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Introduction: Post-COVID-19 condition (PCC) is characterised by a plethora of symptoms, with fatigue appearing as the most frequently reported. The alterations that drive both the persistent and post-acute disease newly acquired symptoms are not yet fully described. Given the lack of robust knowledge regarding the mechanisms of PCC we have examined the impact of inflammation in PCC, by evaluating serum cytokine profile and its potential involvement in inducing the different symptoms reported., Methods: In this cross-sectional study, we recruited 227 participants who were hospitalised with acute COVID-19 in 2020 and came back for a follow-up assessment 6-12 months after hospital discharge. The participants were enrolled in two symptomatic groups: Self-Reported Symptoms group (SR, n  = 96), who did not present major organ lesions, yet reported several debilitating symptoms such as fatigue, muscle weakness, and persistent loss of sense of smell and taste; and the Self-Reported Symptoms and decreased Pulmonary Function group (SRPF, n  = 54), composed by individuals with the same symptoms described by SR, plus diagnosed pulmonary lesions. A Control group ( n  = 77), with participants with minor complaints following acute COVID-19, was also included in the study. Serum cytokine levels, symptom questionnaires, physical performance tests and general clinical data were obtained in the follow-up assessment., Results: SRPF presented lower IL-4 concentration compared with Control ( q = 0.0018) and with SR ( q = 0.030), and lower IFN-α2 serum content compared with Control ( q  = 0.007). In addition, SRPF presented higher MIP-1β serum concentration compared with SR ( q = 0.029). SR presented lower CCL11 ( q = 0.012 and q = 0.001, respectively) and MCP-1 levels ( q = 0.052 for both) compared with Control and SRPF. SRPF presented lower G-CSF compared to Control ( q  = 0.014). Female participants in SR showed lower handgrip strength in relation to SRPF ( q = 0.0082). Male participants in SR and SRPF needed more time to complete the timed up-and-go test, as compared with men in the Control group ( q = 0.0302 and q = 0.0078, respectively). Our results indicate that different PCC symptom profiles are accompanied by distinct inflammatory markers in the circulation. Of particular concern are the lower muscle function findings, with likely long-lasting consequences for health and quality of life, found for both PCC phenotypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 de Castro, Gama, Ramos, Gatti da Silva, Teixeira, Cunha-Neto, de Souza, Marie, Talib, Coelho, Kalil, de Araujo, Ritto, Belon, Santos, Barrére, Sawamura, Lamas, Baldi, Carvalho, Kulikowski, Damiano, Imamura, Rosa Neto, Lira, Otoch, Miguel, Battistella, Forlenza, Busatto and Seelaender.)

Multi-hazard events, characterized by the simultaneous, cascading, or cumulative occurrence of multiple natural hazards, pose a significant threat to human lives and assets. This is primarily due to the cumulative and cascading effects arising from the interplay of various natural hazards across space and time. However, their identification is challenging, which is attributable to the complex nature of natural hazard interactions and the limited availability of multi-hazard observations. This study presents an approach for identifying multi-hazard events during the past 123 years (1900-2023) using the EM-DAT global disaster database. Leveraging the 'associated hazard' information in EM-DAT, multi-hazard events are detected and assessed in relation to their frequency, impact on human lives and assets, and reporting trends. The interactions between various combinations of natural hazard pairs are explored, reclassifying them into four categories: preconditioned/triggering, multivariate, temporally compounding, and spatially compounding multi-hazard events. The results show, globally, approximately 19 % of the 16,535 disasters recorded in EM-DAT can be classified as multi-hazard events. However, the multi-hazard events recorded in EM-DAT are disproportionately responsible for nearly 59 % of the estimated global economic losses. Conversely, single hazard events resulted in higher fatalities compared to multi-hazard events. The largest proportion of multi-hazard events are associated with floods, storms, and earthquakes. Landslides emerge as the predominant secondary hazards within multi-hazard pairs, primarily triggered by floods, storms, and earthquakes, with the majority of multi-hazard events exhibiting preconditioned/triggering and multivariate characteristics. There is a higher prevalence of multi-hazard events in Asia and North America, whilst temporal overlaps of multiple hazards predominate in Europe. These results can be used to increase the integration of multi-hazard thinking in risk assessments, emergency management response plans and mitigation policies at both national and international levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The protocol for treating locally advanced rectal cancer consists of the application of chemoradiotherapy (neoCRT) followed by surgical intervention. One issue for clinical oncologists is predicting the efficacy of neoCRT in order to adjust the dosage and avoid treatment toxicity in cases when surgery should be conducted promptly. Biomarkers may be used for this purpose along with in vivo cell-level images of the colorectal mucosa obtained by probe-based confocal laser endomicroscopy (pCLE) during colonoscopy. The aim of this article is to report our experience with Motiro, a computational framework that we developed for machine learning (ML) based analysis of pCLE videos for predicting neoCRT response in locally advanced rectal cancer patients. pCLE videos were collected from 47 patients who were diagnosed with locally advanced rectal cancer (T3/T4, or N+). The patients received neoCRT. Response to treatment by all patients was assessed by endoscopy along with biopsy and magnetic resonance imaging (MRI). Thirty-seven patients were classified as non-responsive to neoCRT because they presented a visible macroscopic neoplastic lesion, as confirmed by pCLE examination. Ten remaining patients were considered responsive to neoCRT because they presented lesions as a scar or small ulcer with negative biopsy, at post-treatment follow-up. Motiro was used for batch mode analysis of pCLE videos. It automatically characterized the tumoral region and its surroundings. That enabled classifying a patient as responsive or non-responsive to neoCRT based on pre-neoCRT pCLE videos. Motiro classified patients as responsive or non-responsive to neoCRT with an accuracy of ~ 0.62 when using images of the tumor. When using images of regions surrounding the tumor, it reached an accuracy of ~ 0.70. Feature analysis showed that spatial heterogeneity in fluorescence distribution within regions surrounding the tumor was the main contributor to predicting response to neoCRT. We developed a computational framework to predict response to neoCRT by locally advanced rectal cancer patients based on pCLE images acquired pre-neoCRT. We demonstrate that the analysis of the mucosa of the region surrounding the tumor provides stronger predictive power.

