. Until now, various formulations have been created for attaining tissue-specific therapeutic targeting, lowering harmful side effects, and enhancing drug stability. To boost the specificity, efficiency, and durability of active molecules that are targeted in cancer therapy the invention of prodrugs is the potential approach. The latest study illustrates that the solubility, pharmacokinetics, cellular uptake, and stability of chemotherapy drugs can be improved through the incorporation of them into vesicular systems, such as polymeric micelles or cyclodextrins, or via nanocarriers containing chemotherapeutics linked to monoclonal antibodies. In this review article, we provide an overview of the most recent advances in the field of designing very stable prodrugs or nanosystems that are powerful anti-cancer medications and their actions on the body.

Pharmacotherapy of Painful Diabetic Neuropathy: A Clinical Update.

The rising prevalence of diabetes mellitus (DM) leads on to an increase in chronic diabetic complications. Diabetic peripheral neuropathies (DPNs) are common chronic complications of diabetes. Distal symmetric polyneuropathy is the most prevalent form. Most patients with DPN will remain pain-free; however, painful DPN (PDPN) occurs in 6-34% of all DM patients and is associated with reduced health-related-quality-of-life and substantial economic burden. Symptomatic treatment of PDPN and diabetic autonomic neuropathy is the key treatment goals. Using certain patient related characteristics, subjects with PDPN can be stratified and assigned targeted therapies to produce better pain outcomes. The aim of this review is to discuss the various pathogenetic mechanisms of DPN with special reference to the mechanisms leading to PDPN and the various pharmacological and non-pharmacological therapies available for its management. Recommended pharmacological therapies include anticonvulsants, antidepressants, opioid analgesics, and topical medications.

Evaluation of Sequential Head Computed Tomography in Traumatic Brain Injuries.

BACKGROUND: The grading of the severity of head trauma plays a vital role in acute patient management and planning a case-appropriate follow-up protocol. Few studies have been published regarding the Rotterdam scoring. In this study, we have established a correlation between the Rotterdam scores, need for sequential CTs, and the cumulative radiation dose. This correlation has helped develop a preliminary protocol that can be followed for patients hence bringing about better planned and efficient patient care. MATERIALS AND METHODS:  From August 2014 to December 2020, 88 cases of traumatic head injury on whom a minimum of one sequential CT was performed, with no surgical intervention, were included and studied. Sequential head CTs of each patient were evaluated by skilled radiologists with a minimum experience of five years, all of whom were blinded to the findings of the initial and previous head CT findings. The serial head CTs were evaluated for the Rotterdam CT score (RCTS).  Results: Among the patients with extradural hemorrhage (EDH), only 28.6% (8) progressed over successive CTs and 75.5% (34) of patients with subdural hemorrhage (SDH) showed significant progression over sequential CTs. Maximum number of serial CTs were obtained for cases presenting with a score of 3 (34 cases) with about three of them requiring up to a total of three CTs. However, no significant change in findings was noted on serial CTs. On the contrary, significant disease progression was noted in patients with baseline scores of 4 (76.9%) and 5 (100%), with statistical significance obtained on further analysis (P = 0.001). CONCLUSIONS: We are of the opinion that there is no additional role of sequential CT for the cases with Rotterdam score of 1 or 2 in the initial CT unless there is clinical evidence of deterioration. Rotterdam score 3 needs sequential CT after 24 hours and Rotterdam scores 4 and 5 need sequential CT after 12 hours if surgical intervention is delayed. The Rotterdam score may help predict any further need for a second CT, hence decreasing the unwanted radiation exposure.

A randomized controlled trial to study the effect of intratracheal and intravenous lignocaine on airway and hemodynamic response during emergence and extubation following general anesthesia.

OBJECTIVE: Intratracheal (IT) and intravenous (IV) lignocaine suppress airway reflex and hemodynamic response during extubation, but studies regarding this are sparse. The primary aim was to compare the effect of IT and IV lignocaine on attenuation of airway reflex to endotracheal extubation and the secondary aim was to compare the hemodynamic responses to extubation, using lignocaine by the two different routes. METHODS: Seventy-five female patients with comparable age, body mass index, and American Society of Anesthesiologists Physical Status undergoing carcinoma breast surgery were randomized into three groups. Group A received 2% lignocaine 3 mg/kg intratracheally 5 min and Group B received 2% lignocaine 1.5 mg/kg intravenously 3 min before extubation. Group C was control group. The airway and hemodynamic responses were noted in terms of episodes of cough during emergence and extubation. Categorical variables assessed using Fisher's exact test and continuous variables assessed using one-way analysis of variance. RESULTS: Cough suppression was present in Groups A and B, with better results observed with IT than with IV lignocaine. In the control group, Grade III cough reflex was present predominantly. There was a statistically significant difference (p<0.001) in blood pressure and heart rate between Group A versus Group C and in Group B versus Group C, but not between Group A and Group B. CONCLUSION: IT lignocaine administered before extubation significantly attenuates post-extubation cough reflex than IV lignocaine. Both IT and IV lignocaine can effectively attenuate the airway and hemodynamic response to extubation.

