The incidence of cesarean section is dramatically increasing worldwide, whereas the training opportunities for obstetrician/gynecologists to manage complex cesarean section appear to be decreasing. This may be attributed to changing working hours directives and the increasing use of laparoscopy for gynecological surgical procedures, including in gynecological oncology. Various situations can create surgical difficulties during a cesarean section; however, two of the most frequent are complications from previous cesarean (myometrial defects, with or without placental intrusion and peritoneal adhesions) and the high risk of postpartum hemorrhage (uterine overdistension, abnormal placentation, uterine fibroids). Careful surgical dissection, with safe mobilization of the bladder and exposure of the anterior and lateral surfaces of the uterus, are pivotal steps for resolving the technical difficulties inherent in performing a complex cesarean section. We propose a standardized surgical protocol for women at risk of complex cesarean, including the antenatal identification of increased surgical risk, paramedian access to the pelvis, bladder dissection and mobilization, and the selection of a bleeding control strategy, considering uterine anatomy and the arterial pedicles involved in blood loss, which should be tailored to the individual case. We propose preoperative surgical planning to include consideration of the most common situations encountered during a complex cesarean, which facilitates anticipating an appropriate response for common possible scenarios, and can be adapted for low-, middle-, and high-resource settings. This protocol also highlights the importance of self-evaluation, continuous learning, and improvement activities within surgical teams.

A compilation of factors over the past decade-including the availability of increasingly large and rich healthcare datasets, advanced technologies to extract unstructured information from health records and digital sources, advancement of principled study design and analytic methods to emulate clinical trials, and frameworks to support transparent study conduct-has ushered in a new era of real-world evidence (RWE). This review article describes the evolution of the RWE era, including pharmacoepidemiologic methods designed to support causal inferences regarding treatment effects, the role of regulators and other health authorities in establishing distributed real-world data networks enabling analytics at scale, and the many global guidance documents on principled methods of producing RWE. This article also highlights the growing opportunity for RWE to support decision making by regulators, health technology assessment groups, clinicians, patients, and other stakeholders and provides examples of influential RWE studies. RWE holds promise to address important questions that clinical trials typically do not answer about treatment benefits and risks, and to ultimately impact public health by helping to guide decision making across the healthcare ecosystem.

Designing binders to target undruggable proteins presents a formidable challenge in drug discovery. In this work, we provide an algorithmic framework to design short, target-binding linear peptides, requiring only the amino acid sequence of the target protein. To do this, we propose a process to generate naturalistic peptide candidates through Gaussian perturbation of the peptidic latent space of the ESM-2 protein language model and subsequently screen these novel sequences for target-selective interaction activity via a contrastive language-image pretraining (CLIP)-based contrastive learning architecture. By integrating these generative and discriminative steps, we create a Peptide Prioritization via CLIP (PepPrCLIP) pipeline and validate highly ranked, target-specific peptides experimentally, both as inhibitory peptides and as fusions to E3 ubiquitin ligase domains. PepPrCLIP-derived constructs demonstrate functionally potent binding and degradation of conformationally diverse, disease-driving targets in vitro. In total, PepPrCLIP empowers the modulation of previously inaccessible proteins without reliance on stable and ordered tertiary structures.

Deer keds ( spp. and ) are hematophagous ectoparasites that primarily infest white-tailed deer () and other cervids in the United States. The distribution of deer keds in the northeastern United States and the pathogens they harbor remains relatively unexplored. In this study, we examined the geographical distribution and pathogen prevalence of deer keds in Massachusetts by collecting samples from white-tailed deer and testing for tick-borne pathogens. Deer keds were collected across the state, including in four previously unrecorded counties, indicating a wide distribution. Pathogen screening revealed the presence of DNA in 30% of the keds, but no other pathogens were detected. The medical and biological significance of detecting DNA in deer keds requires future studies. This research provides a baseline for the distribution and pathogen prevalence of deer keds in Massachusetts and highlights the potential of deer keds as sentinels for monitoring deer-associated microbes.