The orphan nuclear receptor Tailless (Tll) exhibits conserved roles in brain formation and maintenance that are shared, for example, with vertebrate orthologous forms (Tlx). However, the early expression of tll in two gap domains in the segmentation cascade of Drosophila is unusual even for most other insects. Here we investigate tll regulation on pair-rule stripes. With ectopic misexpression of tll we detected unexpected repression of almost all pair-rule stripes of hairy (h), even-skipped (eve), runt (run), and fushi-tarazu (ftz). Examining Tll embryonic ChIP-chip data with regions mapped as Cis-Regulatory Modules (CRMs) of pair-rule stripes we verified Tll interactions to these regions. With the ChIP-chip data we also verified Tll interactions to the CRMs of gap domains and in the misexpression assay, Tll-mediated repression on Kruppel (Kr), kni (kni) and giant (gt) according to their differential sensitivity to Tll. These results with gap genes confirmed previous data from the literature and argue against indirect repression roles of Tll in the striped pattern. Moreover, the prediction of Tll binding sites in the CRMs of eve stripes and the mathematical modeling of their removal using an experimentally validated theoretical framework shows effects on eve stripes compatible with the absence of a repressor binding to the CRMs. In addition, modeling increased tll levels in the embryo results in the differential repression of eve stripes, agreeing well with the results of the misexpression assay. In genetic assays we investigated eve 5, that is strongly repressed by the ectopic domain and representative of more central stripes not previously implied to be under direct regulation of tll. While this stripe is little affected in tll-, its posterior border is expanded in gt- but detected with even greater expansion in gt-;tll-. We end up by discussing tll with key roles in combinatorial repression mechanisms to contain the expression of medial patterns of the segmentation cascade in the extremities of the embryo., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

In the last decade, there has been a boost in autophagy reports due to its role in cancer progression and its association with tumor resistance to treatment. Despite this, many questions remain to be elucidated and explored among the different tumors. Here, we used omics-based cancer datasets to identify autophagy genes as prognostic markers in cancer. We then combined these findings with independent studies to further characterize the clinical significance of these genes in cancer. Our observations highlight the importance of innovative approaches to analyze tumor heterogeneity, potentially affecting the expression of autophagy-related genes with either pro-tumoral or anti-tumoral functions. In silico analysis allowed for identifying three genes ( TBC1D12 , KERA , and TUBA3D ) not previously described as associated with autophagy pathways in cancer. While autophagy-related genes were rarely mutated across human cancers, the expression profiles of these genes allowed the clustering of different cancers into three independent groups. We have also analyzed datasets highlighting the effects of drugs or regulatory RNAs on autophagy. Altogether, these data provide a comprehensive list of targets to further the understanding of autophagy mechanisms in cancer and investigate possible therapeutic targets.

Little is known about the performance, carcass, and meat traits of locally adapted cattle in Brazil. This study aimed to compare the growth, slaughter, and carcass traits as well as meat quality of two local breeds (Curraleiro Pé-Duro and Pantaneiro) with the Nelore breed. Fifteen 30-month-old steers of each breed were weighted (Curraleiro Pé-Duro = 264.80 kg; Nelore = 346.80 kg; Pantaneiro = 316.20 kg) and raised in a feedlot condition for 112 days, with measurements to assess growth and slaughter, visual and carcass and meat traits. Data were submitted to variance and multivariate analyses. Nelore and Curraleiro Pé-Duro had similar Gluteus medius depths. Pantaneiro and Curraleiro Pé-Duro were superior for leg compactness index (P < 0.05) and had higher eye muscle area than Nelore (P < 0.05). Although there was no difference in daily weight gain and slaughter weight between breeds, Curraleiro Pé-Duro had a lower initial weight (264.80 kg) when compared to Nelore (346.80 kg; P < 0.05). Nelore and Curraleiro Pé-Duro deposited more fat than Pantaneiro (P < 0.05), while Curraleiro Pé-Duro and Pantaneiro had more muscle than Nelore (P < 0.05), which also had more bone and a higher percentage of second-quality cuts (P < 0.05). Meat from Nelore also showed lower succulence than Pantaneiro (P < 0.05) and higher shear force than the other breeds (P < 0.05). Pantaneiro's meat had the most capacity to retain water (P < 0.05), lower shear force (P < 0.05), and was more succulent (P < 0.05) when compared to the other breeds. Multivariate analysis showed that Pantaneiro, Curraleiro Pé-Duro, and Nelore breeds can be considered distinct in growth, carcass, and meat traits, with the local breeds showing superior meat traits. The local breeds Curraleiro Pé-Duro and Pantaneiro presented characteristics similar or better to those of the Nelore, proving to be animals with great productive potential and generate high meat quality under feedlot conditions., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Nearly half of the natural disasters in the world are due to hydro-geomorphological hazards. Therefore, rainfall forecast is a key parameter for the implementation of landslides and flash-floods early warning systems. In this work we developed a routine in R software that enables the validation of a 3-day rainfall forecast by comparison with the daily rainfall data recorded in 101 automatic meteorological stations available in mainland Portugal. The routine integrates the pre-processing of base data, the matching between the 3-day rainfall forecast and the daily rainfall registered in the automatic meteorological stations based on sequence of days, the estimation of the difference between the forecasted and the real rainfall values and the computation of error measures, such as the bias, the mean absolute error, the mean absolute percentage error and the root mean square error. The results from the error measures, estimated for the 101 automatic meteorological stations, are then exported to an excel file. The routine is implemented for mainland Portugal and tested using data from February 2015, however, the spatial and temporal data can be easily updated for other regions.•A routine to validate the rainfall forecast at the regional scale using R programming language is implemented.•The automated routine can be easily updated and adapted with different spatial and temporal scales., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier B.V.)

Portugal is regularly affected by destructive wildfires that have severe social, economic, and ecological impacts. The total burnt area in 2017 (∼540,000 ha) marked the all-time record value since 1980 with a tragic toll of 114 fatalities that occurred in June and October events. The local insurance sector declared it was the costliest natural disaster in Portugal with payouts exceeding USD295 million. Here, the 2017 October event, responsible for more than 200,000 ha of burnt area and 50 fatalities is analyzed from a compound perspective. A prolonged drought led to preconditioned cumulative hydric stress of vegetation in October 2017. In addition, on 15 October 2017, two other major drivers played a critical role: 1) the passage of hurricane Ophelia off the Coast of Portugal, responsible for exceptional meteorological conditions and 2) the human agent, responsible for an extremely elevated number of negligent ignitions. This disastrous combination of natural and anthropogenic drivers led to the uncontrolled wildfires observed on 15 October., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Consideration of compound drivers and impacts are often missing from applications within the Disaster Risk Reduction (DRR) cycle, leading to poorer understanding of risk and benefits of actions. The need to include compound considerations is known, but lack of guidance is prohibiting practitioners from including these considerations. This article makes a step toward practitioner guidance by providing examples where consideration of compound drivers, hazards, and impacts may affect different application domains within disaster risk management. We discern five DRR categories and provide illustrative examples of studies that highlight the role of "compound thinking" in early warning, emergency response, infrastructure management, long-term planning, and capacity building. We conclude with a number of common elements that may contribute to the development of practical guidelines to develop appropriate applications for risk management., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

