פרסומים

Circulating, non-coding RNAs, such as microRNAs (miRNAs) have been proposed to be powerful pathophysiological indicators of pregnancy in animals and humans. Since their discovery, it is known that miRNAs can take part in numerous biological processes, including cell proliferation and differentiation during early embryonic development and establishment of pregnancy. Our recent studies have indicated that maternal blood can carry miRNAs reported previously at the embryo-maternal interface in pigs. To expand the scope of our research, we tested the hypothesis that miRNAs previously identified in conceptuses, trophoblasts, endometriumand uterine lumen-derived extracellular vesicles (EVs) collected before Day 20 of pregnancy can show reproductive status-dependent profiles in the serum of cyclic and pregnant crossbred pigs. Custom-designed TaqMan arrays, multiplex real-time reverse transcription (RT)-PCR and real-time RT-PCR allowed us to identify a number of reproductive status-dependent miRNAs in serum samples collected from pigs during the estrous cycle or pregnancy (Days 16 and 20). We found that serum samples were enriched with miRNAs involved in processes important during the estrous cycle and early pregnancy, e.g. cell sensitivity and viability, angiogenesis, embryonic cell proliferation and differentiation. Further validation revealed different abundance of ssc-miR-143-3p and sscmiR-125b in pregnant and non-pregnant animals and correlation of ssc-miR-125b levels with litter size. In addition, analyzed serum samples contained both EVs and Argonaute2 proteins, which are known to be involved in miRNA transportation and intercellular communication. In summary, we identified several circulating miRNAs that differ in abundance between cyclic and pregnant animals and could serve as potential indicators of reproductive status in pigs during breeding management. (C) 2021 The Authors. Published by Elsevier Inc. on behalf of The Animal Consortium.

In the current work, prolonged systemic delivery of apomorphine via buccal mucosa was shown to be a promising treatment for Parkinson's disease as a substitute for clinically utilized subcutaneous infusions. Due to extensive ‘first-pass' metabolism, apomorphine is administered parenterally to bypass liver metabolism. Drawbacks of parenteral administration cause low patient compliance and adherence to treatment. On the other hand, while also bypassing the liver, delivery through buccal mucosa has a superior safety profile, is less costly, lacks pain and discomfort, and possesses excellent accessibility, overall augmenting patient compliance. Current in vivo study in pigs showed: (1) steady plateau levels of apomorphine in plasma were obtained 30 min following administration and remained constant for 8 h until a delivery device was removed, (2) bioavailability of apomorphine was 55%–80% as opposed to <2% peroral and (3) simulation of the pharmacokinetic profile obtained in pigs predicted therapeutically relevant levels of apomorphine in human. Furthermore, antipyrine was incorporated as a permeation marker to enable mechanistic investigation of apomorphine release from the delivery device and its permeation through the buccal mucosa. In addition, limitations of an Ussing diffusion chamber as an ex vivo research tool were also discussed.

Growing global demands for food, bioenergy, and specialty products, along with the threat posed by various environmental changes, present substantial challenges for agricultural production. Agricultural biotechnology offers a promising avenue for meeting these challenges; however, ethical and sociocultural concerns must first be addressed, to ensure widespread public trust and uptake. To be effective, we need to develop solutions that are ethically responsible, socially responsive, relevant to people of different cultural and social backgrounds, and conveyed to the public in a convincing and straightforward manner. Here, we highlight how ethical approaches, principled decision-making strategies, citizenstakeholder participation, effective science communication, and bioethics education should be used to guide responsible use of agricultural biotechnology.

