Design and development of 3D printed shape memory triphasic polymer-ceramic bioactive scaffolds for bone tissue engineering.

Scaffolds for bone tissue engineering require considerable mechanical strength to repair damaged bone defects. In this study, we designed and developed mechanically competent composite shape memory triphasic bone scaffolds using fused filament fabrication (FFF) three dimensional (3D) printing. Wollastonite particles (WP) were incorporated into the poly lactic acid (PLA)/polycaprolactone (PCL) matrix as a reinforcing agent (up to 40 wt%) to harness osteoconductive and load-bearing properties from the 3D printed scaffolds. PCL as a minor phase (20 wt%) was added to enhance the toughening effect and induce the shape memory effect in the triphasic composite scaffolds. The 3D-printed composite scaffolds were studied for morphological, thermal, and mechanical properties, in vitro degradation, biocompatibility, and shape memory behaviour. The composite scaffold had interconnected pores of 550 µm, porosity of more than 50%, and appreciable compressive strength (∼50 MPa), which was over 90% greater than that of the pristine PLA scaffolds. The flexural strength was improved by 140% for 40 wt% of WP loading. The inclusion of WP did not affect the thermal property of the scaffolds; however, the inclusion of PCL reduced the thermal stability. An accelerated in vitro degradation was observed for WP incorporated composite scaffolds compared to pristine PLA scaffolds. The inclusion of WP improved the hydrophilic property of the scaffolds, and the result was significant for 40 wt% WP incorporated composite scaffolds having a water contact angle of 49.61°. The triphasic scaffold exhibited excellent shape recovery properties with a shape recovery ratio of ∼84%. These scaffolds were studied for their protein adsorption, cell proliferation, and bone mineralization potential. The incorporation of WP reduced the protein adsorption capacity of the composite scaffolds. The scaffold did not leach any toxic substance and demonstrated good cell viability, indicating its biocompatibility and growth-promoting behavior. The osteogenic potential of the WP incorporated scaffolds was observed in MC3T3-E1 cells, revealing early mineralization in pre-osteoblast cells cultured in different WP incorporated composite scaffolds. These results suggest that 3D-printed WP reinforced PLA/PCL composite bioactive scaffolds are promising for load bearing bone defect repair.

SRX3177, a CDK4/6-PI3K-BET inhibitor, in combination with an RdRp inhibitor, Molnupiravir, or an entry inhibitor MU-UNMC-2, has potent antiviral activity against the Omicron variant of SARS-CoV-2.

Despite considerable progress in developing vaccines and antivirals to combat COVID-19, the rapid mutations of the SARS-CoV-2 genome have limited the durability and efficacy of the current vaccines and therapeutic interventions. Hence, it necessitates the development of novel therapeutic approaches or repurposing existing drugs that target either viral life cycle, host factors, or both. Here, we report that SRX3177, a potent triple-activity CDK4/6-PI3K-BET inhibitor, blocks replication of the SARS-CoV-2 Omicron variant with IC50 values at sub-micromolar concentrations without any impact on the cell proliferation of Calu-3 cells at and below its IC50 concentration. When SRX3177 is combined with EIDD-1931 (active moiety of a small-molecule prodrug Molnupiravir) or MU-UNMC-2 (a SARS-CoV-2 entry inhibitor) at a fixed doses matrix, a synergistic effect was observed, leading to the significant reduction in the dose of the individual compounds to achieve similar inhibition of SARS-CoV-2 replication. Herein, we report that the combination of SRX3177/MPV or SRX3177/UM-UNMC-2 has the potential for further development as a combinational therapy against SARS-CoV-2 and in any future outbreak of beta coronavirus.

Surface-Controlled Sialoside-Based Biosensing of Viral and Bacterial Neuraminidases.

Neuraminidases (NA) are sialic acid-cleaving enzymes that are used by both bacteria and viruses. These enzymes have sialoside structure-related binding and cleaving preferences. Differentiating between these enzymes requires using a large array of hard-to-access sialosides. In this work, we used electrochemical impedimetric biosensing to differentiate among several pathogene-related NAs. We used a limited set of sialosides and tailored the surface properties. Various sialosides were grafted on two different surfaces with unique properties. Electrografting on glassy carbon electrodes provided low-density sialoside-functionalized surfaces with a hydrophobic submonolayer. A two-step assembly on gold electrodes provided a denser sialoside layer on a negatively charged submonolayer. The synthesis of each sialoside required dozens of laborious steps. Utilizing the unique protein-electrode interaction modes resulted in richer biodata without increasing the synthetic load. These principles allowed for profiling NAs and determining the efficacy of various antiviral inhibitors.