This study assessed the outcomes of nonsurgical embryo recovery (NSER) after superovulation (SOV) in five locally adapted Brazilian breeds of sheep and goats. The objective was to evaluate the feasibility and efficiency of using SOV combined with a less-invasive embryo collection technique for supplying the Brazilian animal gene bank with germplasm from specific genotypes of interest. Morada Nova ( n  = 20), Santa Inês ( n  = 20), and Somalis ( n  = 20) ewes received an intravaginal progesterone (330 mg) device for 9 days, while Canindé ( n  = 15) and Moxotó ( n  = 15) goats received an intravaginal medroxyprogesterone acetate (60 mg) device for 6 days. All females received 133 mg of porcine follicle-stimulating hormone (pFSH) administrated in six decreasing doses 12 hours apart, starting 60 hours before device removal, plus 37.5 μg of d-cloprostenol at the fifth and sixth pFSH dose. Donors in estrus were mated with fertile males. The corpora lutea (CL) number was assessed by ultrasonography 1 day before NSER. On day 6.5 or 7 after estrus, NSER was performed following hormonally induced cervical relaxation. A total of 97% of sheep and 90% of goats responded with estrus, and among those, 91% of sheep and 85% of goats presented a CL. In ewes, the numbers of CL were greater ( p  < 0.05) in the Santa Inês breed, while similar ( p  > 0.05) CL numbers were found among the goat breeds. All viable embryos were freezable (excellent and good quality) and the number per donor was 7.8 for sheep and 4.9 for goats. All parameters of NSER efficiency, embryo yield, and fertility post-NSER did not differ ( p  > 0.05) between breeds among each species. The SOV-NSER procedures applied for an embryo biobank supply of locally adapted Brazilian breeds of small ruminants were efficient regarding production of cryopreservable embryos, and preservation of donor fertility. Therefore, SOV followed by NSER is recommended for embryo biobank assembly in sheep and goats.

The study aimed to verify the influence of the FecG E mutation in superovulated ewes and to evaluate the probability of logistic models to determine the response capacity of these ewes to superovulatory treatment. Santa Inês ewes (n = 29) were genotyped for the FecG E mutation and separated for their genotype group in carriers of the mutant E allele (FecG E/E , FecG +/E ) and non-carrier (FecG +/+ ) alleles. The ewes underwent hormonal treatment for superovulation. Aside from the genotypes, variables included in the statistical model were reproductive status (empty, early lactation, or late lactation), age (> or < 6 years), and number of births (nulliparous, primiparous, multiparous). The carriers of the mutation could be discriminated from the non-carriers based on the number of corpora lutea, rate of frozen embryos, and fecundity. Recovery rate was significantly higher (P < 0.05) in FecG E/E (94.31%) compared to FecG +/E (63.15%) and FecG +/+ (61.90%) (P < 0.05), whereas fecundity rate of FecG +/+ ewes (50.76%) was significantly higher than FecG +/E (18.96%) and FecG E/E (32.53%) (P < 0.05). We determined in this study that the response to superovulation and embryo production can be discriminated between FecG E/E and FecG +/E ewes in relation to the FecG +/+ genotype. Logistic models that included reproductive status and mutation, or reproductive status and age, or reproductive status and number of births were effective in predicting the response to superovulatory treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Polyethylene (PE) is the most widely used plastic and its accumulation on natural environments has reached alarming levels causing severe damage to wildlife and human health. Despite the significance of this global issue, little is known about specific metabolic mechanisms behind PE biodegradation-a promising and sustainable remediation method. Herein, we describe a novel role of nitrogen metabolism in the fragmentation and oxidation of PE mediated by biological production of NO x in three PE-degrading strains of Comamonas, Delftia, and Stenotrophomonas. Resultant nitrated PE fragments are assimilated and then metabolized by these bacteria in a process assisted by nitronate monooxygenases and nitroreductases to support microbial growth. Due to the conservation of nitrogen metabolism genes, we anticipate that this oxidative mechanism is potentially shared by other nitrifier and denitrifier microbes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We study the stochastic dynamics of the externally regulating gene circuit as an example of an eve-skipped gene stripe in the development of Drosophila. Three gene regulation regimes are considered: an adiabatic phase when the switching rate of the gene from the OFF to ON state is faster than the rate of mRNA degradation; a nonadiabatic phase when the switching rate from the OFF to ON state is slower than that of the mRNA degradation; and a bursting phase when the gene switching is fast and transcription is very fast, while the ON state probability is very low. We found that the rate of thermodynamic cost quantified by the entropy production rate can suppress the fluctuations of the gene circuit. A higher (lower) rate of thermodynamic cost leads to reduced (increased) fluctuations in the number of gene products in the adiabatic (nonadiabatic) regime. We also found that higher thermodynamic cost is often required to sustain the emergence of more gene states and, therefore, more heterogeneity coming from genetic mutations or epigenetics. We also study the stability of the gene state using the mean first passage time from one state to another. We found the monotonic decrease in time, i.e., in the stability of the state, in the transition from the nonadiabatic to adiabatic regimes. Therefore, as the higher rate of thermodynamic cost suppresses the fluctuations, higher stability requires higher thermodynamics cost to maintain.

Livestock production is considered an important factor influencing global warming; however, climate change has also been considered one of the major factors affecting livestock production and reproduction. The present study was carried out in the Southern region of Brazil and aimed to assess the seasonal influence of climatic factors and external morphology of the animals on the semen quality. Three ejaculates were obtained from each bull (Crioulo Lageano and Angus) in summer and winter seasons. Motile cells, sperm vigor, sperm concentration, sperm membrane status, and sperm abnormalities were analyzed in fresh and post-thawed semen. In addition, the sperm kinetics using CASA was assessed on post-thawed semen. Environmental data such as air temperature (AT), relative humidity (RH), mean radiant temperature (MRT) and temperature-humidity index (THI) were measured. Furthermore, body and testicular metrics, as well as hair coat characteristics, were recorded in each season on all bulls. Environmental traits differed significantly between seasons. Results of the PLS regression and Spearman's correlations confirmed a negative relationship between climatic variables and sperm traits in both seasons. Semen quality between breeds and seasons was similar, satisfactory, and heat stress was not sufficient to impair spermatozoa viability. External morphological traits were considered non-important in the final model. The findings of this study suggest that AT, MRT, and THI were the most important factors that could affect seminal characteristics of bulls raised in a subtropical climate., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: to identify and classify blood pressure and self-reported stress in inmates and investigate the association of these events with clinical and sociodemographic data., Methods: a cross-sectional and quantitative study with 240 inmates. A sociodemographic questionnaire, Lipp's Inventory of Stress Symptoms for Adults, blood pressure classification, waist circumference and Body Mass Index were used., Results: mean age of 37.17 years (SD 11.5), 48.8% (n=117) single, 42.9% (n= 103) brown. The majority 67.9% (n=163) had been incarcerated for less than 4 years and 33.8% (n=81) were hypertensive. Blood pressure was compatible with the general population. Smoking, consumption of antihypertensive and hypoglycemic medications, concern about salt consumption, and a family history of hypertension were associated with self-perceived stress (resistance and exhaustion)., Conclusions: the group is exposed to modifiable risk factors, especially stress, which favor hypertension and lack preventive strategies and access to health.

