Assessment of meniscal extrusion with ultrasonography: a systematic review and meta-analysis.

BACKGROUND: Magnetic resonance imaging (MRI) is the imaging of choice for meniscal extrusion (ME). However, they may underappreciate the load-dependent changes of the meniscus. There is growing evidence that weight-bearing ultrasound (WB US) is more suitable, particularly in revealing occult extrusion. We therefore perform a systematic review and meta-analysis on the validity and reliability of US in diagnosing extrusion. Furthermore, we explored whether it detects differences in extrusion between loaded and unloaded positions and those with pathological (osteoarthritis and meniscal injury) and healthy knees. METHODS: The Cochrane Controlled Register of Trials, PubMed, Medline, and Embase were used to perform a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Data pertaining to intra- and interrater reliability of US in measuring meniscal extrusion (ME), its correlation with magnetic resonance imaging (MRI), and head-to-head comparison of potential factors to influence ME were included [loading versus unloading position; osteoarthritis (OA) or pathological menisci (PM) versus healthy knees; mild versus moderate-severe knee OA]. Pooled data were analyzed by random or fixed-effects models. RESULTS: A total of 31 studies were included. Intraclass correlation coefficients (ICC) for intra- and interrater reliability were minimum 0.94 and 0.91, respectively. The correlation between US and MRI was (r = 0.76). US detected ME to be greater in the loaded position in all knees (healthy, p < 0.00001; OA, p < 0.00001; PM, p = 0.02). In all positions, US detected greater extrusion in OA (p < 0.0003) and PM knees (p = 0.006) compared with healthy controls. Furthermore, US revealed greater extrusion in moderate-severe OA knees (p < 0.00001). CONCLUSIONS: This systematic review suggests ultrasonography can play an important role in the measurement of meniscal extrusion, with results comparable to that of MRI. However, to what extent it can differentiate between physiological and pathological extrusion requires further investigation, with an absolute cutoff value yet to be determined. Nevertheless, it is an appropriate investigation to track the progression of disease in those with meniscal pathologies or osteoarthritis. Furthermore, it is a feasible investigation to evaluate the meniscal function following surgery. LEVEL OF EVIDENCE: IV, Systematic review of level III-IV evidence.

Centralization reduces meniscal extrusion, improves joint mechanics and functional outcomes in patients undergoing meniscus surgery: A systematic review and meta-analysis.

PURPOSE: To perform a systematic review and meta-analysis of the existing literature on meniscal centralisation procedures, analysing its impact on meniscal extrusion, joint biomechanics and clinical and radiological outcome measures. METHODS: The Cochrane Controlled Register of Trials, PubMed (MEDLINE) and Embase were used to perform a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. Biomechanical studies on healthy animal or human cadaveric knee joints that assessed meniscal extrusion or tibiofemoral contact mechanics (contact area and pressure) following centralization for meniscal pathologies were included. For clinical studies, those that prospectively or retrospectively assessed patient-reported outcome measures (PROMs), postoperative knee motion, complications and radiological extrusion following centralization for meniscal pathologies were included. RESULTS: Fifteen studies were included in the analysis, comprising eight biomechanical, six clinical and one both. There were 92 knee specimens for biomechanical testing, of which 40 were human cadaveric and 52 porcine models. Biomechanical data revealed centralization to be commonly performed for posterior meniscal root tears and significantly reduced extrusion and contact pressure whilst improving contact area following a tear (p < 0.00001). Centralization restored extrusion to that of the native knee at all flexion angles described (0-90°, p = 0.25) and, compared to the torn state, brought tibiofemoral contact mechanics 3.2-5.0 times closer to the native state. Clinical data showed that 158 patients underwent centralization for extrusion. It improved postoperative Knee Injury and Osteoarthritis Outcome score (KOOS) (p = 0.006) and Lysholm scores (p < 0.00001) at 25.0 months, maintained extrusion reduction at 17.1 months (p < 0.00001) and preserved knee motion. CONCLUSION: Centralisation for various meniscal injuries associated with extrusion can reduce meniscal extrusion and improve joint biomechanics, along with clinical and radiological outcomes. Existing evidence is still scarce and exhibits a notable amount of methodological heterogeneity. LEVEL OF EVIDENCE: Systematic review of Level IV evidence.