Outcome of Open Repair of Thoracoabdominal Aortic Aneurysm in Takayasu Arteritis: A Retrospective Analysis.

BACKGROUND: Takayasu Arteritis (TA) is an immune mediated arteritis causing inflammation of the aorta and its branches, which can result in aortic aneurysms. Our aim is to describe the outcome of surgical management in these patients who presented with Thoracoabdominal aortic aneurysm (TAAA). METHODS: Between 2003 and 2023, 40 TA patients with TAAA underwent operative repair. RESULTS: There were 24 females and 16 males, in the age group of 19-53 years, with hypertension in 20 patients. Raised Erythrocyte sedimentation Rate was present in 13 patients. According to Crawford classification, there were 2 patients with type I, 2 with type II, 17 with type III, 12 patients with type IV and 7 with type V aneurysm. Multiple steno-occlusive lesions of aortic branches were present in 21 patients, with majority affecting the renal artery. Femoral Artery Femoral Vein Partial cardiopulmonary bypass was used for types I, II, III and V. Separate bypass to visceral branches was done in eight patients, of whom five had multiple bypasses and three patients only had renal bypass. Twelve patients underwent reimplantation of branches, out of which nine had multiple vessel reimplantation. Four patients underwent staged repair of the aneurysm, which included visceral debranching in the first day, followed by repair of the aneurysm in the next day. In the immediate postoperative period, ten patients developed acute kidney injury and two required dialysis. Other morbidities included acute respiratory distress syndrome (ARDS), spinal cord dysfunction, bleeding, and wound complications. Three patients expired in the immediate postoperative period. Mean duration of intensive care unit stay was 4.1 days and hospital stay was 12.7 days. Comparison of disease activity with morbidity and mortality was statistically insignificant. Patients were on follow-up for a range of 6 months to 14 years and median follow-up of 25 months. Over this time period four patients expired and four developed anastomotic pseudoaneurysm requiring intervention. On comparing the disease activity at the time of surgery with the long-term arteritis related complications that required intervention, the P value was 0.653 and hence statistically not significant. The 10-year survival rate is 84.4%. CONCLUSIONS: Surgical repair has good and satisfactory outcome, with low early and late mortality rates. Progression of disease can occur at any stage of the disease, hence indicating the need for long term follow-up and frequent imaging.

Health prediction of reciprocating endodontic instrument based on the machine learning and exponential degradation models.

This study proposes an intelligent health prediction and fault prognosis of the endodontic file during the root canal treatment. Root canal treatment is the procedure of disinfecting the infected pulp through the canal with the help of an endodontic instrument. Force signals are acquired with the help of a dynamometer during the canal preparation, and statistical features are extracted. The extracted features are selected through the window-wise feature extraction process. Characteristic features for endodontic file prognostics include time-domain features of the signals are evaluated. The extracted feature has inappropriate information, that is, noise between the signals; hence the smoothing of the feature is required at this stage to observe a trend in the signals. Based on the smoothing feature and post-processing of the feature, defined the health index to calculate the health condition of the endodontic instruments. A machine learning algorithm and exponential degradation model are used to predict the health of the endodontic instrument during the root canal treatment. This model is used to forecast the degradation of the endodontic file so that actions can be taken before actual failures happen. The proposed methodology can analyze the failures and micro-crack initiation of the endodontic instruments. Endodontics practitioners can use the machine learning models as well as an exponential model for estimating the health condition of the endodontic instrument. This study may help the clinician to progress the efficiency of the root canal treatment and the competence of the endodontic instruments.

The role of surgery or definitive chemoradiotherapy in management of localized squamous cell carcinoma of esophagus - What is the verdict?

The management of squamous cell carcinoma (SqCC) of esophagus has significantly changed over last decade with the development of newer surgical techniques such as endoscopic submucosal dissection for early superficial esophageal cancer and refinement of existing surgical techniques (e.g., Ivor-Lewis esophagectomy) that has been associated with an improvement in patient outcomes. The data from the pivotal CROSS study has established neoadjuvant chemoradiotherapy (CRT) as standard of care for patients with locally advanced disease progressing to esophagectomy Simultaneously, definitive chemoradiotherapy (dCRT) has emerged as an effective therapeutic modality with an added advantage of organ preservation. The present review focuses on reviewing the management of localized esophageal SqCC and exploring the evidence regarding the efficacy and caveats of different therapeutic modalities. One of the key objectives is to identify any specific features which may influence choosing a particular modality (e.g. surgery cf. dCRT) and definition of an appropriate evidence-based algorithm for management of early (superficial) and locally advanced SqCC of esophagus.