In this manuscript, we use an exactly solvable stochastic binary model for the regulation of gene expression to analyze the dynamics of response to a treatment aiming to modulate the number of transcripts of a master regulatory switching gene. The challenge is to combine multiple processes with different time scales to control the treatment response by a switching gene in an unavoidable noisy environment. To establish biologically relevant timescales for the parameters of the model, we select the RKIP gene and two non-specific drugs already known for changing RKIP levels in cancer cells. We demonstrate the usefulness of our method simulating three treatment scenarios aiming to reestablish RKIP gene expression dynamics toward a pre-cancerous state: (1) to increase the promoter's ON state duration; (2) to increase the mRNAs' synthesis rate; and (3) to increase both rates. We show that the pre-treatment kinetic rates of ON and OFF promoter switching speeds and mRNA synthesis and degradation will affect the heterogeneity and time for treatment response. Hence, we present a strategy for reaching increased average mRNA levels with diminished heterogeneity while reducing drug dosage by simultaneously targeting multiple kinetic rates that effectively represent the chemical processes underlying the regulation of gene expression. The decrease in heterogeneity of treatment response by a target gene helps to lower the chances of emergence of resistance. Our approach may be useful for inferring kinetic constants related to the expression of antimetastatic genes or oncogenes and for the design of multi-drug therapeutic strategies targeting the processes underpinning the expression of master regulatory genes.

The present study aimed to investigate the effects of a combination of progesterone with different doses of E-17β on following end points: (1) ovarian follicular dynamics and emergence of a new follicular wave, and (2) superovulatory response and embryo yield. In Experiment 1, 28 ewes were randomly divided into four groups ( n = 7) to receive either 2.0 mg, 1.0 mg, 0.5 mg or none E-17β one day after insertion of a progesterone device. The different doses of estradiol similarly delayed the moment of follicular emergence (overall mean = 3.1 ± 1.0 days vs. control group = 0.86 ± 1.0 days; P < 0.01), but the emergence of the new wave showed greater synchronization with the 0.5 mg dosage of E-17β. In Experiment 2, sixty-two donor ewes received an internal progesterone release device (day -1) for 7 d and 1 d after the insertion of this device (day 0) were allocated randomly to receive 0.5 mg of E-17β or only the vehicle (control group). Superstimulation was initiated on day 3 with the administration of 133 mg of pFSH in eight decreasing doses. Contrary to expectations, the protocol with the administration of 0.5 mg E-17β did not improve the percentage of donors with > 2 CL, the number of CL and the production of embryos (P > 0.05). It was concluded that the combination of progesterone and 0.5 mg E-17β was more efficient in synchronizing the emergence of the new follicular wave, however this approach seems to be unnecessary in ewe's superovulation programs., Competing Interests: Conflicts of interest: The authors have no conflict of interest to declare.

Targeted strategies against specific driver molecules of cancer have brought about many advances in cancer treatment since the early success of the first small-molecule inhibitor Gleevec. Today, there are a multitude of targeted therapies approved by the Food and Drug Administration for the treatment of cancer. However, the initial efficacy of virtually every targeted treatment is often reversed by tumor resistance to the inhibitor through acquisition of new mutations in the target molecule, or reprogramming of the epigenome, transcriptome, or kinome of the tumor cells. At the core of this clinical problem lies the assumption that targeted treatments will only be efficacious if the inhibitors are used at their maximum tolerated doses. Such aggressive regimens create strong selective pressure on the evolutionary progression of the tumor, resulting in resistant cells. High-dose single agent treatments activate alternative mechanisms that bypass the inhibitor, while high-dose combinatorial treatments suffer from increased toxicity resulting in treatment cessation. Although there is an arsenal of targeted agents being tested clinically and preclinically, identifying the most effective combination treatment plan remains a challenge. In this review, we discuss novel targeted strategies with an emphasis on the recent cross-disciplinary studies demonstrating that it is possible to achieve antitumor efficacy without increasing toxicity by adopting low-dose multitarget approaches to treatment of cancer and metastasis., Competing Interests: Conflict of interest This research is also the subject of a pending US patent application #17/048282. The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to use estrus synchronization protocols to favor fixed-time artificial insemination and consequently fixed-time embryo collection, and increase embryo production using eCG, in gits. In a cross over design, nine Piau breed gilts were subjected to 18 days of oral progesterone; P4 group did not receive any further; GnRH group received 25µg of GnRH 104 hours after the final application of P4; and eCG+GnRH group received 1000IU of eCG 24 hours after the final P4 in addition to GnRH for subsequent embryo collection, that was performed six days after first AI, by laparotomy. Artificial insemination was performed after 12 and 24 hours of estrus in P4 group, and 128 and 144 hours in GnRH and eCG+GnRH groups. The number of CL (8.6±3.9; 8.3±2.1; 26.7±15.0) and anovulatory follicles (4.3±3.7; 3.9±3.9; 17.2±9.5) was higher in the eCG+GnRH gilts ( P <0.05). However, the use of 1000 IU of eCG reduced ( P <0.05) the number of total structures (5.2±3.6; 5.1±3.1; 1.7±2.7), viable embryos (5.0±3.5; 4.8±3.3; 0.4±0.7), freezable embryos (3.6±3.4; 3.3±3.8; 0.1±0.3) and recovery rate (63.7±38.9; 58.6±24.7; 5.38±9.5). P4 and GnRH protocols were effective in the production and recovery of embryos. However, the use of 1000 IU of eCG, 24 hours after P4, was not effective in promoting the production of embryos, although the animals had superovulated., Competing Interests: Conflicts of interest: The authors have no conflict of interest to declare., (Copyright © The Author(s).)

Metastasis suppression by high-dose, multi-drug targeting is unsuccessful due to network heterogeneity and compensatory network activation. Here, we show that targeting driver network signaling capacity by limited inhibition of core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein (RKIP), that moderately decreases stress-regulated MAP kinase network activity, reducing output to transcription factors such as pro-metastastic BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells. Restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically relevant strategy for anti-metastatic treatment., Competing Interests: AY, DY, AV, PT, AS, LN, JL, XX, SS, CD, LR, ES, TS, CF, EG, GJ, AR No competing interests declared, MR This research is also the subject of a pending US patent application # 17/048,282., (© 2021, Yesilkanal et al.)

Cancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-naïve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study was designed to evaluate the seasonal expression of seminal plasma proteins from two bovine breeds adapted to a subtropical climate and their associations with post-thawing sperm and environmental characteristics. Semen samples were obtained three times in summer and three times in winter from four Crioulo Lageano and four Angus bulls. Seminal plasma was obtained by centrifugation, and the other portion of the semen was cryopreserved. Seminal plasma proteins were identified by 2D-nanoUPLC-MS E . Post-thawing assessments of sperm kinetics, morphology and membrane integrity were performed. Environmental data such as air temperature, air humidity and black globe temperature (BGT) were recorded, and the temperature-humidity index (THI) was calculated in summer and winter. Results showed that the climate varied significantly between seasons. Although no statistical differences were observed in semen quality between breeds, the protein profiles varied within and between seasons. We suggest that the most critical proteins in summer affecting sperm characteristics were TIMP-2, DNase, Clusterin, CFAH and GPx6. TIMP-2 and DNase showed a higher abundance in Crioulo Lageano in comparison with Angus, while Clusterin, CFAH and GPx6 presented a lower abundance. To the best of our knowledge, this is the first report of a recently evolved type of glutathione peroxidase, GPx6, in seminal plasma of bovines. In winter, five proteins were considered to be more critical: BSP1, BSP3, CCL2, Sulfhydryl oxidase and TIMP-2. BSP1 and TIMP-2 showed a lower abundance while BSP3, CCL2 and Sulfhydryl oxidase presented a higher abundance in this season in Crioulo Lageano in comparison with Angus.