Severe magnitude of dental and skeletal fluorosis and its impact on society and environment in a part of Manbhum-Singhbhum Plateau, India.

BACKGROUND: Numerous approaches have been adopted to evaluate limited freshwater resources and the associated health hazards due to excessive amounts of fluoride in drinking water. The study aims to assess the degree and severity of dental and skeletal fluorosis and examine the broader effects of fluorosis on human health and society in the Manbhum-Singhbhum Plateau region, India. METHODS: The Community Fluorosis Index (CFI) and Dean's Index have been used to measure the magnitude and severity of dental and skeletal fluorosis. Questionnaire surveys, Focus Group Discussions (FGDs), and appropriate statistical methods have been applied to identify the social impacts. Risk-prone zones have been identified through overlay analysis using geoinformatics. RESULTS: About 54.60% of people in 67 villages of this part of the Manbhum-Singhbhum Plateau are affected in varying degrees of fluorosis ranging from very mild to mild, moderate, and severe dental fluorosis. Among these 67 villages, Janra (Manbazar I) and Hijla (Barabazar) have the most severely affected people. School dropout (n = 426), social isolation (n = 149), remarriage (n = 21), and physically disabled (n = 75) have also been reported. The study shows that about 414.29 km2 of the Manbhum-Singhbhum Plateau comes under the high-risk-prone category. CONCLUSIONS: The societal and environmental awareness of the fluorosis-affected individuals is almost absent in this region. Economic hardships, lack of education, inadequate health care facilities, water scarcity, and lack of awareness increase the magnitude of health hazards and societal vulnerability of the people in this region, who are largely dependent on natural resources.

Carbon dioxide sensitization delays the postharvest ripening and fatty acids composition of Capsicum fruit by regulating ethylene biosynthesis, malic acid and reactive oxygen species metabolism.

Present study would be significant in the sustenance of quality characters for postharvest storage of Capsicum fruit with CO2-sensitization in biocompatible manner. The present experiment describes effects of CO2 sensitization on delaying postharvest ripening through physiological attributes in Capsicum fruit. The experiment was conducted with acidified bicarbonate-derived CO2 exposure for 2 h on Capsicum fruit, kept under white light at 25 °C through 7 days postharvest storage. Initially, fruits responded well to CO2 as recorded sustenance of greenness and integrity of fruit coat resolved through scanning electron micrograph. Loss of water and accumulation of total soluble solids were marginally increased on CO2-sensitized fruit as compared to non-sensitized (control) fruit. The ethylene metabolism biosynthetic genes like CaACC synthase, CaACC oxidase were downregulated on CO2-sensitization. Accompanying ethylene metabolism cellular respiration was downregulated on CO2 induction as compared to control through 7 days of storage. Fruit coat photosynthesis decarboxylating reaction by NADP malic enzyme was upregulated to maintain the reduced carbon accumulation as recorded on 7 days of storage under the same condition. CO2-sensitization effectively reduced the lipid peroxides as oxidative stress products on ripening throughout the storage. Anti-oxidation reaction essentially downregulates the ROS-induced damages of biomolecules that otherwise are highly required for food preservation during postharvest storage. Thus, the major finding is that CO2-sensitization maintains a higher ratio of unsaturated to saturated fatty acids in fruit coat during storage. Tissue-specific downregulation of ROS also maintained the nuclear stability under CO2 exposure. These findings provide basic as well as applied insights for sustaining Capsicum fruit quality with CO2 exposure under postharvest storage. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01471-4.

Circadian Rhythm and Sleep Analyses in a Fruit Fly Model of Fragile X Syndrome Using a Video-Based Automated Behavioral Research System.

