Surface-localized glycoproteins act through class C ARFs to fine-tune gametophore initiation in Physcomitrium patens.

Arabinogalactan proteins are functionally diverse cell wall structural glycoproteins that have been implicated in cell wall remodeling, although the mechanistic actions remain elusive. Here, we identify and characterize two AGP glycoproteins, SLEEPING BEAUTY (SB) and SB-like (SBL), that negatively regulate the gametophore bud initiation in Physcomitrium patens by dampening cell wall loosening/softening. Disruption of SB and SBL led to accelerated gametophore formation and altered cell wall compositions. The function of SB is glycosylation dependent and genetically connected with the class C auxin response factor (ARF) transcription factors PpARFC1B and PpARFC2. Transcriptomics profiling showed that SB upregulates PpARFC2, which in turn suppresses a range of cell wall-modifying genes that are required for cell wall loosening/softening. We further show that PpARFC2 binds directly to multiple AuxRE motifs on the cis-regulatory sequences of PECTIN METHYLESTERASE to suppress its expression. Hence, our results demonstrate a mechanism by which the SB modulates the strength of intracellular auxin signaling output, which is necessary to fine-tune the timing of gametophore initials formation.

Exploring the role of casein kinase 1α splice variants across cancer cell lines.

Casein kinase 1α (CK1α) is a serine/threonine protein kinase that acts in various cellular processes affecting cell division and signal transduction. CK1α is present as multiple splice variants that are distinguished by the presence or absence of a long insert (L-insert) and a short carboxyl-terminal insert (S-insert). When overexpressed, zebrafish CK1α splice variants exhibit different biological properties, such as subcellular localization and catalytic activity. However, whether endogenous, alternatively spliced CK1α gene products also differ in their biological functions has yet to be elucidated. Here, we identify a panel of splice variant specific CK1α antibodies and use them to show that four CK1α splice variants are expressed in mammals. We subsequently show that the relative abundance of CK1α splice variants varies across distinct mouse tissues and between various cancer cell lines. Furthermore, we identify pathways whose expression is noticeably altered in cell lines enriched with select splice variants of CK1α. Finally, we show that the S-insert of CK1α promotes the growth of HCT 116 cells as cells engineered to lack the S-insert display decreased cell growth. Together, we provide tools and methods to identify individual CK1α splice variants, which we use to begin to uncover the differential biological properties driven by specific splice variants of mammalian CK1α.

The impact of sterility-mortality tolerance and recovery-transmission trade-offs on host-parasite coevolution.

Understanding the coevolutionary dynamics of hosts and their parasites remains a major focus of much theoretical literature. Despite empirical evidence supporting the presence of sterility-mortality tolerance trade-offs in hosts and recovery-transmission trade-offs in parasites, none of the current models have explored the potential outcomes when both trade-offs are considered within a coevolutionary framework. In this study, we consider a model where the host evolves sterility tolerance at the cost of increased mortality and the parasite evolves higher transmission rate at the cost of increased recovery rate (reduced infection duration), and use adaptive dynamics to predict the coevolutionary outcomes under such trade-off assumptions. We particularly aim to understand how our coevolutionary dynamics compare with single species evolutionary models. We find that evolutionary branching in the host can drive the parasite population to branch, but that cycles in the population dynamics can prevent the coexisting strains from reaching their extremes. We also find that varying crowding does not impact the recovery rate when only the parasite evolves, yet coevolution reduces recovery as crowding intensifies. We conclude by discussing how different host and parasite trade-offs shape coevolutionary outcomes, underscoring the pivotal role of trade-offs in coevolution.

Strontium-Substituted Nanohydroxyapatite-Incorporated Poly(lactic acid) Composites for Orthopedic Applications: Bioactive, Machinable, and High-Strength Properties.