One of the most robust signals of climate change is the relentless rise in global mean surface temperature, which is linked closely with the water-holding capacity of the atmosphere. A more humid atmosphere will lead to enhanced moisture transport due to, among other factors, an intensification of atmospheric rivers (ARs) activity, which are an important mechanism of moisture advection from subtropical to extra-tropical regions. Here we show an enhanced evapotranspiration rates in association with landfalling atmospheric river events. These anomalous moisture uptake (AMU) locations are identified on a global scale. The interannual variability of AMU displays a significant increase over the period 1980-2017, close to the Clausius-Clapeyron (CC) scaling, at 7 % per degree of surface temperature rise. These findings are consistent with an intensification of AR predicted by future projections. Our results also reveal generalized significant increases in AMU at the regional scale and an asymmetric supply of oceanic moisture, in which the maximum values are located over the region known as the Western Hemisphere Warm Pool (WHWP) centred on the Gulf of Mexico and the Caribbean Sea.

This manuscript presents a comparison of noise properties exhibited by two stochastic binary models for: (i) a self-repressing gene; (ii) a repressed or activated externally regulating one. The stochastic models describe the dynamics of probability distributions governing two random variables, namely, protein numbers and the gene state as ON or OFF. In a previous work, we quantify noise in protein numbers by means of its Fano factor and write this quantity as a function of the covariance between the two random variables. Then we show that distributions governing the number of gene products can be super-Fano, Fano or sub-Fano if the covariance is, respectively, positive, null or negative. The latter condition is exclusive for the self-repressing gene and our analysis shows the conditions for which the Fano factor is a sufficient classifier of fluctuations in gene expression. In this work, we present the conditions for which the noise on the number of gene products generated from a self-repressing gene or an externally regulating one are quantitatively similar. That is important for inference of gene regulation from noise in gene expression quantitative data. Our results contribute to a classification of noise function in biological systems by theoretically demonstrating the mechanisms underpinning the higher precision in expression of a self-repressing gene in comparison with an externally regulated one.

The promoter state of a gene and its expression levels are modulated by the amounts of transcription factors interacting with its regulatory regions. Hence, one may interpret a gene network as a communicating system in which the state of the promoter of a gene (the source ) is communicated by the amounts of transcription factors that it expresses (the message ) to modulate the state of the promoter and expression levels of another gene (the receptor ). The reliability of the gene network dynamics can be quantified by Shannon's entropy of the message and the mutual information between the message and the promoter state. Here we consider a stochastic model for a binary gene and use its exact steady state solutions to calculate the entropy and mutual information. We show that a slow switching promoter with long and equally standing ON and OFF states maximizes the mutual information and reduces entropy. That is a binary gene expression regime generating a high variance message governed by a bimodal probability distribution with peaks of the same height. Our results indicate that Shannon's theory can be a powerful framework for understanding how bursty gene expression conciliates with the striking spatio-temporal precision exhibited in pattern formation of developing organisms.

We chemically characterize the symmetries underlying the exact solutions of a stochastic negatively self-regulating gene. The breaking of symmetry at a low molecular number causes three effects. Two branches of the solution exist, having high and low switching rates, such that the low switching rate branch approaches deterministic behavior and the high switching rate branch exhibits sub-Fano behavior. The average protein number differs from the deterministically expected value. Bimodal probability distributions appear as the protein number becomes a readout of the ON/OFF state of the gene.

Although redox processes closely interplay with mechanoresponses to control vascular remodeling, redox pathways coupling mechanostimulation to cellular cytoskeletal organization remain unclear. The peri/epicellular pool of protein disulfide isomerase-A1 (pecPDIA1) supports postinjury vessel remodeling. Using distinct models, we investigated whether pecPDIA1 could work as a redox-dependent organizer of cytoskeletal mechanoresponses. In vascular smooth muscle cells (VSMCs), pecPDIA1 immunoneutralization impaired stress fiber assembly in response to equibiaxial stretch and, under uniaxial stretch, significantly perturbed cell repositioning perpendicularly to stretch orientation. During cyclic stretch, pecPDIA1 supported thiol oxidation of the known mechanosensor β 1 -integrin and promoted polarized compartmentalization of sulfenylated proteins. Using traction force microscopy, we showed that pecPDIA1 organizes intracellular force distribution. The net contractile moment ratio of platelet-derived growth factor-exposed to basal VSMCs decreased from 0.90 ± 0.09 (IgG-exposed controls) to 0.70 ± 0.08 after pecPDI neutralization ( P < 0.05), together with an enhanced coefficient of variation for distribution of force modules, suggesting increased noise. Moreover, in a single cell model, pecPDIA1 neutralization impaired migration persistence without affecting total distance or velocity, whereas siRNA-mediated total PDIA1 silencing disabled all such variables of VSMC migration. Neither expression nor total activity of the master mechanotransmitter/regulator RhoA was affected by pecPDIA1 neutralization. However, cyclic stretch-induced focal distribution of membrane-bound RhoA was disrupted by pecPDI inhibition, which promoted a nonpolarized pattern of RhoA/caveolin-3 cluster colocalization. Accordingly, FRET biosensors showed that pecPDIA1 supports localized RhoA activity at cell protrusions versus perinuclear regions. Thus, pecPDI acts as a thiol redox-dependent organizer and noise reducer mechanism of cytoskeletal repositioning, oxidant generation, and localized RhoA activation during a variety of VSMC mechanoresponses. NEW & NOTEWORTHY Effects of a peri/epicellular pool of protein disulfide isomerase-A1 (pecPDIA1) during mechanoregulation in vascular smooth muscle cells (VSMCs) were highlighted using approaches such as equibiaxial and uniaxial stretch, random single cell migration, and traction force microscopy. pecPDIA1 regulates organization of the cytoskeleton and minimizes the noise of cell alignment, migration directionality, and persistence. pecPDIA1 mechanisms involve redox control of β 1 -integrin and localized RhoA activation. pecPDIA1 acts as a novel organizer of mechanoadaptation responses in VSMCs.

