The unexpected fast polymerization during the synthesis of a glycolated polythiophene.

Conjugated polymers with ethylene glycol side chains are emerging as ideal materials for bioelectronics, particularly for application in organic electrochemical transistors (OECTs). To improve the OECT device performance, it is important to develop an efficient synthetic strategy that will provide access to novel high-performing materials besides focusing on molecular design. While a lot of efforts are being devoted to designing of new polymers by modifying the glycol side chains, understanding how their nature affects the polymerization kinetics and eventually the polymer structure and properties is not known. In this work, we have studied the influence of the content of the ethylene glycol side chain and its linkage on the formation of the active Grignard monomer species upon Grignard metathesis in three thiophene derivatives. A strong dependence of the monomer's concentration on polymerization was noted in our study indicating that for synthesizing P3MEEMT, a high-performing OECT material, by Kumada catalyst transfer polymerization (KCTP) a minimum of 0.15 M monomer is needed. Furthermore, kinetic studies by GPC show uncontrolled polymerization behavior contrary to the controlled chain growth characteristics of the KCTP.

High Rate, Dendrite Free Lithium Metal Batteries of Extended Cyclability via a Scalable Separator Modification Approach.

Owing to their great promise of high energy density, the development of safer lithium metal batteries (LMBs) has become the necessity of the hour. Herein, a scalable method based on conventional Celgard membrane (CM) separator modification is adopted to develop high-rate (10 mA cm-2 ) dendrite-free LMBs of extended cyclability (>1000 hours, >1500 cycles with 3 mA cm-2 , the bare fails within 50 cycles) with low over potential losses. The CM modification method entails the deposition of thin coatings of (≈6.6 µm) graphitic fluorocarbon (FG) via a large area electrophoretic deposition, where it helps for the formation of a stable LiF and carbon rich solid electrolyte interface (SEI) aiding a uniform lithium deposition even in higher fluxes. The FG@CM delivers a high transport number for Li ion (0.74) in comparison to the bare CM (0.31), indicating a facile Li ion transport through the membrane. A mechanistic insight into the role of artificial SEI formation with such membrane modification is provided here with a series of electrochemical as well as spectroscopic in situ/ex situ and postmortem analyses. The simplicity and scalability of the technique make this approach unique among other reported ones towards the advancement of safer LMBs of high energy and power density.

Selective Activation of MST1/2 Kinases by Retinoid Agonist Adapalene Abrogates AURKA-Regulated Septic Arthritis.

Septic arthritis is a chronic inflammatory disorder caused by Staphylococcus aureus invasion of host synovium, which often progresses to impairment of joint functions. Although it is known that disease progression is intricately dependent on dysregulated inflammation of the knee joint, identification of molecular events mediating such imbalance during S. aureus-induced septic arthritis still requires detailed investigation. In this article, we report that Aurora kinase A (AURKA) responsive WNT signaling activates S. aureus infection-triggered septic arthritis, which results in inflammation of the synovium. In this context, treatment with adapalene, a synthetic retinoid derivative, in a mouse model for septic arthritis shows significant reduction of proinflammatory mediators with a simultaneous decrease in bacterial burden and prevents cartilage loss. Mechanistically, adapalene treatment inhibits WNT signaling with concomitant activation of HIPPO signaling, generating alternatively activated macrophages. Collectively, we establish adapalene as a promising strategy to suppress S. aureus-induced irreversible joint damage.

Circular Discovery in Small Molecule and Conjugated Polymer Synthetic Methodology.

Simple and efficient methods are a key consideration for small molecule and polymer syntheses. Direct arylation polymerization (DArP) is of increasing interest for preparing conjugated polymers as an effective approach compared to conventional cross-coupling polymerizations. As DArP sees broader utilization, advancements are needed to access materials with improved properties and different monomer structures and to improve the scalability of conjugated polymer synthesis. Presented herein are considerations for developing new methods of conjugated polymer synthesis from small molecule transformations, exploring how DArP has successfully used this approach, and presenting how emerging polymerization methodologies are developing similarly. While it is common to adapt small molecule methods to polymerizations, we demonstrate the ways in which information gained from studying polymerizations can inform and inspire greater advancements in small molecule transformations. This circular approach to organic synthetic method development underlines the value of collaboration between small molecule and polymer-based synthetic research groups.

Comparative evaluation of the analgesic efficacy of ultrasound-guided erector spinae plane block versus intrathecal morphine in patients undergoing percutaneous nephrolithotomy surgery: A prospective randomized pilot study.

