Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.

The mitochondrial unfolded protein response (UPRmt) is triggered through eIF2α phosphorylation in mammals. However, the mechanisms of UPRmt activation and the influence of eIF2α phosphorylation on mitochondrial protein translation remain unclear. In this study, we confirmed that the UPRmt is a rapid and specific stress response that occurs through pharmacological induction of eIF2α phosphorylation, along with the phosphorylation of eIF2α, ATF4, and CHOP. Moreover, with the upregulation of the expression of some chaperones, cytochrome P450 enzymes, and DDIT4, as determined by RNA-Seq and ribosome profiling, eIF2α phosphorylation was found to be essential for the expression of ATF4 and CHOP, after which ATF4 trafficked into the nucleus and initiated CHOP expression. In addition, the generation of ROS and mitochondrial morphology were not affected by the GTPP-induced UPRmt. Furthermore, we investigated the mechanism by which HRI kinase-mediated UPRmt is induced by mitochondrial unfolded proteins via CRISPR-Cas9 technology, mitochondrial recruitment of HRI and interaction with other proteins. Moreover, we confirmed that mitochondrial protein translation and mitochondrial protein import were inhibited through eIF2α phosphorylation with the accumulation of unfolded mitochondrial proteins. These findings reveal the molecular mechanism of the UPRmt and its impact on cellular protein translation, which will offer novel insights into the functions of the UPRmt, including its implications for human disease and pathobiology.

Sero-Epidemiology and Associated Risk Factors of Foot-and-Mouth Disease (FMD) in the Northern Border Regions of Pakistan.

The present cross-sectional survey was carried out to investigate the distribution and risk factors of FMD in Pakistan's northern border regions. About 385 serum samples were compiled from small ruminants (239) and large ruminants (146) and tested using 3ABC-Mab-bELISA. An overall apparent seroprevalence of 67.0% was documented. The highest seroprevalence of 81.1% was reported in the Swat, followed by 76.6% in Mohmand, 72.7% in Gilgit, 65.6% in Shangla, 63.4% in Bajaur, 46.6% in Chitral and lowest 46.5% in Khyber region. Statistically significant variations in seroprevalence of 51.5%, 71.8%, 58.3%, and 74.4% were recorded in sheep, goats, cattle, and buffaloes, respectively. From the different risk factors investigated, age, sex, species of animal, seasons, flock/herd size, farming methods, outbreak location, and nomadic animal movement were found to be significantly associated (p < 0.05) with the seroprevalence of FMD. It was concluded that proper epidemiological study, risk-based FMD surveillance in small ruminants, vaccination strategy, control measures for transboundary animal movement, collaborations, and awareness programs need to be practiced in the study regions to investigate the newly circulating virus strains in large and small ruminants and associated factors for the wide seroprevalence to plan proper control policies to bound the consequence of FMD in the region.

Epidemiology, host range, and associated risk factors of monkeypox: an emerging global public health threat.

Based on recent multiregional epidemiological investigations of Monkeypox (MPX), on 24 July 2022, the World Health Organization declared it a global public health threat. Retrospectively MPX was an ignored zoonotic endemic infection to tropical rainforest regions of Western and Central African rural communities until a worldwide epidemic in May 2022 verified the potential threat of monkeypox virus (MPXV) to be propagated across the contemporary world via transnational tourism and animal movements. During 2018-2022, different cases of MPX diagnosed in Nigerian travelers have been documented in Israel, the United Kingdom, Singapore, and the United States. More recently, on 27 September 2022, 66,000 MPX cases have been confirmed in more than 100 non-endemic countries, with fluctuating epidemiological footprinting from retrospective epidemics. Particular disease-associated risk factors fluctuate among different epidemics. The unpredicted appearance of MPX in non-endemic regions suggests some invisible transmission dynamic. Hence, broad-minded and vigilant epidemiological attention to the current MPX epidemic is mandatory. Therefore, this review was compiled to highlight the epidemiological dynamic, global host ranges, and associated risk factors of MPX, concentrating on its epidemic potential and global public health threat.

Advances in therapeutic and vaccine targets for Cryptosporidium: Challenges and possible mitigation strategies.

Cryptosporidium is known to be the second most common diarrheal pathogen in children, causing potentially fatal diarrhea and associated with long-term growth stunting and cognitive deficits. The only Food and Drug Administration-approved treatment for cryptosporidiosis is nitazoxanide, but this drug has not shown potentially effective results in susceptible hosts. Therefore, a safe and effective drug for cryptosporidiosis is urgently needed. Cryptosporidium genome sequencing analysis may help develop an effective drug, but both in vitro and in vivo approaches to drug evaluation are not fully standardized. On the other hand, the development of partial immunity after exposure suggests the possibility of a successful and effective vaccine, but protective surrogates are not precise. In this review, we present our current perspectives on novel cryptosporidiosis therapies, vaccine targets and efficacies, as well as potential mitigation plans, recommendations and perceived challenges.