Fragile X syndrome (FXS) is caused by the full mutation in the FMR1 gene on the Xq27.3 chromosome region. It is the most common monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). Besides ASD and ID and other symptoms, individuals with FXS may exhibit sleep problems and impairment of circadian rhythm (CR). The Drosophila melanogaster models of FXS, such as dFMR1B55, represent excellent models for research in the FXS field. During this study, sleep patterns and CR in dFMR1B55 mutants were analyzed, using a new platform based on continuous high-resolution videography integrated with a highly-customized version of an open-source software. This methodology provides more sensitive results, which could be crucial for all further research in this model of fruit flies. The study revealed that dFMR1B55 male mutants sleep more and can be considered weak rhythmic flies rather than totally arrhythmic and present a good alternative animal model of genetic disorder, which includes impairment of CR and sleep behavior. The combination of affordable videography and software used in the current study is a significant improvement over previous methods and will enable broader adaptation of such high-resolution behavior monitoring methods.

Deciphering the Origin of Regioselectivity in Ru(II)-Catalyzed C-H Annulation of N-Chlorobenzamides with 1,3-Diynes.

Understanding the reaction mechanism and origin of regioselectivity in transition metal-catalyzed C-H activation/annulation reactions with 1,3-diynes has remained an intriguing challenge. In this article, to establish the mechanism and decipher the origin of regioselectivity, we report a detailed computational density functional theory-based mechanistic investigation on the recently developed Ru(II)-catalyzed [4 + 2] annulation of N-chlorobenzamides with 1,3-diynes for the synthesis of 3-alkynylated isoquinolone derivatives. Our calculations reveal a redox-neutral pathway for the annulation reaction. The stepwise analysis of the reaction channels indicates the migratory insertion step and the concerted reductive elimination/oxidative addition of the Ru(p-cymene) moiety to form the N-C bond leading to the 3-alkynylated product to be the selectivity- and rate-determining steps, respectively. Finally, the distortion/interaction analysis using the activation-strain model suggests the steric effect as the determining factor for the observed regioselectivity for the formation of the 3-alkynylated product. Overall, the computationally obtained key insights into the catalytic mechanism and the origin of regioselectivity in the C-H activation/annulation reaction can be used as a guide to rationally design and develop novel transformation strategies for heterocycle synthesis.

Automated radiosynthesis of [18F]DPA-714 on a commercially available IBA Synthera®.

The goal of this work was to develop a reliable method to produce the well-validated microglial activation PET tracer, [18F]DPA-714, routinely for clinical and preclinical research using an IBA Synthera®. Optimization of literature methods included reduced precursor mass and use of TBA HCO3 as the phase transfer agent in place of Kryptofix® 222 in a 65-min synthesis with an average activity yield of 24.6 ± 3.8% (n = 5). Successful quality control testing and process validation results are reported.

Mitochondrial topoisomerase 1 targeted anticancer therapy using irinotecan encapsulated mesoporous MIL-101(Fe) synthesized via a vapour assisted method.

Mitochondrial topisomerase 1 (Top1mt) is critical for mtDNA replication, transcription, and energy production. Here, we investigate the carrier-mediated targeted delivery of the anticancer drug irinotecan into the mitochondria to selectively trap Top1mt covalent complexes (Top1mtcc) and its role in anticancer therapeutics. We have designed a biocompatible mesoporous metal-organic framework (MOF) material, namely MIL-101(Fe), as the drug delivery carrier that selectively localizes inside mitochondria. In contrast to the traditional way of synthesising MOFs, here we have employed a vapour-assisted solvothermal method for the synthesis of MIL-101(Fe) using terephthalic acid as the organic linker and Fe(III) as the metal source. The advantage of this method is that it recycles the excess solvent (DMF) and reduces the amount of washing solvent. We demonstrate that MIL-101(Fe)-encapsulated irinotecan (MIL-Iri) was selectively targeted towards the mitochondria to poison Top1mtcc in a dose-dependent manner and was achieved at a low nanomolar drug concentration. We provide evidence that Top1mtcc generated by MIL-Iri leads to mtDNA damage in human colon and breast cancer cells and plays a significant role in cellular toxicity. Altogether, this study provides evidence for a new and effective strategy in anticancer chemotherapy.