OBJECTIVES: Existing research on erector spinae plane block and intrathecal morphine in patients undergoing percutaneous nephrolithotomy surgery is limited. METHODS: In this prospective, randomized study, 60 patients aged between 18 and 60 years were randomized into two groups (erector spinae plane block and intrathecal morphine). In the erector spinae plane block group, ultrasound-guided erector spinae plane block was performed, following which a mixture of 20 mL of 0.375% ropivacaine and 0.5 mcg/kg of clonidine was injected. In the intrathecal morphine group, 150 mcg preservative-free morphine with 2 mL of normal saline was administered intrathecally. The primary outcome was to evaluate the perioperative opioid consumption in the first 24 h. The secondary outcomes were to evaluate hemodynamic response to surgical stimulus, visual analogue scale score, time to first analgesic requirement, postoperative nausea and vomiting, postoperative opioid consumption, urethral irritation, and incidence of drug-related adverse effects. RESULTS: Total perioperative opioid consumption in the erector spinae plane block group was 355.0 (265.0, 485.0) µg and 240.0 (145.0, 370.0) µg in the intrathecal morphine group (P = 0.09). However, the patients in the erector spinae plane block group had significantly greater postoperative fentanyl consumption (235.0 [120.0, 345.0] µg) compared with those in the intrathecal morphine group (105.0 [30.0, 225.0] µg). There were no statistically significant differences noted for intraoperative opioid consumption, postoperative visual analogue scale score, time to first analgesic request, postoperative nausea and vomiting, and catheter irritation between the two groups. CONCLUSIONS: Although no statistically significant difference in intraoperative opioid consumption was seen between the erector spinae plane block and intrathecal morphine groups, postoperative opioid consumption was significantly higher in the erector spinae plane block group than in the intrathecal morphine group in patients undergoing percutaneous nephrolithotomy surgery.

Modulating α-Synuclein Liquid-Liquid Phase Separation.

Liquid-liquid phase separation (LLPS) is a crucial phenomenon for the formation of functional membraneless organelles. However, LLPS is also responsible for protein aggregation in various neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease (PD). Recently, several reports, including ours, have shown that α-synuclein (α-Syn) undergoes LLPS and a subsequent liquid-to-solid phase transition, which leads to amyloid fibril formation. However, how the environmental (and experimental) parameters modulate the α-Syn LLPS remains elusive. Here, we show that in vitro α-Syn LLPS is strongly dependent on the presence of salts, which allows charge neutralization at both terminal segments of protein and therefore promotes hydrophobic interactions supportive for LLPS. Using various purification methods and experimental conditions, we showed, depending upon conditions, α-Syn undergoes either spontaneous (instantaneous) or delayed LLPS. Furthermore, we delineate that the kinetics of liquid droplet formation (i.e., the critical concentration and critical time) is relative and can be modulated by the salt/counterion concentration, pH, presence of surface, PD-associated multivalent cations, and N-terminal acetylation, which are all known to regulate α-Syn aggregation in vitro. Together, our observations suggest that α-Syn LLPS and subsequent liquid-to-solid phase transition could be pathological, which can be triggered only under disease-associated conditions (high critical concentration and/or conditions promoting α-Syn self-assembly). This study will significantly improve our understanding of the molecular mechanisms of α-Syn LLPS and the liquid-to-solid transition.

Indian goose berry fortified, anti-oxidant rich bael (Aegle marmelos) fermented beverage.

Bael (Aegle marmelos Correa), an important fruit of Indian subtropics, traditionally utilized in the preparation of preserve, candy, squash, RTS, etc. has immense therapeutic potential. An attempt was made to develop a bael based low alcoholic sweet fermented beverage ( may be called as bael cider), anti-oxidant fortified with 0.25 per cent bael leaf or 10 per cent Indian goose berry (Emblica officinalis Gaertn.) juice in separate batches. Unfortified bael pulp based drink was kept as control. The ameliorated pulp was fermented at 30 ± 2ºC using Saccharomyces cerevisiae. The gooseberry blended bael fermented beverage had higher anti-oxidant content in the form of phenolics (323 mg/100 ml) than leaf extract added fermented beverage (265 mg/100 ml) and control (266 mg/100 ml). Sensory evaluation of product revealed that gooseberry blended fermented beverage scored higher (8.2/10) than bael leaf blended fermented beverage (7.9/10) and control (7.0/10). Twelve months maturation study of beverage revealed increase in reducing sugars and decrease in phenolic content in all the treatments. Bael fermented beverage with gooseberry blend retained highest phenolic content (257 mg/100 ml) and sensory score 7.8/10. The study inferred that an acceptable quality fermented drink could be prepared from bael-gooseberry blend, which could be stored for one year with higher antioxidant value and minimum deterioration in the quality.