In this study, a Pd nanoparticles@hydrogen-bonded organic framework (Pd NPs@HOF) thin film was fabricated at the toluene-water interface. The HOF was formed through the interaction of trimesic acid (TMA) and melamine (Mel) in the water phase, while Pd(0) was produced from the reduction of [PdCl(cod)] in the organic phase. The as-synthesized Pd NPs@HOF thin film was demonstrated to be an effective catalyst for the selective reduction of -nitrophenol and -nitrophenol to -aminophenol and -aminophenol. The porous network of the Pd NPs@HOF introduced strong active sites between Mel, TMA, and Pd(0). Kinetic studies showed that the Pd NPs@HOF catalyst exhibited an enhanced rate of -nitrophenol and -nitrophenol reduction in comparison with Pd@reduced-graphene oxide (r-GO) with rates that were 1.7 times faster for -nitrophenol and 1.5 times faster for -nitrophenol or even 10 times faster than some Pd-based catalysts, with a maximum conversion of 97.1% which was attributed to the higher porosity and greater surface-to-volume ratio of the Pd NPs@HOF material. Furthermore, π-π stacking interactions enhance the catalytic activity of the Pd NPs@HOF catalyst by increasing the active sites, stabilizing the NPs and trapping the nitrophenols, facilitating the electron transfer, and providing the synergistic effect. Also, contributions of hydrogen bonding, van der Waals forces, electrostatic interactions, and π-σ noncovalent interactions are reasons for better performance of Pd NPs@HOF than Pd/r-GO catalyst with the reduced functional groups.

Recently proposed "Rule-of-Five" criteria define compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) using liver stiffness (LS) and platelet count. We aimed to validate these criteria by determining whether they are associated with risk of adverse outcomes.

Immigrants intended to more rely on self-medication because of the difficulty of accessing formal healthcare in host countries. Negative consequences could occur when self-medication was inappropriate. This study aimed to systematically explore the prevalence, sources and determinants of immigrants' self-medication and the extent of their inappropriate self-medication episodes. PubMed, Scopus, SpringerLink, and ScienceDirect were used for data searching. The search date was 10th June 2023, with no beginning date to limit searching articles. Thirty-two studies were included. The prevalence of immigrants' self-medication presented from 18 studies ranged between 20.2% and 94.6%. Major sources of immigrants' self-medication were commonly obtained from their home countries, local markets or shops, and informal networks. The determinants of immigrants' self-medication were systematically collated into four themes: (1) illness and self-medication perception, (2) access to healthcare and medication, including 6 dimensions: accessibility, availability, affordability, acceptability, awareness and accommodation, (3) worry, and (4) predisposing factors of immigrants. About 46% of immigrant's self-medication episodes were inappropriate, especially antibiotic use. About 66% of the included studies described antibiotic self-medication. Prevalence rates of self-medication among different immigrantsvaried based on different time frames, context of diseases and migrated countries. Immigrants' cultural health belief, facing significant worry about job security, legal status, and cultural barriers influenced their self-medication. When immigrants have greater availability, accommodation, awareness, accessibility, acceptability, and affordability of health services in host countries, they are less likely to use self-medication. The predisposing factors like age, income, work status and immigrants' language also influenced their self-medication.

In all kingdoms of life, the enzyme uridine diphosphate-glucose pyrophosphorylase (UGP) occupies a central role in metabolism, as its reaction product uridine diphosphate-glucose (UDP-Glc) is involved in various crucial cellular processes. Pathogens, including fungi, parasites, and bacteria, depend on UGP for the synthesis of virulence factors; in particular, various bacterial species utilize UDP-Glc and its derivatives for the synthesis of lipopolysaccharides, capsular polysaccharides, and biofilm exopolysaccharides. UGPs have, therefore, gained attention as anti-bacterial drug target candidates, prompting us to study their structure-function relationships to provide a basis for the rational development of specific inhibitors. UGP function is tied to its oligomeric state, and the majority of bacterial homologs have been described as tetramers encoded by the gene. Uniquely, enterobacterial species harbor a second gene, , encoding a protein with high homology to UGP, whose function is somewhat controversial. Here, we show that the gene of the opportunistic pathogen encodes a dimeric protein that has lost UGP activity, likely due to a combination of active site mutations and an inability to tetramerize, whereas the functional UGP, encoded by , is an active tetramer. Our AlphaFold-assisted structure-function relationship studies underline that tetramerization is essential for bacterial UGP function and is facilitated by a common mechanism utilizing conserved key residues. Targeting the respective molecular interfaces, which are absent in human UGP, could provide a means of selectively inhibiting the bacterial virulence factor UGP and potentially rendering pathogenic species avirulent.IMPORTANCEThe enzyme uridine diphosphate-glucose pyrophosphorylase (UGP) is important for the virulence of bacterial pathogens and, therefore, a potential drug target. In this study, we identify the gene encoding the functional UGP in , a bacterium notoriously causing severe antibiotic-resistant infections in humans, and reveal structural and functional features that may aid in the development of new antibiotics.