The Role of Anterolateral Ligament Reconstruction or Lateral Extra-articular Tenodesis for Revision Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis of Comparative Clinical Studies.

BACKGROUND: After its success in restoring rotational stability and reducing failure rates in primary anterior cruciate ligament reconstruction (ACLR), lateral extra-articular tenodesis (LET) or anterolateral ligament reconstruction (ALLR) has been endorsed for use in revision ACLR surgery, where failure rates are historically higher. PURPOSE: To perform a systematic review and meta-analysis on whether the addition of a LET or ALLR results in superior clinical outcomes and stability compared with isolated revision ACLR (iACLR). STUDY DESIGN: Meta-analysis; Level of evidence, 4. METHODS: The Cochrane Controlled Register of Trials, PubMed, Medline, and Embase were used to perform a systematic review and meta-analysis of comparative studies using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria with the following search terms: ("extra-articular" OR "tenodesis" OR "anterolateral ligament" OR "iliotibial") AND ("anterior cruciate ligament") AND ("revision" OR "re-operation"). Data pertaining to all patient-reported outcome measures (PROMs), rotational stability, and postoperative complications were extracted from each study. RESULTS: After abstract and full-text screening, 10 clinical comparative studies were included. There were 793 patients, of whom 390 had an iACLR while 403 had an ACLR augmented with a LET or an ALLR (augmented ACLR [aACLR]). The mean time for assessment of PROMs was 35 months. The aACLR group had superior International Knee Documentation Committee (IKDC) scores (standardized mean difference [SMD], 0.27; 95% CI, 0.01 to 0.54; P = .04), rotational stability (odds ratio [OR], 2.77; 95% CI, 1.91 to 4.01; P < .00001), and lower side-to-side difference (OR, -0.53; 95% CI, -0.81 to -0.24; P = .0003) than those without the augmentation. Furthermore, they were less likely to fail (OR, 0.44; 95% CI, 0.24 to 0.80; P = .007). Subgroup analysis in the higher-grade laxity cohort (grade ≥2) revealed an even greater IKDC score (SMD, 0.51; 95% CI, 0.16 to 0.86; P = .005) and an improved Lysholm score (SMD, 0.45; 95% CI, 0.24 to 0.67; P < .0001) in the aACLR group. CONCLUSION: Revision aACLR with a LET or an ALLR can improve subjective IKDC scores, restore rotational stability, and reduce failure rates compared with iACLR. Although controversy remains on the necessity of augmenting all revision ACLRs, the present meta-analysis advocates adding a lateral procedure, particularly in those with a higher-grade pivot shift.

Reverse Regioselective Cp*Co(III)-Catalyzed [4 + 2] C-H Annulation of N-Chloroamides with Vinylsilanes: Synthesis of 4-Silylated Isoquinolones and Their Synthetic Utilities.

We have developed a Cp*Co(III)-catalyzed reverse regioselective [4 + 2] annulation of N-chlorobenzamides/acrylamides with vinylsilanes for the synthesis of 4-silylated isoquinolones. The reaction was performed at ambient temperature under redox-neutral conditions. The reaction utilized the N-Cl bond as an internal oxidant, furnished the required products with excellent regioselectivities, and demonstrated high functional group tolerance. The synthetic utility of 4-silylated isoquinolones has been demonstrated for the preparation of 4-heteroarylated and 4-alkylated isoquinolones via metal-free C-C couplings. Additionally, 3,4-dihydroisoquinolones were synthesized via protodesilylation of 4-silylated isoquinolones, thus making vinylsilane an ethylene surrogate.

High-grade serous ovarian carcinoma, the "Achiles' hill" for clinicians and molecular biologists: a molecular insight.