Nucleoside-Driven Specificity of DNA Methyltransferase.

We have studied the adenosine binding specificities of two bacterial DNA methyltransferases, Taq methyltransferase (M.TaqI), and HhaI methyltransferase (M.HhaI). While they have similar cofactor binding pocket interactions, experimental data showed different specificity for novel S-nucleobase-l-methionine cofactors (SNMs; N=guanosyl, cytidyl, uridyl). Protein dynamics corroborate the experimental data on the cofactor specificities. For M.TaqI the specificity for S-adenosyl-l-methionine (SAM) is governed by the tight binding on the nucleoside part of the cofactor, while for M.HhaI the degree of freedom of the nucleoside chain allows the acceptance of other bases. The experimental data prove catalytically productive methylation by the M.HhaI binding pocket for all the SNMs. Our results suggest a new route for successful design of unnatural SNM analogues for methyltransferases as a tool for cofactor engineering.

The implication of oversampling on the effectiveness of force signals in the fault detection of endodontic instruments during RCT.

This work provides an innovative endodontic instrument fault detection methodology during root canal treatment (RCT). Sometimes, an endodontic instrument is prone to fracture from the tip, for causes uncertain the dentist's control. A comprehensive assessment and decision support system for an endodontist may avoid several breakages. This research proposes a machine learning and artificial intelligence-based approach that can help to diagnose instrument health. During the RCT, force signals are recorded using a dynamometer. From the acquired signals, statistical features are extracted. Because there are fewer instances of the minority class (i.e. faulty/moderate class), oversampling of datasets is required to avoid bias and overfitting. Therefore, the synthetic minority oversampling technique (SMOTE) is employed to increase the minority class. Further, evaluating the performance using the machine learning techniques, namely Gaussian Naïve Bayes (GNB), quadratic support vector machine (QSVM), fine k-nearest neighbor (FKNN), and ensemble bagged tree (EBT). The EBT model provides excellent performance relative to the GNB, QSVM, and FKNN. Machine learning (ML) algorithms can accurately detect endodontic instruments' faults by monitoring the force signals. The EBT and FKNN classifier is trained exceptionally well with an area under curve values of 1.0 and 0.99 and prediction accuracy of 98.95 and 97.56%, respectively. ML can potentially enhance clinical outcomes, boost learning, decrease process malfunctions, increase treatment efficacy, and enhance instrument performance, contributing to superior RCT processes. This work uses ML methodologies for fault detection of endodontic instruments, providing practitioners with an adequate decision support system.

In Situ Electron Microscopy of Transformations of Copper Nanoparticles under Plasmonic Excitation.

Metal nanoparticles are attracting interest for their light-absorption properties, but such materials are known to dynamically evolve under the action of chemical and physical perturbations, resulting in changes in their structure and composition. Using a transmission electron microscope equipped for optical excitation of the specimen, the structural evolution of Cu-based nanoparticles under simultaneous electron beam irradiation and plasmonic excitation was investigated with high spatiotemporal resolution. These nanoparticles initially have a Cu core-Cu2O oxide shell structure, but over the course of imaging, they undergo hollowing via the nanoscale Kirkendall effect. We captured the nucleation of a void within the core, which then rapidly grows along specific crystallographic directions until the core is hollowed out. Hollowing is triggered by electron-beam irradiation; plasmonic excitation enhances the kinetics of the transformation likely by the effect of photothermal heating.

Neoadjuvant Management of Adenocarcinoma of the Esophagus and Esophagogastric Junction: Review of Randomized Evidence and Definition of Optimum Treatment Algorithm.

BACKGROUND: Neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) are accepted standards of care for the management of adenocarcinoma of the esophagus and gastroesophageal junction. SUMMARY: The MRC-OEO2 study established the role of 2 cycles of neoadjuvant cisplatin/fluoropyrimidine. More recently, the FLOT-AIO4 study demonstrated the superiority of perioperative FLOT chemotherapy (5FU, oxaliplatin, and docetaxel) compared to ECX (epirubicin, cisplatin, and capecitabine) regime. The results from the pivotal CROSS study established neoadjuvant CRT as a new standard of care in OG cancer. The survival benefits observed in FLOT and CROSS studies are similar [FLOT - hazard ratio 0.75 (0.62-0.92); CROSS - 0.741 (0.55-0.98)]. KEY MESSAGES: Both nCT and nCRT have been shown to be associated with survival benefit compared to surgery alone. We have performed a comprehensive review of the available evidence to define the optimum treatment algorithm and identify specific patient sub-groups who may be appropriate for the use of one or more of these neoadjuvant options.