Traditional metal-alloy bone fixation devices provide structural support for bone repair but have limitations in actively promoting bone healing and often require additional surgeries for implant removal. In this study, we focused on addressing these challenges by fabricating biodegradable composites using poly(lactic acid) (PLA) and strontium-substituted nanohydroxyapatite (SrHAP) via melt compounding and injection molding. Various percentages of SrHAP (5, 10, 20, and 30% w/w) were incorporated into the PLA matrix. We systematically investigated the structural, morphological, thermal, mechanical, rheological, and dynamic mechanical properties of the prepared composites. Notably, the tensile modulus, a critical parameter for orthopedic implants, significantly improved from 2.77 GPa in pristine PLA to 3.73 GPa in the composite containing 10% w/w SrHAP. The incorporation of SrHAP (10% w/w) into the PLA matrix led to an increased storage modulus, indicating a uniform dispersion of SrHAP within the PLA and good compatibility between the polymer and nanoparticles. Moreover, we successfully fabricated screws using PLA composites with 10% (w/w) SrHAP, demonstrating their formability at room temperature and radiopacity when observed under X-ray microtomography (micro-CT). Furthermore, the water contact angle decreased from 93 ± 2° for pristine PLA to 75 ± 3° for the composite containing SrHAP, indicating better surface wettability. To assess the biological behavior of the composites, we conducted in vitro cell-material tests, which confirmed their osteoconductive and osteoinductive properties. These findings highlight the potential of our developed PLA/SrHAP10 (10% w/w) composites as machinable implant materials for orthopedic applications. In conclusion, our study presents the fabrication and comprehensive characterization of biodegradable composites comprising PLA and strontium-substituted nanohydroxyapatite (SrHAP). These composites exhibit improved mechanical properties, formability, and radiopacity while also demonstrating desirable biological behavior. Our results suggest that these PLA/SrHAP10 composites hold promise as machinable implant materials for orthopedic applications.

A Sterility-Mortality Tolerance Trade-Off Leads to Within-Population Variation in Host Tolerance.

While experimental studies have demonstrated within-population variation in host tolerance to parasitism, theoretical studies rarely predict for polymorphism to arise. However, most theoretical models do not consider the crucial distinction between tolerance to the effects of infection-induced deaths (mortality tolerance) and tolerance to the parasite-induced reduction in the reproduction of infected hosts (sterility tolerance). While some studies have examined trade-offs between host tolerance and resistance mechanisms, none has considered a correlation within different tolerance mechanisms. We assume that sterility tolerance and mortality tolerance are directly traded-off in a host population subjected to a pathogen and use adaptive dynamics to study their evolutionary behaviour. We find that such a trade-off between the two tolerance strategies can drive the host population to branch into dimorphic strains, leading to coexistence of strains with sterile hosts that have low mortality and fully fertile with high mortality rates. Further, we find that a wider range of trade-off shapes allows branching at intermediate- or high-infected population size. Our other significant finding is that sterility tolerance is maximised (and mortality tolerance minimised) at an intermediate disease-induced mortality rate. Additionally, evolution entirely reverses the disease prevalence pattern corresponding to the recovery rate, compared to when no strategies evolve. We provide novel predictions on the evolutionary behaviour of two tolerance strategies concerning such a trade-off.

Creative Long Covid: A qualitative exploration of the experience of Long Covid through the medium of creative narratives.

BACKGROUND: Healthcare is witnessing a new disease with the emergence of Long Covid; a condition which can result in myriad symptoms, varying in frequency and severity. As new data are emerging to help inform treatment guidelines, the perspectives of those living with Long Covid are essential in informing healthcare practice. The research aimed to collect the narratives of people living with Long Covid to better understand the lived experience of this condition. In attempting to narrate complex or traumatic experiences the arts and humanities can offer alternative ways of expressing embodied narratives, representing rich sources of meaning. Therefore, the research specifically sought to elicit creative expressions from participants with lived experience of Long Covid. METHODS: Data were collected via an online repository where participants could submit their pieces of creative writing. Data were collected between August 2021 and January 2022 and a total of 28 submissions were received from participants. These were mostly written creative narratives. However, a small number were submitted as audio or video files of spoken word poetry or songs. Data collection was stopped once data saturation was achieved. RESULTS: The submissions were subjected to thematic analysis and five themes were generated. These five themes are Identity, social relationships, symptoms, interaction with healthcare systems and time. The results provide an insight into the experience of Long Covid as detailed by the participants' creative narratives. CONCLUSION: The results from this study provide a unique insight into the lived experience of Long Covid. In relation to clinical practice, the results suggest that adjustment reaction and loss of sense of self could be added as common symptoms. PATIENT AND PUBLIC CONTRIBUTION: Before undertaking the research, Long Covid community groups were contacted to discuss the potential value of this study and it was widely supported. One of the leading Long Covid support groups was also involved in disseminating information regarding the project. As part of ongoing work within this project, members of the team are actively disseminating the results within Long Covid communities and seeking to develop arts-based workshops specifically for people with Long Covid.