High-grade serous ovarian carcinoma (HGSOC), the deadliest ovarian cancer, alone accounts for 90% of all its subtypes. Characterized by hallmark mutation of TP53, HGSOC show diverse molecular etiology. HGSOC can arise from both ovarian epithelium as well as the fimbrial epithelium of the fallopian tube. Ovulation induced reactive oxygen species, follicular fluid associated growth factor induced stemness, deregulation of hormone receptors like ER, FSHR, AR and hormones like FSH, LH, prolonged ovulation cycle, use of oral contraceptives are agonists of HGSOC while parity, breastfeeding provide protective effect from HGSOC development. Apart from a generic TP53 mutation, mutation of BRCA1/2, RAD51, BRIP1, PALB2, CHEK2, RAD50 etc., were reportedly associated with development of HGSOC. Epigenetic events like methylation of RASSF1A of RAS signaling pathway,OR51L1, OR51I1, OR51F1 etc. has been reported in HGSOC. Micro-RNAs like miR-1290, miR 27-a-3p miR23a, miR205 were reportedly upregulated in HGSOC. Amongst its cognate subtypes viz. differentiated, immunoreactive, mesenchymal, and proliferative, mesenchymal, and proliferative show worst prognosis. A system biology approach showed five major altered pathways in HGSOC, namely, RB, PI3K/RAS, NOTCH, HRR and FOXM1 signaling. For chemonaive patients, drugs that helps in efflux of reduced glutathione or prevent the redox coupling of GSH-GSSG, like Cisplatin, could be considered as the best therapeutic choice for HGSOC. For patients with BRCA1/2 mutations, PARP inhibitors alone or with Bevacizumab can be effective. Immune checkpoint inhibitors could be effective against immunoreactive subtypes. Identification of genes deregulated in chemoresistance could provide better insights in dealing with the disease.

Correlation of CYP2R1 gene promoter methylation with circulating vitamin D levels among healthy adults.

Background & objectives: Despite being a tropical country, vitamin D deficiency is highly prevalent in India with studies indicating 40-99 per cent prevalence. Apart from calcium and phosphate metabolism, vitamin D is involved in cell cycle regulation, cardiovascular, hepatoprotection. The metabolism of vitamin D is regulated by vitamin D tool genes (CYP2R1/CYP27B1/CYP24A1/VDR). The promoter regions of some of these genes have CpG islands, making them prone to methylation induced gene silencing, which may cause a reduction in circulating vitamin D levels. Epigenetic basis of vitamin D deficiency is yet to be studied in India, and hence, this pilot study was aimed to analyze whether methylation levels of CYP2R1 gene were correlated with the levels of 25(OH)D in healthy, adult individuals in Indian population. Methods: In this cross-sectional study, healthy adults of 18-45 yr of age with no history of malabsorption, thyroidectomy, chronic illness or therapeutic vitamin D supplementation were recruited. DNA methylation analysis was carried out by methylation specific quantitative PCR. Serum calcium, phosphate and vitamin D levels were also quantified. Statistical analysis was done by R 4.0.5 software. Results: A total of 61 apparently healthy adults were analyzed. The serum vitamin D levels did not correlate with CYP2R1 methylation levels in our study population. Significant positive correlation was observed between age and serum vitamin D levels. Significant association of gender was found with CYP2R1 methylation levels. Interpretation & conclusions: This study found no significant correlation between levels of CYP2R1 methylation and circulating 25(OH)D deficiency. Further studies on the Indian population having a larger sample size including entire vitamin D tool genes, among different ethnic groups may be conducted to elucidate molecular etiology of circulating 25(OH)D deficiency. The high prevalence of normal serum calcium and phosphate levels among vitamin D deficient subjects in this study coupled with the strikingly high prevalence of the deficiency at the national level, may suggest the need to revise the cut-off criteria for vitamin D deficiency in the Indian population.

Harnessing Vinyl Acetate as an Acetylene Equivalent in Redox-Neutral Cp*Co(III)-Catalyzed C-H Activation/Annulation for the Synthesis of Isoquinolones and Pyridones.