Time-resolved transmission electron microscopy for nanoscale chemical dynamics.

The ability of transmission electron microscopy (TEM) to image a structure ranging from millimetres to Ångströms has made it an indispensable component of the toolkit of modern chemists. TEM has enabled unprecedented understanding of the atomic structures of materials and how structure relates to properties and functions. Recent developments in TEM have advanced the technique beyond static material characterization to probing structural evolution on the nanoscale in real time. Accompanying advances in data collection have pushed the temporal resolution into the microsecond regime with the use of direct-electron detectors and down to the femtosecond regime with pump-probe microscopy. Consequently, studies have deftly applied TEM for understanding nanoscale dynamics, often in operando. In this Review, time-resolved in situ TEM techniques and their applications for probing chemical and physical processes are discussed, along with emerging directions in the TEM field.

Biocatalysis versus Molecular Recognition in Sialoside-Selective Neuraminidase Biosensing.

Sialic acid recognition and hydrolysis are essential parts of cellular function and pathogen infectivity. Neuraminidases are enzymes that detach sialic acid from sialosides, and their inhibition is a prime target for viral infection treatment. The connectivity and type of sialic acid influence the recognition and hydrolysis activity of the many different neuraminidases. The common strategies to evaluate neuraminidase activity, recognition, and inhibition rely on extensive labeling and require a large amount of sialylated glycans. The above limitations make the effort of finding viral inhibitors extremely difficult. We used synthetic sialylated glycans and developed a label-free electrochemical method to show that sialoside structural features lead to selective neuraminidase biosensing. We compared Neu5Ac to Neu5Gc sialosides to evaluate the organism-dependent neuraminidase selectivity-sensitivity relationship. We demonstrated that the type of surface and the glycan monolayer density direct the response to either binding or enzymatic activity. We proved that while the hydrophobic glassy carbon surface increases the interaction with the enzyme hydrophobic interface, the negatively charged interface of the lipoic acid monolayer on gold repels the protein and enables biocatalysis. We showed that the sialoside monolayers can serve as tools to evaluate the inhibition of neuraminidases both by biocatalysis and molecular recognition.

Preparation of 3D printed calcium sulfate filled PLA scaffolds with improved mechanical and degradation properties.

Scaffold is one of the key components for tissue engineering application. Three-dimensional (3D) printing has given a new avenue to the scaffolds design to closely mimic the real tissue. However, material selection has always been a challenge in adopting 3D printing for scaffolds fabrication, especially for hard tissue. The fused filament fabrication technique is one of the economical 3D printing technology available today, which can efficiently fabricate scaffolds with its key features. In the present study, a hybrid polymer-ceramic scaffold has been prepared by combining the benefit of synthetic biodegradable poly (lactic acid) (PLA) and osteoconductive calcium sulphate (CaS), to harness the advantage of both materials. Composite PLA filament with maximum ceramic loading of 40 wt% was investigated for its printability and subsequently scaffolds were 3D printed. The composite filament was extruded at a temperature of 160 °C at a constant speed with an average diameter of 1.66 ± 0.34 mm. PLA-CaS scaffold with ceramic content of 10%, 20%, and 40% was 3D printed with square pore geometry. The developed scaffolds were characterized for their thermal stability, mechanical, morphological, and geometrical accuracy. The mechanical strength was improved by 29% at 20 wt% of CaS. The porosity was found to be 50-60% with an average pore size of 550 µm with well-interconnected pores. The effect of CaS particles on the degradation behaviour of scaffolds was also assessed over an incubation period of 28 days. The CaS particles acted as porogen and improved the surface chemistry for future cellular activity, while accelerating the degradation rate.

Correlation of perceived stress with monthly cyclical changes in the female body.