Melanomas often accumulate gangliosides, sialic acid-containing glycosphingolipids found in the outer leaflet of plasma membranes, as disialoganglioside G D3 and its derivatives. Here, we have transfected the G D3 synthase gene (ST8Sia I) in a normal melanocyte cell line in order to evaluate changes in the biological behavior of non-transformed cells. G D3 -synthase expressing cells converted G M3 into G D3 and accumulated both G D3 and its acetylated form, 9-O-acetyl-G D3 . Melanocytes were rendered more migratory on laminin-1 surfaces. Cell migration studies using the different transfectants, either treated or not with the glucosylceramide synthase inhibitor d-1-threo-1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (PPPP), allowed us to show that while G M3 is a negative regulator of melanocyte migration, G D3 increases it. We showed that gangliosides were shed to the matrix by migrating cells and that G D3 synthase transfected cells shed extracellular vesicles (EVs) enriched in G D3 . EVs enriched in G D3 stimulated cell migration of G D3 negative cells, as observed in time lapse microscopy studies. Otherwise, EVs shed by G M3 +ve G D3 -ve cells impaired migration and diminished cell velocity in cells overexpressing G D3 . The balance of antimigratory G M3 and promigratory G D3 gangliosides in melanocytes could be altered not only by the overexpression of enzymes such as ST8Sia I, but also by the horizontal transfer of ganglioside enriched extracellular vesicles. This study highlights that extracellular vesicles transfer biological information also through their membrane components, which include a variety of glycosphingolipids remodeled in disease states such as cancer., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A Lagrangian analysis is applied to identify the main moisture source areas associated with atmospheric rivers (ARs) making landfall along the west coast of South Africa during the extended austral winter months from 1980 to 2014. The results show that areas that provide the anomalous uptake of moisture can be categorized into four regions: (1) the South Atlantic Ocean between 10°S and 30°S, (2) a clear local maximum in the eastern South Atlantic, (3) a continental source of anomalous uptake to the north of the Western Cape, and (4) over South America at a distance of more than 7000 km from the target region. It emerges that the South American moisture source can be linked to a particular phase of the South American low-level jet, known as a no Chaco jet event (NCJE), which transports moisture to the western and central South Atlantic basin. Concisely, we provide strong evidence that the two margins of the South Atlantic Ocean appear connected by two meteorological structures, with the NCJE playing a key role of transporting moisture from South America to the western and central South Atlantic basin, feeding the AR that transports some of the moisture to the west coast of South Africa., (© 2018 New York Academy of Sciences.)

The effects of randomness, an unavoidable feature of intracellular environments, are observed at higher hierarchical levels of living matter organization, such as cells, tissues, and organisms. Additionally, the many compounds interacting as a well-orchestrated network of reactions increase the difficulties of assessing these systems using only experiments. This limitation indicates that elucidation of the dynamics of biological systems is a complex task that will benefit from the establishment of principles to help describe, categorize, and predict the behavior of these systems. The theoretical machinery already available, or ones to be discovered to help solve biological problems, might play an important role in these processes. Here, we demonstrate the application of theoretical tools by discussing some biological problems that we have approached mathematically: fluctuations in gene expression and cell proliferation in the context of loss of contact inhibition. We discuss the methods that have been employed to provide the reader with a biologically motivated phenomenological perspective of the use of theoretical methods. Finally, we end this review with a discussion of new research perspectives motivated by our results.

For a long time, Pantaneiro and Campeiro breeds were raised only within their places of origin. Consequently, there are few of these horses; therefore, establishing reproductive and clinical standards for these animals is necessary to implant new biotechnologies for reproduction to preserve their genetics. This study aimed to perform a descriptive evaluation of fetal age determination by fetus ocular orbit measurement in mares of the Campeiro and Pantaneiro breeds. We also evaluated sequential changes in hematology and biochemistry for foals from birth to six months of life by counting red blood cells, hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin concentration, leukocytes, neutrophils, lymphocytes, eosinophils, monocytes, basophils, platelet count, fibrinogen, albumin, plasma protein, creatinine, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and globulins. There was no significant difference in relation to fetal gestational age and ocular orbit between the two breeds (P = 0.578). There was no significant difference in the hematological parameters between the Campeiro and Pantaneiro foals, but there were differences in the means and changes in the blood variables when compared to the literature. These hematological and biochemical variations provide useful information for clinical evaluations from Campeiro and Pantaneiro foals up to six months of age., Competing Interests: Conflict of Interest Statement
The authors declare that they have no conflict of interest.

Background: Models that incorporate specific chemical mechanisms have been successful in describing the activity of Drosophila developmental enhancers as a function of underlying transcription factor binding motifs. Despite this, the minimum set of mechanisms required to reconstruct an enhancer from its constituent parts is not known. Synthetic biology offers the potential to test the sufficiency of known mechanisms to describe the activity of enhancers, as well as to uncover constraints on the number, order, and spacing of motifs., Results: Using a functional model and in silico compensatory evolution, we generated putative synthetic even-skipped stripe 2 enhancers with varying degrees of similarity to the natural enhancer. These elements represent the evolutionary trajectories of the natural stripe 2 enhancer towards two synthetic enhancers designed ab initio. In the first trajectory, spatially regulated expression was maintained, even after more than a third of binding sites were lost. In the second, sequences with high similarity to the natural element did not drive expression, but a highly diverged sequence about half the length of the minimal stripe 2 enhancer drove ten times greater expression. Additionally, homotypic clusters of Zelda or Stat92E motifs, but not Bicoid, drove expression in developing embryos., Conclusions: Here, we present a functional model of gene regulation to test the degree to which the known transcription factors and their interactions explain the activity of the Drosophila even-skipped stripe 2 enhancer. Initial success in the first trajectory showed that the gene regulation model explains much of the function of the stripe 2 enhancer. Cases where expression deviated from prediction indicates that undescribed factors likely act to modulate expression. We also showed that activation driven Bicoid and Hunchback is highly sensitive to spatial organization of binding motifs. In contrast, Zelda and Stat92E drive expression from simple homotypic clusters, suggesting that activation driven by these factors is less constrained. Collectively, the 40 sequences generated in this work provides a powerful training set for building future models of gene regulation.

Contact inhibition is a central feature orchestrating cell proliferation in culture experiments; its loss is associated with malignant transformation and tumorigenesis. We performed a co-culture experiment with human metastatic melanoma cell line (SKMEL- 147) and immortalized keratinocyte cells (HaCaT). After 8 days a spatial pattern was detected, characterized by the formation of clusters of melanoma cells surrounded by keratinocytes constraining their proliferation. In addition, we observed that the proportion of melanoma cells within the total population has increased. To explain our results we propose a spatial stochastic model (following a philosophy of the Widom-Rowlinson model from Statistical Physics and Molecular Chemistry) which considers cell proliferation, death, migration, and cell-to-cell interaction through contact inhibition. Our numerical simulations demonstrate that loss of contact inhibition is a sufficient mechanism, appropriate for an explanation of the increase in the proportion of tumor cells and generation of spatial patterns established in the conducted experiments.