In vitro activity of the novel antifungal olorofim against dermatophytes and opportunistic moulds including Penicillium and Talaromyces species.

OBJECTIVES: Olorofim is a novel antifungal agent with in vitro activity against Aspergillus and other opportunistic moulds. We investigated the in vitro activity of olorofim against a range of filamentous fungi comprising isolates of Aspergillus species, Scedosporium species, Alternaria alternata, dermatophytes, including terbinafine- and multidrug-resistant Trichophyton species, and Penicillium/Talaromyces species originating from patients in North India. METHODS: Antifungal susceptibility of olorofim was tested against 241 mould isolates of Penicillium/Talaromyces species, Trichophyton species, A. fumigatus and cryptic Aspergillus species, Scedosporium species, and Alternaria alternata using CLSI broth microdilution. The comparators were five systemic azoles, amphotericin B, terbinafine, and luliconazole. RESULTS: Overall, olorofim showed highly potent in vitro activity against dermatophytes and opportunistic moulds (MIC range of 0.004-0.125 mg/L) except for Alternaria alternata. Penicillium, and Talaromyces species and Trichophyton species exhibited a low geometric mean (GM) MIC (GM 0.027 mg/L and 0.015 mg/L, respectively) of olorofim. Importantly, a 2-12 dilution step decrease in in vitro activity of olorofim as compared with azoles was observed against Penicillium and Talaromyces. Notably, olorofim displayed potent in vitro activity against Trichophyton isolates including terbinafine-resistant and azole-resistant Trichophyton mentagrophytes/interdigitale with a modal MIC value of 0.008 mg/L. Further, azole-resistant A. fumigatus isolates harbouring mutations in azole target Cyp51A genes and several cryptic aspergilli displayed low MICs (range 0.004-0.03 mg/L) of olorofim. However, no in vitro activity of olorofim against Alternaria alternata was observed. CONCLUSIONS: The potent in vitro activity of olorofim against drug-resistant dermatophytes and opportunistic moulds is promising, warranting evaluation of the clinical utility of olorofim.

Simultaneous evolution of host resistance and tolerance to parasitism.

Tolerance and resistance are two modes of defence mechanisms used by hosts when faced with parasites. Here, we assume tolerance reduces infection-induced mortality rate and resistance reduces the susceptibility of getting infected. Importantly, a negative association between these two strategies has often been found experimentally. We study the simultaneous evolution of resistance and tolerance in a host population where they are related by such a trade-off. Using evolutionary invasion theory, we examine the patterns of optimal investment in each defence strategy, under different ecological scenarios. Our focus is on predicting which of the two strategies is favoured under various epidemiological and ecological conditions. Our key findings surround the impact of recovery and sterility of infected hosts. As the rate at which infected hosts recover from the infection, that is the recovery rate increases, the investment in tolerance increases (resistance decreases) when infected hosts are sterile, but this pattern reverses when infected hosts can reproduce. We further found that a change in the parameter determining the intraspecies competition for resources leading to a reduction in birth rate, that is the crowding factor affects investments in tolerance and resistance only when infected hosts can reproduce. These results emphasize the role of fecundity in driving the evolutionary dynamics of a host. We also find that disease prevalence can increase or decrease depending on whether or not the host evolves: prevalence is highest at low recovery rates when the host does not evolve, but the feedback of a change in tolerance and resistance reverses this pattern, leading to lower prevalence at low recovery rates as host evolves.

Evaluation of DermaGenius® resistance real-time polymerase chain reaction for rapid detection of terbinafine-resistant Trichophyton species.