The oncofetal long noncoding RNA (lncRNA) H19 is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is a subject of controversy. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generated Mdr2-KO/H19-KO double knockout (dKO) mice and followed spontaneous tumor development in the dKO and control Mdr2-KO mice. Cellular localization of H19 and effects of H19 loss in the liver were determined in young and old Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO versus Mdr2-KO females. The expression levels of H19 and Igf2 were variable in nontumor liver tissues of Mdr2-KO females and were significantly downregulated in most matched tumors. In nontumor liver tissue of aged Mdr2-KO females, H19 was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared to dKO females. At an early age, dKO females displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples, H19 expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated with CTNNB1 (beta-catenin) mutations and patients' survival (in tumors). Our data demonstrate that the lncRNA H19 is pro-oncogenic during the development of chronic inflammation-mediated HCC in the Mdr2-KO mouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.

To sustain the nutrient demands of rapid fetal growth, parturition, and milk synthesis, periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis. This process induces an inflammatory response within AT that is resolved as lactation progresses; however, excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases. The suppression of lipolytic action and inflammation, along with amplification of adipogenesis and lipogenesis, serve as prospective therapeutic targets for improving the health of periparturient dairy cows. Generally, the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis, suppresses lipolysis, and increases appetite in mammals. These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows' health, although much is still to be revealed in this context. This review summarizes the current knowledge surrounding the components of the endocannabinoid system, elaborates on the metabolic effects of its activation, and explores the potential to modulate its activity in periparturient dairy cows.

To sustain the nutrient demands of rapid fetal growth, parturition, and milk synthesis, periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis. This process induces an inflammatory response within AT that is resolved as lactation progresses; however, excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases. The suppression of lipolytic action and inflammation, along with amplification of adipogenesis and lipogenesis, serve as prospective therapeutic targets for improving the health of periparturient dairy cows. Generally, the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis, suppresses lipolysis, and increases appetite in mammals. These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows' health, although much is still to be revealed in this context. This review summarizes the current knowledge surrounding the components of the endocannabinoid system, elaborates on the metabolic effects of its activation, and explores the potential to modulate its activity in periparturient dairy cows.

To sustain the nutrient demands of rapid fetal growth, parturition, and milk synthesis, periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis. This process induces an inflammatory response within AT that is resolved as lactation progresses; however, excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases. The suppression of lipolytic action and inflammation, along with amplification of adipogenesis and lipogenesis, serve as prospective therapeutic targets for improving the health of periparturient dairy cows. Generally, the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis, suppresses lipolysis, and increases appetite in mammals. These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows' health, although much is still to be revealed in this context. This review summarizes the current knowledge surrounding the components of the endocannabinoid system, elaborates on the metabolic effects of its activation, and explores the potential to modulate its activity in periparturient dairy cows.

To sustain the nutrient demands of rapid fetal growth, parturition, and milk synthesis, periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis. This process induces an inflammatory response within AT that is resolved as lactation progresses; however, excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases. The suppression of lipolytic action and inflammation, along with amplification of adipogenesis and lipogenesis, serve as prospective therapeutic targets for improving the health of periparturient dairy cows. Generally, the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis, suppresses lipolysis, and increases appetite in mammals. These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows' health, although much is still to be revealed in this context. This review summarizes the current knowledge surrounding the components of the endocannabinoid system, elaborates on the metabolic effects of its activation, and explores the potential to modulate its activity in periparturient dairy cows.

To sustain the nutrient demands of rapid fetal growth, parturition, and milk synthesis, periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis. This process induces an inflammatory response within AT that is resolved as lactation progresses; however, excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases. The suppression of lipolytic action and inflammation, along with amplification of adipogenesis and lipogenesis, serve as prospective therapeutic targets for improving the health of periparturient dairy cows. Generally, the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis, suppresses lipolysis, and increases appetite in mammals. These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows' health, although much is still to be revealed in this context. This review summarizes the current knowledge surrounding the components of the endocannabinoid system, elaborates on the metabolic effects of its activation, and explores the potential to modulate its activity in periparturient dairy cows.