We have developed Cp*Co(III)-catalyzed redox-neutral synthesis of 3,4-unsubstituted isoquinoline 1(2H)-ones at ambient temperature using N-chloroamides as a starting material. The reaction utilizes vinyl acetate as an inexpensive and benign acetylene surrogate. The N-Cl bond of the N-chlorobenzamides plays the role of an internal oxidant and hence precludes the need for an external oxidant. The reaction works with a wide range of substrates having various functional groups and a substrate containing a heterocyclic ring. Notably, the reaction is extended to the N-chloroacrylamides in which vinylic C-H activation occurs to furnish the 2-pyridone derivatives. Preliminary mechanistic studies were also conducted to shed light on the mechanism of this reaction.

TRPV4 regulates osteoblast differentiation and mitochondrial function that are relevant for channelopathy.

Different ion channels present in the osteoblast regulate the cellular functions including bio-mineralization, a process that is a highly stochastic event. Cellular events and molecular signaling involved in such process is poorly understood. Here we demonstrate that TRPV4, a mechanosensitive ion channel is endogenously present in an osteoblast cell line (MC3T3-E1) and in primary osteoblasts. Pharmacological activation of TRPV4 enhanced intracellular Ca2+-level, expression of osteoblast-specific genes and caused increased bio-mineralization. TRPV4 activation also affects mitochondrial Ca2+-levels and mitochondrial metabolisms. We further demonstrate that different point mutants of TRPV4 induce different mitochondrial morphology and have different levels of mitochondrial translocation, collectively suggesting that TRPV4-mutation-induced bone disorders and other channelopathies are mostly due to mitochondrial abnormalities. These findings may have broad biomedical implications.

Ru(II)-Catalyzed Regioselective Redox-Neutral [4 + 2] Annulation of N-Chlorobenzamides with 1,3-Diynes at Room Temperature for the Synthesis of Isoquinolones.

Herein, we report Ru(II)-catalyzed C-H/N-H bond functionalization of N-chlorobenzamides with 1,3-diynes via regioselective (4 + 2) annulation for the synthesis of isoquinolones under redox-neutral conditions at room temperature. This represents the first example of C-H functionalization of N-chlorobenzamides using an inexpensive and commercially available [Ru(p-cymene)Cl2]2 catalyst. The reaction is operationally simple, works in the absence of any silver additives, and is also applicable to a broad range of substrates with good functional group tolerance. The synthetic utility of the isoquinolone is demonstrated for the synthesis of bis-heterocycles consisting of isoquinolone-pyrrole and isoquinolone-isocoumarin scaffolds.

Fibular- Versus Tibiofibular-Based Reconstruction of the Posterolateral Corner of the Knee: A Systematic Review and Meta-analysis.

BACKGROUND: Fibular- and tibiofibular-based reconstructions are the gold standard treatment for posterolateral corner (PLC) injuries of the knee. Despite comparable outcomes in biomechanical studies, clinical results comparing these constructs remain elusive with no consensus reached regarding the best treatment option. PURPOSE: To perform a systematic review and meta-analysis to compare fibular- and tibiofibular-based techniques for posterolateral corner reconstruction. We aimed to identify whether any differences existed between the 2 techniques in terms of clinical outcomes and rotational and varus stability. STUDY DESIGN: Meta-analysis; Level of evidence, 4. METHODS: The Cochrane Controlled Register of Trials, PubMed, Medline, and Embase were used to perform a systematic review and meta-analysis using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria with the following search terms ("posterolateral corner" OR "fibular collateral ligament" OR "lateral collateral ligament" OR "popliteus tendon" OR "popliteofibular ligament") AND ("reconstruction" OR "LaPrade" OR "Larson" OR "Arciero"). Data pertaining to all patient-reported outcome measures (PROMs), postoperative complications, and valgus and rotational stability were extracted from each study. The pooled outcome data were analyzed by random- and fixed-effects models. RESULTS: After abstract and full-text screening, 6 clinical studies were included. In total, there were 183 patients, of which 90 received fibular-based and 93 tibiofibular-based reconstruction. The majority of studies used similar surgical techniques regarding tunnel orientation, attachment sites, and graft fixation sequence. There were no differences between the groups in terms of PROMs and subjective knee scores at a mean of 20.3 months. The techniques were equally effective in restoring varus and rotational stability. Subgroup analysis revealed that the stability of a posterior cruciate ligament reconstruction postoperatively was not affected by either construct. CONCLUSION: Both constructs had comparable clinical outcomes and were equally effective in restoring varus and rotational stability for PLC knee injuries. The fibular-based technique may offer advantages in view of being less technically demanding and invasive and requiring fewer grafts with a quicker operative time. However, higher quality studies are required to reinforce or refute such conclusions, as the majority of studies in this review were poor to fair quality.