(EL) is a wild fruit known for containing several health-promoting compounds. This study aimed to evaluate the effects of EL fruit extract on high-fat diet (HFD)-induced obesity and lipopolysaccharide (LPS)-activated macrophages. Mice fed an HFD and given EL fruit extract for 10 weeks exhibited significantly lower body weight, reduced lipid accumulation, diminished oxidative stress in adipocytes, and decreased macrophage infiltration compared to those not receiving the EL extract. Moreover, the EL fruit extract activated the transcription factors and , initiating adipogenesis and modulating the expression of NF-κB/Nrf-2-induced target genes. This resulted in smaller adipocyte size, reduced inflammation, and less oxidative stress in HFD-fed mice. In vitro, the EL extract induced a shift in macrophage phenotype from M1 to M2, reduced IκBα/NF-κB phosphorylation, and effectively decreased energy production in macrophages by downregulating the expression of several proteins involved in glycolysis and the tricarboxylic acid cycle. This mechanistic study suggests that administering EL fruit extract could be an effective strategy for managing obesity and its associated pathologies.

Six fundamental chemical transformations of aryl carbonyls are achieved by properly adjusting the stoichiometry of the borane-amine and titanium tetrachloride reagent system. This set of reagents acts collectively as a hydride donor, Lewis acid catalyst, and halogen source for the reduction of carbonyls to alcohols, reductive halogenation of carbonyls to halides, deoxygenation of carbonyls to alkanes, dehydroxyhalogenation of alcohols to halides, deoxygenation of alcohols to alkanes, and hydrodehalogenation of halides to alkanes. While the carbonyl reduction is broadly applicable to both aromatic and aliphatic substrates, the remaining reactions are dependent on the stability of the proposed carbocationic intermediates, enabling highly selective reactions at the substrates' benzylic position. This unique selectivity allows benzylic dehalogenation in the presence of aryl and alkyl halides in addition to highly selective dehydroxyhalogenation of alcohols even for tertiary versus secondary aliphatic and secondary versus primary benzylic substrates using only titanium tetrachloride as the chlorinating agent.

We study percolation transition of run and tumble particles (RTPs) on a two dimensional square lattice. RTPs in these models run to the nearest neighbour along their internal orientation with unit rate, and to other nearest neighbours with rates . In addition, they tumble to change their internal orientation with rate . We show that for small tumble rates, RTP-clusters created by joining occupied nearest neighbours irrespective of their orientation form a phase separated state when the rate of positional diffusion crosses a threshold; with further increase of the clusters disintegrate and another transition to a mixed phase occurs. The critical exponents of this re-entrant site-percolation transition of RTPs vary continuously along the critical line in the - plane, but a scaling function remains invariant. This function is identical to the corresponding universal scaling function of percolation transition observed in the Ising model. We also show that the critical exponents of the underlying motility induced phase separation transition are related to corresponding percolation-critical-exponents by constant multiplicative factors known from the correspondence of magnetic and percolation critical exponents of the Ising model.

Covalent organic frameworks (COFs) are a class of highly efficient photocatalytic organic semiconductor materials, which have been developed for the design of photoactive nanozymes. Nitrogen (N)-heterocycles could effectively improve their photocatalytic activity of COFs. However, the systematic exploration of photoactive nanozymes based on N-containing COFs is still lacking. In this work, a series of N-containing Schiff-base linkages of COFs are designed and synthesized to explore high-performance photoactive nanozymes. In addition, Fe ions are introduced through post-modification of COFs, which can not only effectively extend the band-edge absorption of COFs to the red-light region and thereby broaden its biological applications, but also introduce single site of Fe to enrich the types of free radicals in the catalytic products. The activities of photoactive nanozymes based on N-containing COFs are systematically studied, and their catalytic mechanisms are uncovered. Interestingly, it is not as commonly recognized that the more content of N, the better for photocatalysis or the construction of photoactive nanozyme. Furthermore, the selected photoactive nanozymes are used for antibacterial applications, which showed good activity against Escherichia coli.

