Functional consequences of a p53-MDM2-p21 incoherent feedforward loop.

Genetically identical cells can respond heterogeneously to cancer therapy, with a subpopulation of cells often entering a temporarily arrested treatment-tolerant state before repopulating the tumor. To investigate how heterogeneity in the cell cycle arrest protein p21 arises, we imaged the dynamics of p21 transcription and protein expression along with those of p53, its transcriptional regulator, in single cells using live cell fluorescence microscopy. Surprisingly, we found that the rate of p21 transcription depends on the change in p53 rather than its absolute level. Through combined theoretical and experimental modeling, we determined that p21 transcription is governed by an incoherent feedforward loop mediated by MDM2. This network architecture facilitates rapid induction of p21 expression and variability in p21 transcription. Abrogating the feedforward loop overcomes rapid S-phase p21 degradation, with cells transitioning into a quiescent state that transcriptionally resembles a treatment-tolerant persister state. Our findings have important implications for therapeutic strategies based on activating p53.

Impact of efavirenz on hormone-positive breast cancer survival in women living with HIV.

Women living with HIV and breast cancer have poorer survival than HIV-negative women. Efavirenz-estrogen interactions are documented; however, the survival impact is unknown. Survival between women with estrogen-receptor positive breast cancer taking efavirenz (n = 38) and nonefavirenz regimens (n = 51) were compared. The 5-year overall-survival was 48.9% [95% confidence interval (CI) 33.0-72.2 and 51.1% (95% CI 34.0-76.8)] in the efavirenz and nonefavirenz groups, respectively suggesting efavirenz is unlikely driving poorer survival in women living with HIV and estrogen-receptor positive breast cancer.

Angular momentum transfer from swift electrons to non-spherical nanoparticles within the dipolar approximation.

In this work, we study the angular momentum transfer from a single swift electron to non-spherical metallic nanoparticles, specifically investigating spheroidal and polyhedral (Platonic Solids) shapes. While previous research has predominantly focused on spherical nanoparticles, our work expands the knowledge by exploring various geometries. Employing classical electrodynamics and the small particle limit, we calculate the angular momentum transfer by integrating the spectral density, ensuring causality through Fourier-transform analysis. Our findings demonstrate that prolate spheroidal nanoparticles exhibit a single blueshifted plasmonic resonance, compared to spherical nanoparticles of equivalent volume, resulting in lower angular momentum transfer. Conversely, oblate nanoparticles display two resonances - one blueshifted and one redshifted - resulting in a higher angular momentum transfer than their spherical counterparts. Additionally, Platonic Solids with fewer faces exhibit significant redshifts in plasmonic resonances, leading to higher angular momentum transfer due to edge effects. We also observe resonances and angular momentum transfers with similar characteristics in specific pairs of Platonic Solids, known as duals. These results highlight promising applications, particularly in electron tweezers technology.

The effect of intergroup competition outcome on ingroup cooperation: insights from the male warrior hypothesis.

Introduction: The Male Warrior Hypothesis (MWH) proposes that sex-specific selective pressures have promoted male cooperation with the ingroup members to outcompete rival groups. However, intergroup conflicts do not occur in isolation and the outcomes of previous competitions may influence group cooperativeness. Since this phenomenon is not well understood, we aimed to shed light on the effect of previous competition outcome on later cooperative behavior under intergroup conflicts. Based on the MWH, we hypothesized that repeated contests between groups could enhance ingroup cooperation, regardless of the outcome of the previous contest because status is at risk, but when competition is not present, participants would move to the symmetric equilibria. Methods: To test this hypothesis, we recruited 246 individuals organized in groups of 6 and measured cooperation using a threshold public good game over two rounds, manipulating the outcome in the first round to create groups of winners and losers. Results: Our results show that intergroup conflict scenarios promoted cooperation in both victory and defeat conditions, whereas, in the control scenario only losers increased their cooperation. Discussion: We argue that winners under the presence of an external threat may enhance in-group cooperation in order to assure their status; whereas, losers may be attempting to regain it.

Endogenous innate sensor NLRP3 is a key component in peritoneal macrophage dynamics required for cestode establishment.