The objective of this study was to evaluate hormone and energy profiles in the postpartum period and to correlate these profiles with the resumption of ovarian cyclicity, as well as characterizing the postpartum short estrous cycle of Curraleiro Pé-Duro cows. Twelve Curraleiro Pé-Duro cows were examined via rectal palpation and ultrasound at 10 days postpartum, and subsequently examined daily to evaluate the resumption of ovarian cyclicity as well as every five days in order to evaluate uterine involution. Upon analysis of the data, it was possible to observe the formation of two distinct groups, one of which was comprised of those animals which returned to cyclicity within 60 days postpartum and another comprised of those animals which returned to cyclicity more than 105 days postpartum. Therefore, animals were divided into two groups; precocious, designated Ov Group, and delayed, designated NOv Group, wherein the cut-off time for all tests was 60 days postpartum. Statistically significant differences (P < 0.01) between the groups occurred only regarding the day of 1st ovulation, which in the Ov Group averaged 51.4 ± 9.3 days and in the NOv Group averaged 138.3 ± 19.8 days postpartum. The other postpartum short estrous cycle variables assessed did not show statistically significant differences (P > 0.05) between the groups. NEFA, BHBA and thyroxine concentration levels did not differ (P > 0.05) between the groups in any of the statistical analyses. However, in the analysis comparing growth curves, triglycerides levels were higher for the Ov Group (P = 0.04) and cholesterol levels were higher for the NOv Group (P = 0.02). In this experiment, a small influence of a negative energy balance between the groups was observed, suggesting that these animals can present significant genetic variability due to natural selection, as evidenced by the formation of groups of animals with precocious and delayed reproductive characteristics., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study investigated the influence of feed intake on superovulatory response and embryo production of Nelore heifers. Pubertal heifers were kept in a feedlot and were submitted to the same diets, but with different levels of feed consumption: High (1.7 M; n = 20) or Low (0.7 M; n = 19) feed intake. Heifers in the 1.7 M treatment consumed 170% (2.6% of body weight [BW] in dry matter) and the 0.7 M heifers ate 70% (1.1% of BW in dry matter) of a maintenance diet. After 7 wk on these diets, heifers were treated with eight decreasing doses of follicle-stimulating hormone (FSH) given every 12 h, totaling 133 mg Folltropin (Folltropin-V; Bioniche Animal Health, Canada) per heifer. Seven d after AI, heifers had their uteri flushed and embryos were recovered and graded according to the International Embryo Technology Society standards. Data were analyzed using the GLIMMIX procedure of SAS and results are presented as least-squares means ± SEM (P < 0.05). At the onset of the FSH treatment (Day 0 of the protocol), 1.7 M heifers had greater body condition score (BCS), BW and serum insulin concentrations than 0.7 M heifers (4.1 ± 0.1 vs. 3.0 ± 0.1; 462.5 ± 10.1 vs. 382.7 ± 10.4 kg; and 14.3 ± 1.7 vs. 3.5 ± 0.8 μIU/mL, respectively). The 0.7 M heifers had more follicles ≥6 mm at the time of the last FSH (Day 7; 47.9 ± 6.4 vs. 23.5 ± 4.3 follicles), related to a better follicle superstimulatory response to FSH. Similarly, 0.7 M heifers had more corpora lutea at the time of embryo collection (33.6 ± 1.4 vs. 15.7 ± 0.9) than the 1.7 M heifers, which resulted in greater number of recovered embryos and ova (9.9 ± 0.7 vs. 6.7 ± 0.6) and viable embryos (5.3 ± 0.5 vs. 3.8 ± 0.4), despite having similar proportions of viable embryos (∼62%). A negative correlation between circulating insulin and follicle superstimulatory response to FSH was observed (r = -0.68). Therefore, we conclude that high feed intake, for a long period of time, compromised the superovulatory response and embryo production potential of Bos indicus heifers possibly related to the elevation in circulating insulin., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this article, we introduce a backward method to model stochastic gene expression and protein-level dynamics. The protein amount is regarded as a diffusion process and is described by a backward stochastic differential equation (BSDE). Unlike many other SDE techniques proposed in the literature, the BSDE method is backward in time; that is, instead of initial conditions it requires the specification of end-point ("final") conditions, in addition to the model parametrization. To validate our approach we employ Gillespie's stochastic simulation algorithm (SSA) to generate (forward) benchmark data, according to predefined gene network models. Numerical simulations show that the BSDE method is able to correctly infer the protein-level distributions that preceded a known final condition, obtained originally from the forward SSA. This makes the BSDE method a powerful systems biology tool for time-reversed simulations, allowing, for example, the assessment of the biological conditions (e.g., protein concentrations) that preceded an experimentally measured event of interest (e.g., mitosis, apoptosis, etc.).

Tropically adapted Bos taurus breeds are descended from the cattle which were brought from the Iberian Peninsula to Latin America by the colonizers and which adapted over time to local conditions. These breeds have become a genetic treasure that must be preserved. The objective of this study was to characterize ovarian follicular emergence and divergence in tropically adapted B. taurus cows and heifers. Cyclic heifers (n = 11) and nonlactating, multiparous cows (n = 11) were examined at 8-hour intervals using ultrasonography starting on the day following the final application of PGF 2α , which was used to synchronize the estrous cycle, and ending 5 days after ovulation. Blood samples were collected immediately following the ultrasonographic examinations in order to evaluate FSH and estradiol-17β (E 2 ) concentrations. The interval between ovulation and follicular wave emergence (11.6 ± 3.3 hours vs. 20.3 ± 2.5 hours, P < 0.05) and ovulation and follicular wave divergence (52.4 ± 5.2 hours vs. 71.8 ± 4.1 hours, P < 0.05) was shorter in the cows than in the heifers, respectively. Plasma FSH concentrations increased (P < 0.05) and serum E 2 concentrations decreased earlier in cows than in heifers before ovulation. Following follicular wave emergence, no difference in follicular development was found between the cows and the heifers. Consequently, following follicular wave emergence, the data from both the cows and the heifers were combined and categorized by dominant follicle (DF) and second largest follicle (SF). The DF and SF were identified at the same time (P > 0.05). The mean number of small (≤4 mm, 7.2 ± 5.1) and medium (4 to ≤ 8 mm, 6.8 ± 3.5) follicles was greater than that of large follicles (≥8 mm, 0.6 ± 0.5) from ovulation until 5 days after ovulation. The DF diameter (8.1 ± 1 mm) did not differ (P = 0.09) from SF diameter (7.6 ± 0.9 mm) at the time of follicular divergence (around 45 hours after follicular emergence). The DF and SF growth rates were similar (P > 0.05) until follicular divergence, at which point the SF growth rate decreased, whereas the DF growth rate remained constant. Serum E 2 concentrations did not change (P > 0.05) during the divergence period, whereas FSH concentrations decreased between 48 and 32 hours before follicular wave divergence. In conclusion, cows and heifers differed only in the interval from ovulation to follicular wave emergence and divergence, which was confirmed by the different patterns of FSH and E 2 concentrations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We examine immunostaining experimental data for the formation of stripe 2 of even-skipped (eve) transcripts on D. melanogaster embryos. An estimate of the factor converting immunofluorescence intensity units into molecular numbers is given. The analysis of the eve dynamics at the region of stripe 2 suggests that the promoter site of the gene has two distinct regimes: an earlier phase when it is predominantly activated until a critical time when it becomes mainly repressed. That suggests proposing a stochastic binary model for gene transcription on D. melanogaster embryos. Our model has two random variables: the transcripts number and the state of the source of mRNAs given as active or repressed. We are able to reproduce available experimental data for the average number of transcripts. An analysis of the random fluctuations on the number of eves and their consequences on the spatial precision of stripe 2 is presented. We show that the position of the anterior or posterior borders fluctuate around their average position by ∼1% of the embryo length, which is similar to what is found experimentally. The fitting of data by such a simple model suggests that it can be useful to understand the functions of randomness during developmental processes.