Local Criteria for Triangulating General Manifolds.

We present criteria for establishing a triangulation of a manifold. Given a manifold M, a simplicial complex  A , and a map H from the underlying space of A to M, our criteria are presented in local coordinate charts for M, and ensure that H is a homeomorphism. These criteria do not require a differentiable structure, or even an explicit metric on M. No Delaunay property of A is assumed. The result provides a triangulation guarantee for algorithms that construct a simplicial complex by working in local coordinate patches. Because the criteria are easily verified in such a setting, they are expected to be of general use.

Glucogallin Attenuates the LPS-Induced Signaling in Macrophages and Protects Mice against Sepsis.

The anti-oxidant and anti-inflammatory effect of beta-glucogallin (BGG), a plant-derived natural product, was evaluated in both in vitro and in vivo studies. For the in vitro study, the ability of BGG pre-treatment to quench LPS-induced effects compared to LPS alone in macrophages was investigated. It was found that BGG pre-treatment showed a significant decrease in ROS, NO, superoxide, and pro-inflammatory cytokines (TNF-alpha, IL-4, IL-17, IL-1ß, and IL-6) and increased reduced glutathione coupled with the restoration of mitochondrial membrane potential. Gene profiling and further validation by qPCR showed that BGG pre-treatment downregulated the LPS-induced expression of c-Fos, Fas, MMP-9, iNOS, COX-2, MyD88, TRIF, TRAF6, TRAM, c-JUN, and NF-κB. We observed that BGG pre-treatment reduced nuclear translocation of LPS-activated NF-κB and thus reduced the subsequent expressions of NLRP3 and IL-1ß, indicating the ability of BGG to inhibit inflammasome formation. Molecular docking studies showed that BGG could bind at the active site of TLR4. Finally, in the LPS-driven sepsis mouse model, we showed that pre-treatment with BGG sustained toxic shock, as evident from their 100% survival. Our study clearly showed the therapeutic potential of BGG in toxic shock syndrome.

Autonomous Untethered Microinjectors for Gastrointestinal Delivery of Insulin.

The delivery of macromolecular drugs via the gastrointestinal (GI) tract is challenging as these drugs display low stability as well as poor absorption across the intestinal epithelium. While permeation-enhancing drug delivery methods can increase the bioavailability of low molecular weight drugs, the effective delivery of high molecular weight drugs across the tight epithelial cell junctions remains a formidable challenge. Here, we describe autonomous microinjectors that are deployed in the GI tract, then efficiently penetrate the GI mucosa to deliver a macromolecular drug, insulin, to the systemic circulation. We performed in vitro studies to characterize insulin release and assess the penetration capability of microinjectors and we measured the in vivo release of insulin in live rats. We found that the microinjectors administered within the luminal GI tract could deliver insulin transmucosally to the systemic circulation at levels similar to those with intravenously administered insulin. Due to their small size, tunability in sizing and dosing, wafer-scale fabrication, and parallel, autonomous operation, we anticipate that these microinjectors will significantly advance drug delivery across the GI tract mucosa to the systemic circulation in a safe manner.