The NLRP3 receptor can assemble inflammasome platforms to trigger inflammatory responses; however, accumulating evidence suggests that it can also display anti-inflammatory properties. Here, we explored the role of nucleotide-binding oligomerization domain pyrin-containing protein 3 (NLRP3) in Taenia crassiceps experimental infection, which requires immune polarization into a Th2-type profile and peritoneal influx of suppressive macrophages for successful colonization. NLRP3 deficient mice (NLRP3-/-) were highly resistant against T. crassiceps, relative to wild-type (WT) mice. Resistance in NLRP3-/- mice was associated with a diminished IL-4 output, high levels of IL-15, growth factor for both innate and adaptive lymphocytes, and a dramatic decrease in peritoneum-infiltrating suppressive macrophages. Also, a transcriptional analysis on bone marrow-derived macrophages exposed to Taenia-secreted antigens and IL-4 revealed that NLRP3-/- macrophages express reduced transcripts of relm-α and PD-1 ligands, markers of alternative activation and suppressive ability, respectively. Finally, we found that the resistance displayed by NLRP3-/- mice is transferred through intestinal microbiota exchange, since WT mice co-housed with NLRP3-/- mice were significantly more resistant than WT animals preserving their native microbiota. Altogether, these data demonstrate that NLRP3 is a component of innate immunity required for T. crassiceps to establish, most likely contributing to macrophage recruitment, and controlling lymphocyte-stimulating cytokines such as IL-15.

Direct interaction between marine cyanobacteria mediated by nanotubes.

Microbial associations and interactions drive and regulate nutrient fluxes in the ocean. However, physical contact between cells of marine cyanobacteria has not been studied thus far. Here, we show a mechanism of direct interaction between the marine cyanobacteria Prochlorococcus and Synechococcus, the intercellular membrane nanotubes. We present evidence of inter- and intra-genus exchange of cytoplasmic material between neighboring and distant cells of cyanobacteria mediated by nanotubes. We visualized and measured these structures in xenic and axenic cultures and in natural samples. We show that nanotubes are produced between living cells, suggesting that this is a relevant system of exchange material in vivo. The discovery of nanotubes acting as exchange bridges in the most abundant photosynthetic organisms in the ocean may have important implications for their interactions with other organisms and their population dynamics.

The prognostic value of blood cellular indices in pulmonary embolism.

Prognostication in acute pulmonary embolism (PE) requires reliable markers. While cellular indices such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) appear promising, their utility in PE prognostication needs further exploration. We utilized data from the RIETE registry and the Loyola University Medical Center (LUMC) to assess the prognostic value of NLR, PLR, and SII in acute PE, using logistic regression models. The primary outcome was 30-day all-cause mortality. We compared their prognostic value versus the simplified Pulmonary Embolism Severity Index (sPESI) alone. We included 10 085 patients from RIETE and 700 from the LUMC. Thirty-day mortality rates were 4.6% and 8.3%, respectively. On multivariable analysis, an elevated NLR (>7.0) was associated with increased mortality (adjusted odds ratio [aOR]: 3.46; 95% CI: 2.60-4.60), outperforming the PLR > 220 (aOR: 2.36; 95% CI: 1.77-3.13), and SII > 1600 (aOR: 2.52; 95% CI: 1.90-3.33). The c-statistic for NLR in patients with low-risk PE was 0.78 (95% CI: 0.69-0.86). Respective numbers were 0.66 (95% CI: 0.63-0.69) and 0.68 (95% CI: 0.59-0.76) for intermediate-risk and high-risk patients. These findings were mirrored in the LUMC cohort. Among 9810 normotensive patients in RIETE, those scoring 0 points in sPESI and with an NLR ≤ 7.0 (35% of the population) displayed superior sensitivity (97.1%; 95% CI: 95.5-98.7) and negative predictive value (99.7%; 95% CI: 99.5-99.8) than sPESI alone (87.1%; 95% CI: 83.9-90.3, and 98.7%; 95% CI: 98.4-99.1, respectively) for 30-day mortality. The NLR is a significant prognostic marker for 30-day mortality in PE patients, especially useful to identify patients with very low-risk PE.