Multidimensional control of therapeutic human cell function with synthetic gene circuits.

Synthetic gene circuits that precisely control human cell function could expand the capabilities of gene- and cell-based therapies. However, platforms for developing circuits in primary human cells that drive robust functional changes in vivo and have compositions suitable for clinical use are lacking. Here, we developed synthetic zinc finger transcription regulators (synZiFTRs), which are compact and based largely on human-derived proteins. As a proof of principle, we engineered gene switches and circuits that allow precise, user-defined control over therapeutically relevant genes in primary T cells using orthogonal, US Food and Drug Administration-approved small-molecule inducers. Our circuits can instruct T cells to sequentially activate multiple cellular programs such as proliferation and antitumor activity to drive synergistic therapeutic responses. This platform should accelerate the development and clinical translation of synthetic gene circuits in diverse human cell types and contexts.

2D Materials-Based Aptamer Biosensors: Present Status and Way Forward.

Current advances in constructing functional nanomaterials and elegantly designed nanostructures have opened up new possibilities for the fabrication of viable field biosensors. Two-dimensional materials (2DMs) have fascinated much attention due to their chemical, optical, physicochemical, and electronic properties. They are ultrathin nanomaterials with unique properties such as high surface-to-volume ratio, surface charge, shape, high anisotropy, and adjustable chemical functionality. 2DMs such as graphene-based 2D materials, Silicate clays, layered double hydroxides (LDHs), MXenes, transition metal dichalcogenides (TMDs), and transition metal oxides (TMOs) offer intensified physicochemical and biological functionality and have proven to be very promising candidates for biological applications and technologies. 2DMs have a multivalent structure that can easily bind to single-stranded DNA/RNA (aptamers) through covalent, non-covalent, hydrogen bond, and π-stacking interactions, whereas aptamers have a small size, excellent chemical stability, and low immunogenicity with high affinity and specificity. This review discussed the potential of various 2D material-based aptasensor for diagnostic applications, e.g., protein detection, environmental monitoring, pathogens detection, etc.

Incidence and predictors of cetuximab hypersensitivity reactions in a North Carolina academic medical center.

OBJECTIVES: Previous research has indicated a high incidence of cetuximab hypersensitivity reactions in the southern US. This study documents the incidence of hypersensitivity reactions in North Carolina, and explores whether factors such as patient demographics, allergy history, premedications, and cancer type are potential predictors for cetuximab reactions. METHODS: This retrospective chart review consisted of 72 consecutively treated patients from Duke University's Morris Oncology treatment center between September 2005 and August 2007. Data regarding stage of malignancy, premedications, and hypersensitivity reactions were collected from electronic databases. The number and type of reactions were characterized. Patients with and without hypersensitivity reactions were compared using bivariate statistics and multivariate logistic regression. RESULTS: Of the 72 patients, 21 (29%) experienced hypersensitivity reactions. The majority of reactions (62%) were grades III or IV. Of the 21 patients having a reaction, 9 (43%) were sent to the emergency room and 5 (24%) had an overnight hospitalization. Three hospitalized patients were admitted to the intensive care unit. Both male gender (p = 0.039) and head/neck cancer (p = 0.014) were related to an increased likelihood of hypersensitivity reaction in bivariate analyses. In multivariate analyses, controlling for demographics, allergy history, premedications, and cancer type/stage, only type of cancer was predictive of hypersensitivity reaction (colon vs head/neck OR = 0.177; 95% CI 0.036-0.858). CONCLUSION: This study confirms a high rate of cetuximab hypersensitivity reactions in a southern region of the US. Patients with head/neck cancers were significantly more likely to have hypersensitivity reactions than patients with colon cancers.

High-throughput virtual screening followed by in vitro investigation to identify new lead inhibitors of Cyclin Dependent Kinase 4.

In the family of serine/threonine kinases, Cyclin Dependent Kinase 4 (CDK4), is an important regulator in numerous signal transduction pathways. The cell cycle is dysregulated in human breast adenocarcinoma (MCF-7). A set of various categorical QSAR models were generated and validated in the current examination. A recursive partition model, with predictive ability shown by an accuracy of greater than 0.90, was used for virtual screening of 500,000 molecules. Following a consecutive series of molecular docking procedures, followed by pharmacokinetic analysis of 49759 molecules predicted to have pIC50 greater than 7.39, 25 molecules displayed properties that could be described as drug-like. We selected the lead molecules in the MCF-7 cell line based on its ability to promote cell cycle progression.