BACKGROUND: Treatment-resistant dermatophytosis caused by Trichophyton mentagrophytes/interdigitale complex has emerged as a global public health threat, particularly in endemic countries like India and has spread to many other countries. This veritable spread is alarming due to increase in resistance to terbinafine, which targets the ergosterol biosynthetic pathway by inhibiting the enzyme squalene epoxidase (SQLE). About two third of studies worldwide have reported amino acid substitutions Phe397Leu and Leu393Phe in the SQLE protein to be responsible for high terbinafine MICs. OBJECTIVES: We evaluated the efficacy of the newly developed DermaGenius® Resistance real-time PCR assay to rapidly identify Trichophyton isolates harbouring most common SQLE mutant (Phe397Leu and Leu393Phe) conferring high terbinafine resistance from wild-type susceptible isolates. METHODS: A total of 97 Trichophyton isolates confirmed by ITS sequencing as T. mentagrophytes/interdigitale (recently named T. indotineae n = 90), T. rubrum/T. soudanense (n = 3), T mentagrophytes (n = 2) and T tonsurans (n = 2) were analysed to evaluate DermaGenius® Resistance real-time PCR assay. All 40 T. indotineae isolates exhibiting amino acid substitutions Phe397Leu or Leu393Phe identified by SQLE gene sequencing were evaluated for detection of non-wild-type strains by real-time PCR. Antifungal susceptibility testing for terbinafine was done by CLSI microbroth dilution method. RESULTS: All terbinafine-resistant isolates harbouring amino acid substitutions Phe397Leu or Leu393Phe in SQLE gene were correctly recorded as SQLE mutants by the DermaGenius® Resistance real-time PCR assay. CONCLUSIONS: The DermaGenius® Resistance real-time PCR assay effectively identified Trichophyton species and distinguished wild-type from SQLE mutant genotype that harbour Phe397Leu and Leu393Phe amino acid substitutions.

Prevalence of recurrent wheezing in infants and toddlers in Barbados: findings from a prospective study of a cohort of babies born during 2015-2017.

OBJECTIVES: The main objective was to determine the prevalence of recurrent wheezing (RW) among infants and toddlers as well as the prevalence of asthma predictive risk factors among those with RW. MATERIALS AND METHODS: A prospective study of a cohort of babies recruited after their birth during July 2015-June 2017. Mothers were contacted using the WhatsApp messaging system for digital follow-up on their baby's condition at 3-monthly intervals until they were 18 months old. Information on wheezing and its correlates were collected by digital follow-up and corroborated at an in-person interview and examination of their baby at 18 months of age. Recurrent wheezing was defined as more than three episodes of wheezing or its correlates during the follow-up period. RESULTS: There were 338 males (41.5%) and 476 (58.5%) females. Overall, 31.1% (95% CI = 27.9%, 34.4%) had RW by 18 months and the same number had RW during their first year of life. Of the infants with RW, 121 (47.8%; 95% CI = 41.6, 54.2) had at least one or both of the major criteria and/or at least two minor criteria of the stringent Asthma Predictive Index (API). Of those with RW, 32.0% received antihistamine and 20% had received antibiotics on their last visit to a physician for wheezing or symptoms of cough, cold, and/or breathing difficulty. CONCLUSIONS: Nearly a third of infants and toddlers had RW and nearly half of the infants with RW had risk factors fulfilling the criteria of the stringent API.

Populism, Nationalism, and Nationalist Populism.

This article builds an original, analytical framework to understand one of the most important developments of our times - the global ascendance of leaders who fuse populist anti-elite rhetoric with nationalist appeals. In contrast to arguments that treat populism and nationalism as either completely separate or essentially equivalent phenomena, I begin from an understanding of the two as distinct ideologies that grow from a shared foundational claim to represent an "us" versus a "them." In part 1, I first juxtapose populism and nationalism around this common, undergirding us-them boundary to bring out their core features. I then analyze how populism and nationalism vary across the twin axes of intensity and inclusiveness to bring out their distinct sub-types. In part 2, I use this theoretical map of populism and nationalism to navigate the conceptual terrain of their intersection. I focus, in particular, on the implications of nationalist populism for those seen as "us" versus those viewed as "them," where the "us" and "them" are determined by the dimensions of intensity and inclusiveness. In contrast to characterizations of nationalist populism in directional terms as negative, I suggest that it is instead better understood as an amplifying force that exacerbates both the positive and negative consequences of populism. All else equal, relative to populism, those beyond nationalist populist boundaries are subject to heightened hostility and discrimination, while those within benefit from enhanced life opportunities.