Somatostatin: a possible mediator of the long-term effects of experimental vertical gastrectomy on glucose metabolism in rats?

BACKGROUND: Sleeve gastrectomy (SG) is one of the most commonly performed bariatric surgeries. SG treats type 2 diabetes mellitus better than several drugs. The mechanisms that underlie this phenomenon are not clear. This study proposed that somatostatin (SST) isoforms SST-14 and SST-28 are key in the carbohydrate after SG. METHODS: Surgeries were performed on 3 groups of Wistar rats: the fasting, surgery control, and SG groups. Plasma levels of glucose, insulin, SST-14, and SST-28 were measured at 2 survival periods after surgery. Islet SST receptor (SSTR) and cell populations were studied. We performed a pasireotide (SST-28 analogue) infusion assay in another group of rats to confirm the influence of SST-28 plasma levels on the delta-cell population. RESULTS: This study found an elevation in the insulin response after SG in animals but a decrease in the insulin response over the long term with a loss of beta-cell mass. An increase in duodenal SST-28-producing cells in the duodenum and a loss of pancreatic SST-14-producing cells were observed after SG in animals but not in controls. The expression of SSTR type 5 in delta-cell populations from each group and the ability of the pasireotide infusion assay to decrease the delta-cell population indicated the effect of SST-28 plasma levels on delta-cell maintenance. CONCLUSION: After SG initiates a compensatory response in the duodenum, beta-cell mass is depleted after loss of the brake that regulates SST-14 at the paracrine level in a nonobese, normoglycemic rat model. This was an experimental model, with no clinical translation to the human clinic, with a preliminary importance regarding new pathophysiologic perspectives or pathways.

[Economic burden assessment for the management of asthma patients at Mexico's National Institute for Respiratory Diseases]. / Evaluación de la carga económica para el tratamiento de pacientes con asma en el Instituto Nacional de Enfermedades Respiratorias de México.

OBJETIVO: Determinar la carga económica anual del asma, desde una perspectiva institucional y con base en la clasificación recomendada por GINA, en una cohorte retrospectiva de adultos atendidos en el Instituto Nacional de Enfermedades Respiratorias (INER) de México. MÉTODOS: Estudio observacional, longitudinal y retrospectivo, llevado a cabo a partir de la información recabada de 247 pacientes femeninas con asma. Se estimaron los costos directos anuales: visitas, pruebas de laboratorio, tratamiento farmacológico y de las crisis o exacerbaciones, para determinar la carga anual de la enfermedad desde una perspectiva institucional, y según la clasificación de la Iniciativa Global para el Asma. RESULTADOS: El costo promedio anual fue de $43,813,92, que aumentó en relación con la necesidad de aumento de dosis de corticoides inhalados y beta-agonistas de acción prolongada. El costo promedio de la consulta médica fue de $2004.57, $982.82 por gestión de crisis y $2645.95 por pruebas de laboratorio. El tratamiento farmacológico representó la principal carga económica, con un costo promedio anual de $38,180.58. CONCLUSIONES: Los resultados resaltan una carga económica del asma estimada en un costo anual por paciente de $43,813.92 MXN (DE=93,348.85), en el contexto del tercer nivel de atención en el sistema de salud público mexicano. La gravedad del asma, los tratamientos y los biológicos fueron los principales factores que aumentaron los costos directos de la atención.

OBJECTIVE: Determine the annual economic burden of the disease from an institutional perspective and based on GINA's recommended classification in a retrospective cohort of adults treated at Instituto Nacional de Enfermedades Respiratorias (INER) of Mexico City. METHODS: A retrospective, longitudinal observational study comprised by data from 247 female asthma patients, annual direct costs were estimated including: visits, laboratory tests, pharmacological treatment and management of crisis or exacerbations, to determine the annual burden of the disease from an institutional perspective and according to Global Initiative for Asthma classification. RESULTS: The average annual cost was $43,813.92, which increased in relation to the need of inhaled corticosteroids and long-acting beta agonists dosage increase. The average doctor's appointment cost was $2,004.57, $982.82 for crisis management and $2,645.95 for laboratory testing. Pharmacological treatment represented the main economic burden with an annual average cost of $38,180.58. CONCLUSIONS: The results highlight an economic burden of asthma estimated at an annual cost per patient of $43,813.92 MXN (SD=93,348.85) in the context of the third level of care in the Mexican public health system. The asthma severity and treatments such as biologics were the main factors that increased direct costs of care.