Background: Women are liable to stress-related disorders as female sex hormone, estrogen has been indicated to be protective against stress disorders. The hormone level varies with different phases of menstrual cycle. Moreover, postmenopausal women are at risk for stress-related disorders. So this study was done to correlate the different phases of menstrual cycle with the perceived stress in different phases of monthly cycle. Methods: This study was conducted in the Department of Physiology, Shri Guru Ram Rai Institute of Medical and Health Sciences (SGRRIMHS), Dehradun. Four hundred girls in the age group of 18-26 years were selected for the study. The Perceived Stress Scale (PSS) questionnaire was circulated via Google forms after briefing them about the study. Informed consent was also taken. The menstrual history of the subjects was enquired by one-to-one interaction. The participants completed the PSS questionnaire twice in the same cycle. Data collected were statistically analyzed, using Independent t-test and Chi-square test and point biserial correlation test. Result: The analysis showed strong statistical association of PSS with two phases of menstrual cycle. The PSS score was higher in the late luteal and menstrual phase, while it was less in the late follicular phase (P < 0.05). Conclusion: The decreased oestrogen levels in the late luteal & menstrual phase are strongly associated with perceived stress in our study. Hormonal changes in the monthly cycles are related with stress, behavioral shift and many other physical changes in females. This information to the family physicians would be beneficial in counseling the females regarding various changes occurring during the menstrual cycle.

Design of surface tailored carboxymethyl dextran-protein based nanoconjugates for paclitaxel: Spectroscopical characterizations and cytotoxicity assay.

Paclitaxel (PTX) is an essential anticancer drug from the biopharmaceutical classification system (BCS) class IV. Unfortunately, PTX has some drawbacks including low solubility, cell toxicity, adverse cell reaction, etc. Therefore, folic acid (FA) tailored carboxymethyl-dextran (CMD), and bovine serum albumin (BSA) mediated nanoconjugates of paclitaxel (PTX) (FA-CMD-BSA-PTX) were designed. At first, esterification reaction between FA and CMD resulted in FA-CMD conjugate whereas FA-CMD-BSA conjugate was synthesized via the Maillard reaction. Finally, FA-CMD-BSA conjugates of PTX were achieved via hydrophobic interaction and gelation of BSA. Herein, heating offers the gelation of BSA that furnishes the cross-linking wherein PTX gets fixed inside BSA. Thermogram of FA-CMD-BSA-PTX showed the absence of PTX peak that concluding PTX has been molecularly dispersed in polymer matrix and entrapment inside polymeric conjugate. As an effect, surface decorated FA-CMD-BSA-PTX showed low hemolytic toxicity over free PTX. Cytotoxicity assay on A549 human lung cancer cells shows cell viability decreased from 60 % to 10 % with increasing concentration from 1 to 5 µg/mL. In conclusion, CMD facilitates the circulation time of PTX and BSA acts as a carrier to target tumor locations effectively. The nano-conjugate formulation significantly reduces toxicity and can be used for the treatment of lung cancer.

Hot Carrier Lifetimes and Electrochemical Water Dissociation Enhanced by Nickel Doping of a Plasmonic Electrocatalyst.

Hot carriers generated by localized surface plasmon resonance (LSPR) excitation of plasmonic metal nanoparticles are known to enhance electrocatalytic reactions. However, the participation of plasmonically generated carriers in interfacial electrochemical reactions is often limited by fast relaxation of these carriers. Herein, we address this challenge by tuning the electronic structure of a plasmonic electrocatalyst. Specifically, we design an electrocatalyst for alkaline hydrogen evolution reaction (HER) that consists of nanoparticles of a ternary Cu-Pt-Ni ternary alloy. The CuPt alloy has both plasmonic attributes and electrocatalytic HER activity. Ni doping contributes an electron-deficient 3d band and fully filled 4s band, which promotes water adsorption and prolongs the lifetimes of excited carriers generated by plasmonic excitation. As an outcome, the Cu-Pt-Ni nanoparticles exhibit boosted activity for electrochemical water dissociation and HER under LSPR excitation.

Profiling Heparan Sulfate-Heavy Metal Ions Interaction Using Electrochemical Techniques.

Heparan sulfate glycosaminoglycans provides extracellular matrix defense against heavy metals cytotoxicity. Identifying the precise glycan sequences that bind a particular heavy metal ion is a key for understanding those interactions. Here, electrochemical and surface characterization techniques were used to elucidate the relation between the glycans structural motifs, uronic acid stereochemistry, and sulfation regiochemistry to heavy metal ions binding. A divergent strategy was employed to access a small library of structurally well-defined tetrasaccharides analogs with different sulfation patterns and uronic acid compositions. These tetrasaccharides were electrochemically grafted onto glassy carbon electrodes and their response to heavy metal ions was monitored by electrochemical impedance spectroscopy. Key differences in the binding of Hg(II), Cd(II), and Pb(II) were associated with a combination of the uronic acid type and the sulfation pattern.