Feature Enhancement in Medical Ultrasound Videos Using Contrast-Limited Adaptive Histogram Equalization.

Speckle noise reduction algorithms are extensively used in the field of ultrasound image analysis with the aim of improving image quality and diagnostic accuracy. However, significant speckle filtering induces blurring, and this requires the enhancement of features and fine details. We propose a novel framework for both multiplicative noise suppression and robust contrast enhancement and demonstrate its effectiveness using a wide range of clinical ultrasound scans. Our approach to noise suppression uses a novel algorithm based on a convolutional neural network that is first trained on synthetically modeled ultrasound images and then applied on real ultrasound videos. The feature improvement stage uses an improved contrast-limited adaptive histogram equalization (CLAHE) method for enhancing texture features, contrast, resolvable details, and image structures to which the human visual system is sensitive in ultrasound video frames. The proposed CLAHE algorithm also considers an automatic system for evaluating the grid size using entropy, and three different target distribution functions (uniform, Rayleigh, and exponential), and interpolation techniques (B-spline, cubic, and Lanczos-3). An extensive comparative study has been performed to find the most suitable distribution and interpolation techniques and also the optimal clip limit for ultrasound video feature enhancement after speckle suppression. Subjective assessments by four radiologists and experimental validation using three quality metrics clearly indicate that the proposed framework generates superior performance compared with other well-established methods. The processing pipeline reduces speckle effectively while preserving essential information and enhancing the overall visual quality and therefore could find immediate applications in real-time ultrasound video segmentation and classification algorithms.

Ginkgolic Acid Rescues Lens Epithelial Cells from Injury Caused by Redox Regulated-Aberrant Sumoylation Signaling by Reviving Prdx6 and Sp1 Expression and Activities.

Sumoylation is a downstream effector of aging/oxidative stress; excess oxidative stress leads to dysregulation of a specificity protein1 (Sp1) and its target genes, such as Peroxiredoxin 6 (Prdx6), resulting in cellular damage. To cope with oxidative stress, cells rely on a signaling pathway involving redox-sensitive genes. Herein, we examined the therapeutic efficacy of the small molecule Ginkgolic acid (GA), a Sumoylation antagonist, to disrupt aberrant Sumoylation signaling in human and mouse lens epithelial cells (LECs) facing oxidative stress or aberrantly expressing Sumo1 (small ubiquitin-like modifier). We found that GA globally reduced aberrant Sumoylation of proteins. In contrast, Betulinic acid (BA), a Sumoylation agonist, augmented the process. GA increased Sp1 and Prdx6 expression by disrupting the Sumoylation signaling, while BA repressed the expression of both molecules. In vitro DNA binding, transactivation, Sumoylation and expression assays revealed that GA enhanced Sp1 binding to GC-boxes in the Prdx6 promoter and upregulated its transcription. Cell viability and intracellular redox status assays showed that LECs pretreated with GA gained resistance against oxidative stress-driven aberrant Sumoylation signaling. Overall, our study revealed an unprecedented role for GA in LECs and provided new mechanistic insights into the use of GA in rescuing LECs from aging/oxidative stress-evoked dysregulation of Sp1/Prdx6 protective molecules.

Adiponectin-resistin index and its strong association with acute coronary syndrome in South Indian men.

BACKGROUND: India has the highest burden of acute coronary syndromes worldwide. Apart from certain lipid alterations that have been established to be definite risk factors, low level of adiponectin, high levels of resistin, and IL-6 have been shown to be risk factors for cardiovascular events. Insulin resistance is also a significant predictor of poor outcome in patients admitted with ACS. METHODS: 69 male patients with ACS and 70 age-matched healthy males were recruited in the study. Insulin, total adiponectin, resistin, and IL-6 levels were assayed in all study subjects. Indices of insulin resistance and novel adipokine indices were calculated using standard formulae. Multiple logistic regression analysis was done to find out the best predictor of ACS. RESULTS: Resistin, IL-6, insulin resistance indices, AR index, and IRAR index were found to be significantly higher, while insulin sensitivity indices and total adiponectin were found to be lower in cases, as compared with controls (p < 0.001). Insulin resistance was found to be higher in the admission sample, when compared to the fasting sample in patients with ACS (p = 0.01). On multivariate logistic regression analysis, HOMA-IR and AR index were found to be significantly associated with ACS. AR index was the best independent predictor of ACS, with the highest odds ratio (AR index: adjusted OR 17.528, p < 0.0001 versus HOMA-IR: adjusted OR 1.146, p = 0.001). CONCLUSIONS: The present results implicate that adipokines are significantly associated with pathogenesis of ACS, warranting adequate and early appropriate treatment to reverse this metabolic dysregulation. In our study, AR index was the best predictor of ACS. Hence, the novel AR index might be useful in routine clinical practice for screening persons with increased risk of future development of ACS.