The presence and clinical significance of hepatic tissue alterations as assessed by cardiac magnetic resonance imaging in patients with ST-segment-elevation myocardial infarction (STEMI), are unclear. This study aimed to investigate associations of hepatic T1 patterns with myocardial tissue damage and clinical outcomes in patients suffering from STEMI.

Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAM). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either protumoral or antitumoral signals to glioma cells. Here, we performed bulk RNA sequencing and single-cell RNA sequencing on samples from patients with GBM, which revealed increased ATP synthase expression and oxidative phosphorylation activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP-P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP-P2X7R signaling axis as a therapeutic strategy in GBM. Significance: Glioblastoma-mediated metabolic reprogramming in tumor-associated microglia increases ATP secretion that supports cancer cell proliferation and invasion by activating P2X7R, which can be inhibited to attenuate tumor growth.

This study investigates the Brazilian low-latitude ionospheric response to CIR/HSS-driven geomagnetic storms during the declining phase of solar cycle 24, from 2016 to 2017. In this period the geomagnetic storms were mostly moderate, SymH ≈ -72 nT, AE ≈ 1580 nT, Vsw ≈ 690 km/s and lasted, on average, for 6 days. We analyze the variations in Vertical Total Electron Content (VTEC) at three representative regions: bele, over the equatorial region; boav and cuib, at the northern and southern crests of the Equatorial Ionization Anomaly. Our findings reveal the role of High-Speed Solar Wind Streams and Corotating Interaction Region-driven geomagnetic storms. The VTEC intensifications were up to 30 TECu, during the daytime and nighttime. Additionally, three categories of nighttime enhancements were observed and analyzed with distinct characteristics and levels of pre-reversal strengthening; Depletions up to 20 TECu also occurred during the day and nighttime. The delay between the storm commencement and the positive and negative variations were, on average, 7 and 20 hours, respectively. We discuss the Prompt Penetration Electric Fields and Disturbance Dynamo Electric Fields following the magnetic reconnection between Earth's and interplanetary magnetic field, using observational data and modeling. Furthermore, this study presents catalogs of low-latitude ionospheric storms, providing detailed information for space weather applications and ionospheric modeling.

Macropinocytosis has emerged as a scavenging pathway that cancer cells exploit to survive in a nutrient-deprived microenvironment. Tumor cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCζ and PKCι, as regulators of macropinocytosis. In normal epithelial cells, aPKCs associate with the scaffold proteins Par3 and Par6 to regulate cell polarity, affecting several targets, including the Par1 kinases and we find that each of these proteins is required for macropinocytosis. Mechanistically, aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the Par3 relocation to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and aPKCs support PDAC growth in vivo. Our findings enhance our understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.

Although the increased burden of mental health problems among patients with classic 46,XX congenital adrenal hyperplasia (CAH) is well-documented, it remains unclear if this comorbidity is attributable to the burden of living with a chronic medical condition or the potential psychosocial/sexual consequences of being born with a difference of sex development (DSD) and its associated clinical management.

Lipid extracts from the microalgae and have great potential to prevent ultraviolet A (UVA)-induced metabolic disorders. Therefore, the aim of this study has been to analyze their cytoprotective effect, focused on maintaining intracellular redox balance and inflammation in UVA-irradiated skin fibroblasts, at the proteome level. The above lipid extracts reversed the suppression of the antioxidant response caused by UVA radiation, which was more visible in the case of . Modulations of interactions between heme oxygenase-1 and matrix metalloproteinase 1/Parkinson's disease protein 7/transcript1-α/β, as well as thioredoxin and migration inhibitory factor/Parkinson's disease protein 7/calnexin/ATPase p97, created key molecular signaling underlying their cytoprotective actions. Moreover, they reduced pro-inflammatory processes in the control group but they also showed the potential to regulate the cellular inflammatory response by changing inflammasome signaling associated with the changes in the caspase-1 interaction area, including heat shock proteins HSP90, HSPA8, and vimentin. Therefore, lipid extracts from and protect skin fibroblast metabolism from UVA-induced damage by restoring the redox balance and regulating inflammatory signaling pathways. Thus, those extracts have proven to have great potential to be used in cosmetic or cosmeceutical products to protect the skin against the effects of solar radiation. However, the possibility of their use requires the evaluation of their effects at the skin level in in vivo and clinical studies.