Deregulated AUF1 Assists BMP-EZH2-Mediated Delayed Wound Healing during Candida albicans Infection.

Tissue repair is a complex process that necessitates an interplay of cellular processes, now known to be dictated by epigenetics. Intriguingly, macrophages are testimony to a large repertoire of evolving functions in this process. We identified a role for BMP signaling in regulating macrophage responses to Candida albicans infection during wound repair in a murine model. In this study, the RNA binding protein, AU-rich element-binding factor 1, was posttranslationally destabilized to bring about ubiquitin ligase, NEDD4-directed activation of BMP signaling. Concomitantly, PI3K/PKCδ mobilized the rapid phosphorylation of BMP-responsive Smad1/5/8. Activated BMP pathway orchestrated the elevated recruitment of EZH2 at promoters of genes assisting timely wound closure. In vivo, the repressive H3K27 trimethylation was observed to persist, accompanied by a robust upregulation of BMP pathway upon infection with C. albicans, culminating in delayed wound healing. Altogether, we uncovered the signaling networks coordinated by fungal colonies that are now increasingly associated with the infected wound microbiome, resulting in altered wound fate.

A De novo Peptide from a High Throughput Peptide Library Blocks Myosin A -MTIP Complex Formation in Plasmodium falciparum.

Apicomplexan parasites, through their motor machinery, produce the required propulsive force critical for host cell-entry. The conserved components of this so-called glideosome machinery are myosin A and myosin A Tail Interacting Protein (MTIP). MTIP tethers myosin A to the inner membrane complex of the parasite through 20 amino acid-long C-terminal end of myosin A that makes direct contacts with MTIP, allowing the invasion of Plasmodium falciparum in erythrocytes. Here, we discovered through screening a peptide library, a de-novo peptide ZA1 that binds the myosin A tail domain. We demonstrated that ZA1 bound strongly to myosin A tail and was able to disrupt the native myosin A tail MTIP complex both in vitro and in vivo. We then showed that a shortened peptide derived from ZA1, named ZA1S, was able to bind myosin A and block parasite invasion. Overall, our study identified a novel anti-malarial peptide that could be used in combination with other antimalarials for blocking the invasion of Plasmodium falciparum.

Design and synthesis of imidazolidinone derivatives as potent anti-leishmanial agents by bioisosterism.

Bioisosterism is a useful strategy in rational drug design to improve pharmacodynamic and pharmacokinetic properties of lead compounds. Imidazolidinones have been reported as potent kinase inhibitors and antileishmanial agents. In this study, bioisosteres of imidazolidinones (compounds 1-3) were evaluated for their antileishmanial properties. The modified imidazolidinones exhibited potent antileishmanial activity against extracellular as well as intracellular Leishmania donovani parasites in nanomolar concentrations. The selectivity index of these compounds on host cells was found to be more than 1000, emphasizing their specificity toward the parasite. Using SwissTargetPrediction software, we assessed the potential targets of these compounds and found MAPK as the most probable target. To in vitro validate, we developed a novel in vitro kinase assay that mimics the in vivo nature of the functional kinome. Compounds 1-3 displayed specific inhibition of parasite kinase activity accompanied by an increase in intracellular sodium levels in the parasites. This might be the effect of kinase inhibition that regulates sodium homeostasis through Na-ATPases. Finally, the compound-treated parasites underwent apoptosis-like death. This study represents bioisoterism as a novel approach for drug design to establish the structure-activity relationship, which in turn helps to improve the therapeutic activity of lead compounds.