The Differential Impact of Medical Therapy and Lifestyle Modification on Cardiovascular Health and Risk of Adverse Cardiovascular Events: A Narrative Review.

Cardiovascular diseases (CVDs) continue to be a worldwide health concern, requiring effective strategies for risk reduction. This article explores the extensive collaboration between medical therapy and lifestyle modifications in the management of CVDs, aiming to interpret whether a single approach holds the key to reducing major cardiovascular events. In the realm of pharmaceutical therapy, statins, beta-blockers, angiotensin-converting-enzyme (ACE) inhibitors, and antiplatelet agents have shown significant effectiveness, as evidenced by landmark trials such as Scandinavian Simvastatin Survival Study (4S) and Heart Outcomes Prevention Evaluation (HOPE). Concurrently, lifestyle adjustments, encompassing physical activity, dietary changes, and management of stress, emerge as indispensable elements in cardiovascular care. The article discusses the pivotal role of patient adherence, tailored approaches, and the synergistic impact of combining medical therapy and lifestyle modifications. Challenges, such as socioeconomic disparities and uncertainties in lipid management, underscore the need for ongoing research and precision medicine. Digital health interventions offer novel avenues for personalized care. Despite advancements, uncertainties persist regarding the optimal balance between medical and lifestyle interventions in lowering major cardiovascular event risks. This article emphasizes the ongoing evolution of cardiovascular care, highlighting the imperative need for evidence-based guidelines tailored to individual patient needs.

Anti-proliferative, -migratory and -clonogenic effects of long-lasting nitric oxide release in HepG2 cells.

Nitric oxide (NO) holds promise as a cytotoxic agent against tumors, but its gaseous nature and short half-life hinder direct administration to tumor tissues. Herein, we present novel 6,9-disubstituted purine derivatives designed to ensure sustained NO release, followed by study of their significant anti-proliferative, anti-migratory, and anti-clonogenic effects on HepG2 cell lines, highlighting NO release as a potent effector for treating hepatocellular carcinoma.

Laser-assisted synthesis of nano-hydroxyapatite and functionalization with bone active molecules for bone regeneration.

The main goal of bone tissue engineering research is to replace the allogenic and autologous bone graft substitutes that can promote bone repair. Owing to excellent biocompatibility and osteoconductivity, hydroxyapatite is in extensive research and high demand for both medical and non-medical applications. Although various methods have been developed for the synthesis of hydroxyapatite, in the present study we have shown the use of nanosecond laser energy in the wet precipitation method of nano-hydroxyapatite (nHAP) synthesis without using ammonium solution or any other chemicals for pH maintenance. Here, the present study aimed to fabricate the nanohydroxyapatite using a nanosecond laser. The X-ray diffraction and Fourier transform infrared spectroscopy have confirmed the hydroxyapatite formation under laser irradiation in less time without aging. A transmission electron microscopy confirmed the nano size of synthesized nHAP, which is comparable to conventional nHAP. The length and width of the laser-assisted nHAP were found to be in the range of 50-200 nm and 15-20 nm, respectively, at various laser parameters. The crystallite size obtained by Debye Scherrer formulae was found to be in the range of ∼ 16-36 nm. In addition, laser-assisted nHAP based composite cryogel (nanohydroxyapatite/gelatin/collagen I) was synthesized and impregnated with bioactive molecules (bone morphogenic protein and zoledronic acid) that demonstrated significant osteogenic potential both in vitro in cell experiment and in vivo rat muscle pouch model (abdomen and tibia muscles). Dual-energy X-ray analysis, micro-CT, and histological analysis confirmed ectopic bone regeneration. Micro-CT based histomorphometry showed a higher amount (more than 10-fold) of mineralization for animal groups implanted with composite cryogels loaded with bioactive molecules compared to only composite cryogels groups. Our findings thus demonstrate a controlled and rapid synthetic method for the synthesis of nHAP with various physical, chemical, and biological properties exhibited as comparable to conventionally synthesized nHAP.