Helminth-derived molecules improve 5-fluorouracil treatment on experimental colon tumorigenesis.

Colorectal cancer (CRC) is one of the most prevalent fatal neoplasias worldwide. Despite efforts to improve the early diagnosis of CRC, the mortality rate of patients is still nearly 50%. The primary treatment strategy for CRC is surgery, which may be accompanied by chemotherapy and radiotherapy. The conventional and first-line chemotherapeutic agent utilized is 5-fluorouracil (5FU). However, it has low efficiency. Combination treatment with leucovorin and oxaliplatin or irinotecan improves the effectiveness of 5FU therapy. Unfortunately, most patients develop drug resistance, leading to disease progression. Here, we evaluated the effect of a potential alternative adjuvant treatment for 5FU, helminth-derived Taenia crassiceps (TcES) molecules, on treating advanced colitis-associated colon cancer. The use of TcES enhanced the effects of 5FU on established colonic tumors by downregulating the expression of the immunoregulatory cytokines, Il-10 and Tgf-ß, and proinflammatory cytokines, Tnf-α and Il-17a, and reducing the levels of molecular markers associated with malignancy, cyclin D1, and Ki67, both involved in apoptosis inhibition and the signaling pathway of ß-catenin. TcES+5FU therapy promoted NK cell recruitment and the release of Granzyme B1 at the tumor site, consequently inducing tumor cell death. Additionally, it restored P53 activity which relates to decreased Mdm2 expression. In vitro assays with human colon cancer cell lines showed that therapy with TcES+5FU significantly reduced cell proliferation and migration by modulating the P53 and P21 signaling pathways. Our findings demonstrate, for the first time in vivo, that helminth-derived excreted/secreted products may potentiate the effect of 5FU on established colon tumors.

Performance of a stool-based quantitative PCR assay for the diagnosis of tuberculosis in adolescents and adults: a multinational, prospective diagnostic accuracy study.

BACKGROUND: Despite increasing availability of rapid molecular tests for the diagnosis of tuberculosis in high-burden settings, many people with tuberculosis are undiagnosed. Reliance on sputum as the primary specimen for tuberculosis diagnostics contributes to this diagnostic gap. We evaluated the diagnostic accuracy and additive yield of a novel stool quantitative PCR (qPCR) assay for the diagnosis of tuberculosis in three countries in Africa with high tuberculosis burdens. METHODS: We undertook a prospective diagnostic accuracy study in Eswatini, Mozambique, and Tanzania from Sept 21, 2020, to Feb 2, 2023, to compare the diagnostic accuracy for tuberculosis of a novel stool qPCR test with the current diagnostic standard for Mycobacterium tuberculosis DNA detection from sputum and stool, Xpert-MTB/RIF Ultra (Xpert Ultra). Sputum, stool, and urine samples were provided by a cohort of participants, aged 10 years or older, diagnosed with tuberculosis. Participants with tuberculosis (cases) were enrolled within 72 h of treatment initiation for tuberculosis diagnosed clinically or following laboratory confirmation. Participants without tuberculosis (controls) consisted of household contacts of the cases who did not develop tuberculosis during a 6-month follow-up. The performance was compared with a robust composite microbiological reference standard (CMRS). FINDINGS: The cohort of adolescents and adults (n=408) included 268 participants with confirmed or clinical tuberculosis (cases), 147 (55%) of whom were living with HIV, and 140 participants (controls) without tuberculosis. The sensitivity of the novel stool qPCR was 93·7% (95% CI 87·4-97·4) compared with participants with detectable growth on M tuberculosis culture, and 88·1% (81·3-93·0) compared with sputum Xpert Ultra. The stool qPCR had an equivalent sensitivity as sputum Xpert Ultra (94·8%, 89·1-98·1) compared with culture. Compared with the CMRS, the sensitivity of the stool qPCR was higher than the current standard for tuberculosis diagnostics on stool, Xpert Ultra (80·4%, 73·4-86·2 vs 73·5%, 66·0-80·1; p=0·025 on paired comparison). The qPCR also identified 17-21% additional tuberculosis cases compared to sputum Xpert Ultra or sputum culture. In controls without tuberculosis, the specificity of the stool qPCR was 96·9% (92·2-99·1). INTERPRETATION: In this study, a novel qPCR for the diagnosis of tuberculosis from stool specimens had a higher accuracy in adolescents and adults than the current diagnostic PCR gold standard on stool, Xpert-MTB/RIF Ultra, and equivalent sensitivity to Xpert-MTB/RIF Ultra on sputum. FUNDING: National Institutes of Health (NIH) Allergy and Infectious Diseases, and NIH Fogarty International Center.