The rapid and accurate detection of SARS-CoV-2 in environmental settings is crucial for effective public health management during the COVID-19 pandemic. This study compares the performance of the Reverse Transcription quantitative polymerase chain reaction (RT-qPCR) and the Reverse Transcription loop-mediated isothermal amplification (RT-LAMP) for SARS-CoV-2 detection from 100 surface samples collected in healthcare environments. The reference method, RT-qPCR, identified a percentage of 25% of positive samples, while RT-LAMP detected a percentage of 27% of positive surfaces. Our findings reveal a sensitivity of 32% and specificity of 75% for RT-LAMP, with a positive predictive value of 30% and a negative predictive value of 77%. The overall accuracy and concordance with RT-qPCR was 64% for both methods. Despite its lower sensitivity compared to RT-qPCR, RT-LAMP had an advantage due to its rapid screening and environmental surveillance, which is particularly useful for confirming negative results. These results underscore the potential of RT-LAMP not only as a valuable method in the environmental monitoring of SARS-CoV-2 but also as a system to control the sanitation process in ordinary and emergency conditions, providing further optimization and validation for its reliability in routine surveillance and outbreak response efforts.

Melanoma is one of the most malignant forms of skin cancer, characterised by the highest mortality rate among affected patients. This study aims to analyse and compare the effects of lipid extracts from the microalgae () and () on the intra and extracellular proteome of UVA-irradiated melanoma cells using a three-dimensional model. Proteomic analysis revealed that UVA radiation significantly increases the levels of pro-inflammatory proteins in melanoma cells. Treatment with algae extracts reduced these protein levels in both non-irradiated and irradiated cells. Furthermore, untreated cells released proteins responsible for cell growth and proliferation into the medium, a process hindered by UVA radiation through the promotion of pro-inflammatory molecules secretion. The treatment with algae extracts effectively mitigated UVA-induced alterations. Notably, UVA radiation significantly induced the formation of 4-HNE and 15-PGJ2 protein adducts in both cells and the medium, while treatment with algae extracts stimulated the formation of 4-HNE-protein adducts and reduced the level of 15-PGJ2-protein adducts. However, both algae extracts successfully prevented these UVA-induced modifications. In conclusion, lipid extracts from and appear to be promising agents in supporting anti-melanoma therapy. However, their potent protective capacity may limit their applicability, particularly following cells exposure to UVA.

X-chromosomal short tandem repeats (X-STRs) are crucial in forensic applications, particularly in complex kinship cases, and play an important role in population genetics. However, there is limited data on X-STR variation in Pakistani populations, especially among ethnic groups like Kashmiri and Punjabi. This study investigates the forensic and genetic properties of 12 X-STRs from the Investigator Argus X-12 Kit (QIAGEN, Hilden, Germany) in 125 families (75 Kashmiri, 50 Punjabi) from Azad Jammu and Kashmir and Punjab, Pakistan. In both populations, a total of 222 alleles were identified across the 12 X-STR loci (Punjabi 171 alleles, Kashmiri 161 alleles), with allele frequencies ranging from 0.0056 to 0.3033. DXS10148 was the most polymorphic locus with 28 alleles, while DXS7132 was the least polymorphic with 9 alleles. Most loci were in linkage equilibrium, except for the DXS10135/DXS10148 pair in males, with no loci exhibiting significant linkage disequilibrium in females. The combined power of discrimination was 0.999 999 9977 for Kashmiri males, 0.999 999 999 999 9746 for Kashmiri females, and 0.999 999 999 999 9781 for Punjabi females. In Kashmiri males, 34, 31, 28, and 32 haplotypes were observed across the four linkage groups (LG1, LG2, LG3, and LG4), though these groups did not form stable haplotypes, as indicated by Linkage Equilibrium within and significant Linkage Disequilibrium between groups. Genetic structure analysis using Principal Component Analysis and STRUCTURE revealed distinct clustering patterns for the Kashmiri and Punjabi populations, indicating unique genetic backgrounds and ancestry influences, particularly distinguishing them from East Asian populations. This study provides a comprehensive analysis of X-STR variation in Punjabi and Kashmiri populations, offering valuable insights for forensic and population genetic studies.