A multifunctional silk-hyaluronic acid self-healing hydrogel laden with alternatively activated macrophage-derived exosomes reshape microenvironment of diabetic wound and accelerate healing.

The impairment of phenotype switching of pro-inflammatory M1 to pro-healing M2 macrophage induced by hyperglycemic microenvironment often elevates oxidative stress, impairs angiogenesis, and leads to chronic non-healing wounds in diabetic patients. Administration of M2 macrophage-derived exosomes (M2Exo) at wound site is known to polarize M1 to M2 macrophage and can accelerate wound healing by enhancing collagen deposition, angiogenesis, and re-epithelialization. In the present study, M2Exo were conjugated with oxidized hyaluronic acid and mixed with PEGylated silk fibroin to develop self-healing Exo-gel to achieve an efficient therapy for diabetic wounds. Exo-gel depicted porous networked morphology with self-healing and excellent water retention behaviour. Fibroblast cells treated with Exo-gel showed significant uptake of M2Exo that increased their proliferation and migration in vitro. Interestingly, in a diabetic wound model of wistar rats, Exo-gel treatment induced 75 % wound closure within 7 days with complete epithelial layer regeneration by modulating cytokine levels, stimulating fibroblast-keratinocyte interaction and migration, angiogenesis, and organized collagen deposition. Taken together, this study suggests that Exo-gel depict properties of an excellent wound healing matrix and can be used as a therapeutic alternative to treat chronic non-healing diabetic wounds.

A Study of Clinical Profile and Treatment in Adult Hemophilia Patients with Special Reference to the Inhibitor Levels.

Introduction Hemophilia is an uncommon, X-linked recessive bleeding condition characterized by a lack of either factor VIII or factor IX. It is more prevalent in men. Due to the substantial impact inhibitor development has on patient prognosis, the primary treatment for hemophilia is the transfusion of recombinant factors. The aim of our study is to investigate 40 adult patients with hemophilia in terms of their clinical profile, clinically relevant risk factors for inhibitor development, therapy-related aspects such as treatment duration, factor requirements, transfusion frequency, presence of inhibitors, and complications. Methods This cross-sectional observational study involving 40 patients of hemophilia over 12 years of age was conducted at a tertiary care hospital in Gujarat. Data on sociodemographic characteristics, presenting complaints, bleeding episodes, hemophilia type, and medical history were gathered over a one-year span. Patients were stratified into mild, moderate, and severe groups based on their respective levels of factor activity. Various parameters, including the frequency of factor therapy, percentage of factor concentrate, inhibitor presence, and disease and therapy-related complications, were analyzed. The distribution of patients across these parameters was calculated and illustrated using pie charts. Results Nineteen out of 40 patients were from 20 to 40 years of age. The majority of cases (n=24), however, had been diagnosed before the patients reached the age of 10. All patients were male, and half of the patients (n=20) suffered from mild disease. The most common site of bleeding was the knee joint, and 33 cases had one to 10 bleeding episodes per year. Thirty-two out of 40 patients needed less than 40 factor vial transfusions, whereas eight needed more than 40 factor vial transfusions. Two cases of severe disease were positive for inhibitors of factor VIII, whereas one patient was found to have a hepatitis B virus (HBV) infection. Conclusions Hemophilia, a rare bleeding disorder, has primarily been studied in pediatric populations. This study, however, shifts the focus toward adult individuals. Our cohort consisted exclusively of male patients, with the predominant group diagnosed with hemophilia A and falling within the age range of 20 to 40 years. Most patients had been diagnosed before 10 years of age. The primary complication observed was joint bleeding, with the knee joint being the most commonly affected site. Approximately two-thirds of cases had a history of minor trauma necessitating factor replacement, yet only 5% exhibited the presence of inhibitors.