The role of exogenous testosterone and social environment on the expression of sociosexuality and status-seeking behaviors in young Chilean men.

Testosterone plays an important role as a social hormone. Current evidence suggests that testosterone is positively related to sociosexuality increasing the psychological attitudes toward investing in short-term versus long-term mating and promotes status-seeking behaviors both by dominance and prestige. In addition, the social environment may play an important role in the expression of mating effort through changes in sociosexuality and status-seeking behaviors. However, the causal relationships among the mentioned variables are still debated. We employed a double-blind, placebo-controlled within-individual design, in order to test and integrate the proposed causal relationships between testosterone and social environment over short-term and long-term mating orientation and dominant and prestigious status-seeking behaviors in a sample of 95 young Chilean men. We did not find evidence that the administration of exogenous testosterone increased short-term or decreased long-term mating orientation as expected. Moreover, exogenous testosterone did not affect either aggressive or cooperative behavior failing to support the social status hypothesis. We also did not find any relationship between short or long-term mating orientation with status-seeking behaviors. Finally, we found support for the effect of social environment on sociosexual attitudes but not over status-seeking behaviors. Thus, men reported higher levels of short-term mating orientation in the presence of a woman compared to a man and no differences were found for long-term mating orientation. We argue that sociosexuality may be expressed flexibly, but contextual factors such as the presence of women seem more important than changes in testosterone levels.

Serpine1 mRNA confers mesenchymal characteristics to the cell and promotes CD8+ T cells exclusion from colon adenocarcinomas.

Serine protease inhibitor clade E member 1 (SERPINE1) inhibits extracellular matrix proteolysis and cell detachment. However, SERPINE1 expression also promotes tumor progression and plays a crucial role in metastasis. Here, we solve this apparent paradox and report that Serpine1 mRNA per se, independent of its protein-coding function, confers mesenchymal properties to the cell, promoting migration, invasiveness, and resistance to anoikis and increasing glycolytic activity by sequestering miRNAs. Expression of Serpine1 mRNA upregulates the expression of the TRA2B splicing factor without affecting its mRNA levels. Through transcriptional profiling, we found that Serpine1 mRNA expression downregulates through TRA2B the expression of genes involved in the immune response. Analysis of human colon tumor samples showed an inverse correlation between SERPINE1 mRNA expression and CD8+ T cell infiltration, unveiling the potential value of SERPINE1 mRNA as a promising therapeutic target for colon tumors.

SWI/SNF-dependent genes are defined by their chromatin landscape.

SWI/SNF complexes are evolutionarily conserved, ATP-dependent chromatin remodeling machines. Here, we characterize the features of SWI/SNF-dependent genes using BRM014, an inhibitor of the ATPase activity of the complexes. We find that SWI/SNF activity is required to maintain chromatin accessibility and nucleosome occupancy for most enhancers but not for most promoters. SWI/SNF activity is needed for expression of genes with low to medium levels of expression that have promoters with (1) low chromatin accessibility, (2) low levels of active histone marks, (3) high H3K4me1/H3K4me3 ratio, (4) low nucleosomal phasing, and (5) enrichment in TATA-box motifs. These promoters are mostly occupied by the canonical Brahma-related gene 1/Brahma-associated factor (BAF) complex. These genes are surrounded by SWI/SNF-dependent enhancers and mainly encode signal transduction, developmental, and cell identity genes (with almost no housekeeping genes). Machine-learning models trained with different chromatin characteristics of promoters and their surrounding regulatory regions indicate that the chromatin landscape is a determinant for establishing SWI/SNF dependency.