SMN deficiency alters Nrxn2 expression and splicing in zebrafish and mouse models of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease affecting lower motor neurons. SMA is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, which result in reduced levels of functional SMN protein. Biochemical studies have linked the ubiquitously expressed SMN protein to the assembly of pre-mRNA processing U snRNPs, raising the possibility that aberrant splicing is a major defect in SMA. Accordingly, several transcripts affected upon SMN deficiency have been reported. A second function for SMN in axonal mRNA transport has also been proposed that may likewise contribute to the SMA phenotype. The underlying etiology of SMA, however, is still not fully understood. Here, we have used a combination of genomics and live Ca(2+) imaging to investigate the consequences of SMN deficiency in a zebrafish model of SMA. In a transcriptome analyses of SMN-deficient zebrafish, we identified neurexin2a (nrxn2a) as strongly down-regulated and displaying changes in alternative splicing patterns. Importantly, the knock-down of two distinct nrxn2a isoforms phenocopies SMN-deficient fish and results in a significant reduction of motor axon excitability. Interestingly, we observed altered expression and splicing of Nrxn2 also in motor neurons from the Smn(-/-);SMN2(+/+) mouse model of SMA, suggesting conservation of nrxn2 regulation by SMN in mammals. We propose that SMN deficiency affects splicing and abundance of nrxn2a. This may explain the pre-synaptic defects at neuromuscular endplates in SMA pathophysiology.

Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling.

In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features.

Glyceride-Mimetic Prodrugs Incorporating Self-Immolative Spacers Promote Lymphatic Transport, Avoid First-Pass Metabolism, and Enhance Oral Bioavailability.

First-pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first-pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first-pass drug, glyceride-mimetic prodrugs incorporating self-immolative (SI) spacers, resulted in remarkable increases (up to 90-fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first-pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue.

Synthesis and Sensing Applications of Fluorescent 3-Cinnamoyl Coumarins.

We have synthesized two novel fluorescent 3-(4-diethylaminocinnamoyl) coumarins that exhibit fluorescence quenching upon exposure to a nerve agent simulant, diethylchlorophosphate (DCP), providing a basis for rapid and sensitive DCP chemosensing. Furthermore, these coumarin derivatives display two-photon fluorescence upon illumination with near-infrared laser pulses and their two-photon (TP) absorption cross-section was evaluated. The potential for TP bio-imaging of these compounds was investigated by their cellular uptake in HeLa cells by TP confocal microscopy.

Role of Na(v)1.9 in activity-dependent axon growth in motoneurons.

Spontaneous neural activity promotes axon growth in many types of developing neurons, including motoneurons. In motoneurons from a mouse model of spinal muscular atrophy (SMA), defects in axonal growth and presynaptic function correlate with a reduced frequency of spontaneous Ca(2+) transients in axons which are mediated by N-type Ca(2+) channels. To characterize the mechanisms that initiate spontaneous Ca(2+) transients, we investigated the role of voltage-gated sodium channels (VGSCs). We found that low concentrations of the VGSC inhibitors tetrodotoxin (TTX) and saxitoxin (STX) reduce the rate of axon growth in cultured embryonic mouse motoneurons without affecting their survival. STX was 5- to 10-fold more potent than TTX and Ca(2+) imaging confirmed that low concentrations of STX strongly reduce the frequency of spontaneous Ca(2+) transients in somatic and axonal regions. These findings suggest that the Na(V)1.9, a VGSC that opens at low thresholds, could act upstream of spontaneous Ca(2+) transients. qPCR from cultured and laser-microdissected spinal cord motoneurons revealed abundant expression of Na(V)1.9. Na(V)1.9 protein is preferentially localized in axons and growth cones. Suppression of Na(V)1.9 expression reduced axon elongation. Motoneurons from Na(V)1.9(-/-) mice showed the reduced axon growth in combination with reduced spontaneous Ca(2+) transients in the soma and axon terminals. Thus, Na(V)1.9 function appears to be essential for activity-dependent axon growth, acting upstream of spontaneous Ca(2+) elevation through voltage-gated calcium channels (VGCCs). Na(V)1.9 activation could therefore serve as a target for modulating axonal regeneration in motoneuron diseases such as SMA in which presynaptic activity of VGCCs is reduced.

Reconstruction of Midface Defects after Radical Tumor Resection - a Rare Case Report of Solitary Fibrous Tumour of the Hard Palate.