{It has been suggested that lipid lowering therapy causes impaired cognitive changes. The association between the use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk of neurocognitive adverse events remains unclear. This meta-analysis aims to assess neurocognitive safety of PCSK9 inhibitors in randomized controlled trials (RCTs).\\ = -0.0037

{BACKGROUND: It has been suggested that lipid lowering therapy causes impaired cognitive changes. The association between the use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk of neurocognitive adverse events remains unclear. This meta-analysis aims to assess neurocognitive safety of PCSK9 inhibitors in randomized controlled trials (RCTs). METHODS AND RESULTS: The research was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed (MEDLINE), Embase and Cochrane library were searched through September 2019. Selection criteria included RCTs that addressed to neurocognitive adverse events of participants using Alirocumab, Evolocumab or Bococizumab, with a follow up duration of at least 6 months. The search results were screened by two independent reviewers. Safety data from included papers were extracted. Random effects meta-analysis was used to pool results, and meta-regression was utilized when applicable. Twenty-one studies were included. Among 59,733 patients, 31,611 were treated with PCSK9 inhibitors. The follow-up period ranged from 24 weeks to 48 months. No significant difference in the incidence of neurocognitive adverse effects between the groups was identified (RR = 1.01, 95% CI: 0.86-1.19, I(2) = 3%). Similar results were seen in subgroup analysis for each of the medications (alirocumab- RR = 0.88, 95% CI: 0.72-1.08, I(2) = 0%, evolocumab- RR = 1.42, 95% CI: 0.74-2.73, I(2) = 55%). A meta-regression analysis for evolocumab revealed that prolonged study duration was associated with decreased risk for neurocognitive adverse events ($\beta$(week) = -0.0037

{Background: It has been suggested that lipid lowering therapy causes impaired cognitive changes. The association between the use of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk of neurocognitive adverse events remains unclear. This meta-analysis aims to assess neurocognitive safety of PCSK9 inhibitors in randomized controlled trials (RCTs). Methods and results: The research was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed (MEDLINE), Embase and Cochrane library were searched through September 2019. Selection criteria included RCTs that addressed to neurocognitive adverse events of participants using Alirocumab, Evolocumab or Bococizumab, with a follow up duration of at least 6 months. The search results were screened by two independent reviewers. Safety data from included papers were extracted. Random effects meta-analysis was used to pool results, and meta-regression was utilized when applicable. Twenty-one studies were included. Among 59,733 patients, 31,611 were treated with PCSK9 inhibitors. The follow-up period ranged from 24 weeks to 48 months. No significant difference in the incidence of neurocognitive adverse effects between the groups was identified (RR = 1.01, 95% CI: 0.86–1.19

Plant breeders and conservationist depend on knowledge about the genetic variation of their species of interest. Pisum fulvum, a wild relative of domesticated pea, has attracted attention as a genetic resource for crop improvement, yet little information about its diversity in the wild has been published hitherto. We sampled 15 populations of P. fulvum from Israeli natural habitats and conducted genotyping by sequencing to analyse their genetic diversity and adaptive state. We also attempted to evaluate the species past demography and the prospects of its future reaction to environmental changes. The results suggest that genetic diversity of P. fulvum is low to medium and is distributed between well diverged populations. Surprisingly, with 56 % in the total population the selfing rate was found to be significantly lower than expected from a species that is commonly assumed to be a predominant selfer. We found a strong genetic bottleneck during the last glacial period and only limited patterns of isolation by distance and environment, which explained 13 %–18 % of the genetic variation. Despite the weak signatures of genome-wide IBE, 1,354 markers were significantly correlated with environmental factors, 1,233 of which were located within known genes with a nonsynonymous to synonymous ratio of 0.382. Species distribution modelling depicted an ongoing fragmentation and decreased habitable area over the next 80 years under two different socio-economic pathways. Our results suggest that complex interactions of substantial drift and selection shaped the genome of P. fulvum. Climate changeis likely to cause further erosion of genetic diversity in P. fulvum. Systematic ex-situ conservation may be advisable to safeguard genetic variability for future utilization of this species.