Burning Question: How Does Our Brain Process Positive and Negative Cues Associated with Thermosensation?

Whether it is the dramatic suffocating sensation from a heat wave in the summer or the positive reinforcement arising from a hot drink on a cold day; we can certainly agree that our thermal environment underlies our daily rhythms of sensation. Extensive research has focused on deciphering the central circuits responsible for conveying the impact of thermogenesis on mammalian behavior. Here, we revise the recent literature responsible for defining the behavioral correlates that arise from thermogenic fluctuations in mammals. We transition from the physiological significance of thermosensation to the circuitry responsible for the autonomic or behavioral responses associated with it. Subsequently, we delve into the positive and negative valence encoded by thermoregulatory processes. Importantly, we emphasize the crucial junctures where reward, pain, and thermoregulation intersect, unveiling a complex interplay within these neural circuits. Finally, we briefly outline fundamental questions that are pending to be addressed in the field. Fully deciphering the thermoregulatory circuitry in mammals will have far-reaching medical implications. For instance, it may lead to the identification of novel targets to overcome thermal pain or allow the maintenance of our core temperature in prolonged surgeries.

Global availability of parenteral nutrition: Pre- and post-COVID-19 pandemic surveys.

OBJECTIVE: Parenteral nutrition represents a therapeutic option for patients with type 3 intestinal failure. If used exclusively, parenteral nutrition has to be complete to provide all essential nutrients. The aim was to assess the availability of parenteral nutrition in all parts of the world, to better comprehend the global situation, and to prepare an action plan to increase access to parenteral nutrition. METHODS: An international survey using an electronic questionnaire was conducted in August 2019 and repeated in May 2022. An electronic questionnaire was sent to 52 members or affiliates of the International Clinical Nutrition Section of the American Society for Parenteral and Enteral Nutrition. Questions addressed the availability of parenteral nutrition admixtures and their components, reimbursement, and prescribing pre- and post-COVID-19 pandemic. All participating countries were categorized by their economic status. RESULTS: Thirty-six country representatives responded, answering all questions. Parenteral nutrition was available in all countries (100%), but in four countries (11.1%) three-chamber bags were the only option, and in six countries a multibottle system was still used. Liver-sparing amino acids were available in 18 (50%), kidney-sparing in eight (22.2%), and electrolyte-free in 11 (30.5%) countries (30.5%). In most countries (n = 28; 79.4%), fat-soluble and water-soluble vitamins were available. Trace elements solutions were unavailable in four (11.1%) countries. Parenteral nutrition was reimbursed in most countries (n = 33; 91.6%). No significant problems due to the coronavirus pandemic were reported. CONCLUSIONS: Despite the apparent high availability of parenteral nutrition worldwide, there are some factors that may have a substantial effect on the quality of parenteral nutrition admixtures. These shortages create an environment of inequality.

Alternative conformations of a group 4 Late Embryogenesis Abundant protein associated to its in vitro protective activity.

Late Embryogenesis Abundant (LEA) proteins are a group of intrinsically disordered proteins implicated in plant responses to water deficit. In vitro studies revealed that LEA proteins protect reporter enzymes from inactivation during low water availability. Group 4 LEA proteins constitute a conserved protein family, displaying in vitro protective capabilities. Under water deficiency or macromolecular crowding, the N-terminal of these proteins adopts an alpha-helix conformation. This region has been identified as responsible for the protein in vitro protective activity. This study investigates whether the attainment of alpha-helix conformation and/or particular amino acid residues are required for the in vitro protective activity. The LEA4-5 protein from Arabidopsis thaliana was used to generate mutant proteins. The mutations altered conserved residues, deleted specific conserved regions, or introduced prolines to hinder alpha-helix formation. The results indicate that conserved residues are not essential for LEA4-5 protective function. Interestingly, the C-terminal region was found to contribute to this function. Moreover, alpha-helix conformation is necessary for the protective activity only when the C-terminal region is deleted. Overall, LEA4-5 shows the ability to adopt alternative functional conformations under the tested conditions. These findings shed light on the in vitro mechanisms by which LEA proteins protect against water deficit stress.