Introduction- Spindle cell neoplasm is a variant of squamous cell carcinoma. One of its subtypes is solitary fibrous tumor. Its occurrence in head and neck is very rare and rarer in hard palate. But if occurs, radical excision is the only choice as it has malignant potential but coverage of such large mid face defects imposes a challenge in front of a Plastic Surgeon as it demands both soft tissue coverage and skeletal support. Report of the case- A 33 year male presented to our department with swelling of left side face involving the anterior palate, maxilla, nose, and upper lip. With the help of the surgical oncology team, wide local excision of the neoplasm along with bilateral infrastructure maxillectomy, total rhinectomy, total upper lip resection and total hard palatectomy was done. This created large defect in the mid face which was covered with free anterolateral thigh flap. Biopsy was done which revealed the swelling as a solitary fibrous tumor of hard palate. All the margins were free of tumour. The flap settled well. Nostrils were secured with nasal stents. After 3 months, an expander was placed in forehead of the patient for future nasal reconstruction. After 3 months, nasal reconstruction was done using expanded forehead flap and costal cartilage. After 21 days flap detachment and insetting was done. White roll creation was also done. One more secondary procedure was done for flap thinning as patient had complain of nasal obstruction. After 6 months vascularised free fibula bone graft was introduced to reconstruct maxilla for future dental rehabilitation. The patient is in regular follow up and he is satisfied with the results. Discussion- Mid face defects involving perioral and nasomaxillar areas are very uncommon and require composite reconstruction. In such cases, microvascular free flap coverage is an irreplaceable option. Multiple stages might have to be done for further refinement. Conclusion- Reconstruction after oncological resection is always very demanding. With proper preoperative planning and skilled execution, the patient can be benefited functionally, aesthetically and psychosocially.

A rare case of chikungunya encephalitis and its management: A case report and literature review.

Key Clinical Message: Chikungunya encephalitis, though rare, warrants clinical attention due to its severe complications. Early identification and appropriate management are crucial for improved outcomes in patients with this rare manifestation of chikungunya virus (CHIKV) infection. Abstract: CHIKV infection is commonly associated with fever and joint pains, but neurological complications such as encephalitis are rare. Here, we present a unique case of confirmed chikungunya encephalitis in a 12-year-old male exhibiting atypical neurological symptoms. The diagnostic journey involved comprehensive neuroimaging and serological investigations, revealing intriguing findings on magnetic resonance imaging and positive CHIKV RNA in serum and cerebrospinal fluid. We discuss the clinical presentation, radiological characteristics, and management strategies, emphasizing the importance of recognizing this uncommon neurological manifestation of CHIKV infection.

Association between baseline insulin resistance and hospital mortality in moderate-to-severe coronavirus disease 2019 patients without diabetes mellitus: An observational study.

Background: Insulin resistance is often implicated as a risk factor of cell-mediated immune dysfunction in sepsis patients and results in poor clinical outcome. However, it is unclear whether early insulin resistance is contributory to T-cell dysfunction and poor clinical outcome in coronavirus disease 2019 (COVID-19) patients. Methods: Adult patients with moderate-to-severe or critically ill COVID-19 infection were included in this study. Serum samples were collected at the time of diagnosis for fasting plasma glucose, serum insulin, serum cortisol, and serum glucagon measurements, and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) score was calculated. Results: One hundred and twenty-six subjects with a mean (standard deviation) age of 49.6 (16.3) years were recruited in this study, and 62.4% (78 of 125 patients) were male. HOMA-IR was a predictor of inhospital mortality with the area under the receiver operating characteristics curve (AUROC) (95% confidence interval [CI] of 0.61 [0.49-0.73]). With a cutoff value of 1.91, sensitivity was 75.5% and specificity was 45.2%. Higher serum insulin was associated with higher survival with AUROC (95% CI) of 0.65 (0.53-0.76), and the best cutoff was 7.15, with a sensitivity and specificity of 62.1% and 64.5%. Serum cortisol was also a predictor of inhospital mortality with an AUROC (95% CI) of 0.67 (0.56-0.77). Conclusion: An independent association between baseline serum cortisol and poor outcome in moderate-to-severe COVID-19 patients was observed. Hyperglycemia and HOMA-IR can also predict poor outcome in these patients with some accuracy.

Prosthetic rehabilitation of a hemisected maxillary molar: a rare entity.

Gingival recession beyond grade III and grade IV level involving furcation defects can lead to tooth loss if not intervened at appropriate time. The treatment options include scaling and root planing, Furcation-plasty, Tunnel preparation, Root separation and resection. The chief complaint of the patient was pain in the upper left first molar because of grade III furcation involvement. Since it was a four rooted molar, the treatment of choice was hemisection of the tooth and extraction of the distal half following endodontic treatment. As the second molar was mesially tilted the prosthodontic rehabilitation was done with a hybrid prosthesis involving a full coverage conventional porcelain fused to metal retainer on the hemisected molar and a resin bonded partial coverage retainer on the tilted second molar. The resultant prosthesis is termed as "Hybrid prosthesis".