Here we characterize the low-noise regime of a stochastic model for a negative self-regulating binary gene. The model has two stochastic variables, the protein number and the state of the gene. Each state of the gene behaves as a protein source governed by a Poisson process. The coupling between the two gene states depends on protein number. This fact has a very important implication: There exist protein production regimes characterized by sub-Poissonian noise because of negative covariance between the two stochastic variables of the model. Hence the protein numbers obey a probability distribution that has a peak that is sharper than those of the two coupled Poisson processes that are combined to produce it. Biochemically, the noise reduction in protein number occurs when the switching of the genetic state is more rapid than protein synthesis or degradation. We consider the chemical reaction rates necessary for Poisson and sub-Poisson processes in prokaryotes and eucaryotes. Our results suggest that the coupling of multiple stochastic processes in a negative covariance regime might be a widespread mechanism for noise reduction.

We consider a general class of mathematical models for stochastic gene expression where the transcription rate is allowed to depend on a promoter state variable that can take an arbitrary (finite) number of values. We provide the solution of the master equations in the stationary limit, based on a factorization of the stochastic transition matrix that separates timescales and relative interaction strengths, and we express its entries in terms of parameters that have a natural physical and/or biological interpretation. The solution illustrates the capacity of multiple states promoters to generate multimodal distributions of gene products, without the need for feedback. Furthermore, using the example of a three states promoter operating at low, high, and intermediate expression levels, we show that using multiple states operons will typically lead to a significant reduction of noise in the system. The underlying mechanism is that a three-states promoter can change its level of expression from low to high by passing through an intermediate state with a much smaller increase of fluctuations than by means of a direct transition.

Rearrangements of about 2.5 kilobases of regulatory DNA located 5' of the transcription start site of the Drosophila even-skipped locus generate large-scale changes in the expression of even-skipped stripes 2, 3, and 7. The most radical effects are generated by juxtaposing the minimal stripe enhancers MSE2 and MSE3 for stripes 2 and 3 with and without small "spacer" segments less than 360 bp in length. We placed these fusion constructs in a targeted transformation site and obtained quantitative expression data for these transformants together with their controlling transcription factors at cellular resolution. These data demonstrated that the rearrangements can alter expression levels in stripe 2 and the 2-3 interstripe by a factor of more than 10. We reasoned that this behavior would place tight constraints on possible rules of genomic cis-regulatory logic. To find these constraints, we confronted our new expression data together with previously obtained data on other constructs with a computational model. The model contained representations of thermodynamic protein-DNA interactions including steric interference and cooperative binding, short-range repression, direct repression, activation, and coactivation. The model was highly constrained by the training data, which it described within the limits of experimental error. The model, so constrained, was able to correctly predict expression patterns driven by enhancers for other Drosophila genes; even-skipped enhancers not included in the training set; stripe 2, 3, and 7 enhancers from various Drosophilid and Sepsid species; and long segments of even-skipped regulatory DNA that contain multiple enhancers. The model further demonstrated that elevated expression driven by a fusion of MSE2 and MSE3 was a consequence of the recruitment of a portion of MSE3 to become a functional component of MSE2, demonstrating that cis-regulatory "elements" are not elementary objects., Competing Interests: The authors have declared that no competing interests exist.

The aim of the work described herein was to study projection scenarios in order to find changes in the synoptic variability of the northwest Iberian Peninsula in the 21st century. To this end, we investigated the changes in the frequency of the different circulation types computed for the study area using three different models used in the IPCC 4(th) assessment report. The circulation types were computed using the procedure known as Lamb circulation types. The control simulation for the late 20th century was evaluated objectively from the results obtained using data from the NCEP/NCAR reanalysis, as to evaluate the ability of the model to reproduce the present climate. We have compared not only seasonal mean sea level pressure fields but also the mean seasonal frequency of circulation types. The results for the end of the 21st century show a decrease in the frequency of cyclonic, W, and SW circulation types in the spring and summer months. This trend also appears in the autumn, with a concomitant increase in the anticyclonic types.

An analysis of the frequency of cyclones and surface wind velocity for the Euro-Atlantic sector is performed by means of an objective methodology. Monthly and seasonal trends of cyclones and wind speed magnitude are computed and trends between 1960 and 2000 evaluated. Results reveal a significant frequency decrease (increase) in the western Mediterranean (Greenland and Scandinavia), particularly in December, February, and March. Seasonal and monthly analysis of wind magnitude trends shows similar spatial patterns. We show that these changes in the frequency of low-pressure centers and the associated wind patterns are partially responsible for trends in the significant height of waves. Throughout the extended winter months (October-March), regions with positive (negative) wind magnitude trends, of up to 5 cm/s/year, often correspond to regions of positive (negative) significant wave height trends. The cyclone and wind speed trends computed for January-March are well matched by the corresponding trends in significant wave height, with February being the month with the highest trends (negative south of lat 50 degrees N up to -3 cm/year, and positive up to 5 cm/year just north of Scotland). Trends in European precipitation are assessed using the Climatic Research Unit data set. The results of the assessment emphasize the link with the corresponding tendencies of cyclone frequencies. Finally, it is shown that these changes are associated, to a large extent, with the preferred phases of major large-scale atmospheric circulation modes, particularly with the North Atlantic Oscillation, the eastern Atlantic pattern, and the Scandinavian pattern.

Lorentz-like noncompact Lie symmetry SO(2,1) is found in a spin-boson stochastic model for gene expression. The invariant of the algebra characterizes the switch decay to equilibrium. The azimuthal eigenvalue describes the affinity between the regulatory protein and the gene operator site. Raising and lowering operators are constructed and their actions increase or decrease the affinity parameter. The classification of the noise regime of the gene arises from the group theoretical numbers.

Introduction: Diabetes is not only a risk factor for coronary artery disease but also influences its presentation and evolution., Objectives: The objective of this work is to define the risk factors, clinical and angiographic characteristics, and evolution of acute coronary syndrome in a population of diabetic patients., Methodology: We studied 521 patients suffering from acute coronary syndrome, consecutively hospitalized in the Cardiology Intensive Care Unit who underwent cardiac catheterization during their hospitalization, in terms of risk factors for coronary disease, pathology (unstable angina versus acute myocardial infarction), coronary morphology, left ventricular function, need for intervention during hospitalization, evolution and complications during one-year follow-up. The characteristics of the diabetic patients with acute coronary syndrome were compared to those of non-diabetic patients., Results: Of the 521 patients suffering from acute coronary syndrome (391 male), 159 (30.5%) were diabetic. The diabetic patients suffering from acute coronary syndrome generally presented fewer risk factors for coronary artery disease, with a lower prevalence of smoking (p < 0.001), greater prevalence of family history of coronary artery disease (p < 0.01), more unstable angina and less acute myocardial infarction (both p < 0.001), than the nondiabetic patients. After the acute coronary syndrome the diabetic patients more frequently presented disease of the left anterior descending artery, left ventricular function was worse and there was a greater need for coronary artery bypass graft surgery and less percutaneous transluminal coronary angioplasty than in the non-diabetic patients (p < 0.05 for all). In terms of evolution, they presented greater complications and more mortality over a year (p < 0.05)., Conclusion: Diabetes constitutes a powerful risk factor for coronary artery disease and its complications, and should therefore be taken into consideration in clinical approaches to this pathology.