The improvement of block chain technology simulation in supply chain management (case study: pesticide company).

This research was conducted on industrial agriculture in Indonesia. Risk analysis was carried out based on previous research. One source of risk was obtained, namely raw materials that did not meet specifications, which was then proposed to be mitigated by evaluating supplier performance. This activity involves a lot of data, requiring efficient and effective data storage and access. The level in the simulation layout includes analysing system needs, using problem diagrams, compiling activity diagrams, deciding subprocesses, and filtering information. The analysis is carried out by comparing the use of supply chains with Blockchain and without Blockchain, which is then obtained to determine whether there is an increase. A sequentially stored data scenario describes a situation when the transaction process is in progress and is stored sequentially according to the process that occurs. Storing data in groups explains a problem when a transaction has been completed and stored in groups with similar data, making it easier to track specific data. In this regard, a simulation will be carried out using a website, namely a blockchain demo. The design stage starts with identifying system requirements, creating use case diagrams, compiling activity diagrams, determining subprocesses, and selecting information. The simulation results obtained will be analysed to determine the feasibility of Blockchain as a means of supporting risk mitigation related to data using aspects, including security, trust, traceability, sustainability, and costs.

Systematic review of pathologic markers in skin ischemia with and without reperfusion injury in microsurgical reconstruction: Biomarker alterations precede histological structure changes.

BACKGROUND: Ischemia and ischemia-reperfusion injury contribute to partial or complete flap necrosis. Traditionally, skin histology has been used to evaluate morphological and structural changes, however histology does not detect early changes. We hypothesize that morphological and structural skin changes in response to ischemia and IRI occur late, and modification of gene and protein expression are the earliest changes in ischemia and IRI. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Studies reporting skin histology or gene/protein expression changes following ischemia with or without reperfusion injury published between 2002 and 2022 were included. The primary outcomes were descriptive and semi-quantitative histological structural changes, leukocyte infiltration, edema, vessel density; secondary outcomes were quantitative gene and protein expression intensity (PCR and western blot). Model type, experimental intervention, ischemia method and duration, reperfusion duration, biopsy location and time point were collected. RESULTS: One hundred and one articles were included. Hematoxylin and eosin (H&E) showed inflammatory infiltration in early responses (12-24 h), with structural modifications (3-14 days) and neovascularization (5-14 days) as delayed responses. Immunohistochemistry (IHC) identified angiogenesis (CD31, CD34), apoptosis (TUNEL, caspase-3, Bax/Bcl-2), and protein localization (NF-κB). Gene (PCR) and protein expression (western blot) detected inflammation and apoptosis; endoplasmic reticulum stress/oxidative stress and hypoxia; and neovascularization. The most common markers were TNF-α, IL-6 and IL-1ß (inflammation), caspase-3 (apoptosis), VEGF (neovascularization), and HIF-1α (hypoxia). CONCLUSION: There is no consensus or standard for reporting skin injury during ischemia and IRI. H&E histology is most frequently performed but is primarily descriptive and lacks sensitivity for early skin injury. Immunohistochemistry and gene/protein expression reveal immediate and quantitative cellular responses to skin ischemia and IRI. Future research is needed towards a universally-accepted skin injury scoring system.

Effects of Voice Pitch on Social Perceptions Vary With Relational Mobility and Homicide Rate.

Fundamental frequency ( fo) is the most perceptually salient vocal acoustic parameter, yet little is known about how its perceptual influence varies across societies. We examined how fo affects key social perceptions and how socioecological variables modulate these effects in 2,647 adult listeners sampled from 44 locations across 22 nations. Low male fo increased men's perceptions of formidability and prestige, especially in societies with higher homicide rates and greater relational mobility in which male intrasexual competition may be more intense and rapid identification of high-status competitors may be exigent. High female fo increased women's perceptions of flirtatiousness where relational mobility was lower and threats to mating relationships may be greater. These results indicate that the influence of fo on social perceptions depends on socioecological variables, including those related to competition for status and mates.