Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation.

PKM2 is a key metabolic enzyme central to glucose metabolism and energy expenditure. Multiple stimuli regulate PKM2's activity through allosteric modulation and post-translational modifications. Furthermore, PKM2 can partner with KDM8, an oncogenic demethylase and enter the nucleus to serve as a HIF1α co-activator. Yet, the mechanistic basis of the exon-10 region in allosteric regulation and nuclear translocation remains unclear. Here, we determined the crystal structures and kinetic coupling constants of exon-10 tumor-related mutants (H391Y and R399E), showing altered structural plasticity and reduced allostery. Immunoprecipitation analysis revealed increased interaction with KDM8 for H391Y, R399E, and G415R. We also found a higher degree of HIF1α-mediated transactivation activity, particularly in the presence of KDM8. Furthermore, overexpression of PKM2 mutants significantly elevated cell growth and migration. Together, PKM2 exon-10 mutations lead to structure-allostery alterations and increased nuclear functions mediated by KDM8 in breast cancer cells. Targeting the PKM2-KDM8 complex may provide a potential therapeutic intervention

Identifying Hendra Virus Diversity in Pteropid Bats

Hendra virus (HeV) causes a zoonotic disease with high mortality that is transmitted to humans from bats of the genus Pteropus (flying foxes) via an intermediary equine host. Factors promoting spillover from bats to horses are uncertain at this time, but plausibly encompass host and/or agent and/or environmental factors. There is a lack of HeV sequence information derived from the natural bat host, as previously sequences have only been obtained from horses or humans following spillover events. In order to obtain an insight into possible variants of HeV circulating in flying foxes, collection of urine was undertaken in multiple flying fox roosts in Queensland, Australia. HeV was found to be geographically widespread in flying foxes with a number of HeV variants circulating at the one time at multiple locations, while at times the same variant was found circulating at disparate locations. Sequence diversity within variants allowed differentiation on the basis of nucleotide changes, and hypervariable regions in the genome were identified that could be used to differentiate circulating variants. Further, during the study, HeV was isolated from the urine of flying foxes on four occasions from three different locations. The data indicates that spillover events do not correlate with particular HeV isolates, suggesting that host and/or environmental factors are the primary determinants of bat-horse spillover. Thus future spillover events are likely to occur, and there is an on-going need for effective risk management strategies for both human and animal health

A Survey of Air-to-Ground Propagation Channel Modeling for Unmanned Aerial Vehicles

In recent years, there has been a dramatic increase in the use of unmanned aerial vehicles (UAVs), particularly for small UAVs, due to their affordable prices, ease of availability, and ease of operability. Existing and future applications of UAVs include remote surveillance and monitoring, relief operations, package delivery, and communication backhaul infrastructure. Additionally, UAVs are envisioned as an important component of 5G wireless technology and beyond. The unique application scenarios for UAVs necessitate accurate air-to-ground (AG) propagation channel models for designing and evaluating UAV communication links for control/non-payload as well as payload data transmissions. These AG propagation models have not been investigated in detail when compared to terrestrial propagation models. In this paper, a comprehensive survey is provided on available AG channel measurement campaigns, large and small scale fading channel models, their limitations, and future research directions for UAV communication scenarios

Women with endometriosis have higher comorbidities: Analysis of domestic data in Taiwan

AbstractEndometriosis, defined by the presence of viable extrauterine endometrial glands and stroma, can grow or bleed cyclically, and possesses characteristics including a destructive, invasive, and metastatic nature. Since endometriosis may result in pelvic inflammation, adhesion, chronic pain, and infertility, and can progress to biologically malignant tumors, it is a long-term major health issue in women of reproductive age. In this review, we analyze the Taiwan domestic research addressing associations between endometriosis and other diseases. Concerning malignant tumors, we identified four studies on the links between endometriosis and ovarian cancer, one on breast cancer, two on endometrial cancer, one on colorectal cancer, and one on other malignancies, as well as one on associations between endometriosis and irritable bowel syndrome, one on links with migraine headache, three on links with pelvic inflammatory diseases, four on links with infertility, four on links with obesity, four on links with chronic liver disease, four on links with rheumatoid arthritis, four on links with chronic renal disease, five on links with diabetes mellitus, and five on links with cardiovascular diseases (hypertension, hyperlipidemia, etc.). The data available to date support that women with endometriosis might be at risk of some chronic illnesses and certain malignancies, although we consider the evidence for some comorbidities to be of low quality, for example, the association between colon cancer and adenomyosis/endometriosis. We still believe that the risk of comorbidity might be higher in women with endometriosis than that we supposed before. More research is needed to determine whether women with endometriosis are really at risk of these comorbidities

Toxoplasma gondii-Induced Activation of EGFR Prevents Autophagy Protein-Mediated Killing of the Parasite

Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome-lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3(+) structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Pediatric Ovarian Torsion in a Medical Center in Taiwan: Case Analysis

Abdominal pain is one of the most common complaints made by patients visiting emergency departments; however, ovarian torsion is an uncommon cause of abdominal pain, especially in young children. Early diagnosis is essential in order to salvage the ovaries. We performed a retrospective analysis of patients under 18 years of age who visited Changhua Christian Hospital with adnexal torsion between June 2003 and June 2010. Methods: Medical records were reviewed for age, associated symptoms, past and present medical histories, physical findings, diagnostic tests performed, clinical course, pathological findings, and diagnoses. Results: A total of 21 patients were identified and included in the analysis; their mean (SD) age was 13.62 (3.75) years. Abdominal pain was the universal symptom. Vomiting or nausea was the second most common symptom (33.3%). The average period between symptom onset and diagnosis was 3.29 (6.39) days. Right-side adnexal torsion occurred in 14 patients, and left-side torsion in seven patients. Ovarian cysts, most often dermoid cysts (e.g., teratomas), were found in 16 patients (76%). Except for one conservatively treated case and one malignant case (adult granulose cell tumor), the other results of the pathological examination were as follows: eight dermoid cysts, two cystadenomas, one follicular cyst, and eight simple cysts. Conclusion: Although it is uncommon, adnexal torsion should be included in the differential diagnosis of lower abdominal pain in all girls, regardless of age. Sonography is helpful for making such a diagnosis. Time is a critical factor, and early laparoscopy or laparotomy may save a viable ovary

Effects of unilateral posterior missing-teeth on the temporomandibular joint and the alignment of cervical atlas.

Cervical atlas alignment changes are associated with craniofacial development. Disturbance of craniofacial development may be associated with temporal mandibular joint function. Therefore, we examined the possibility of a correlation between unilateral missing teeth and morphologic changes of the spine and posture. We collected eighty-nine patients (38 men and 51 women) with unilateral posterior missing teeth and twenty patients without previous orthodontic treatment or missing posterior teeth by tracing and analyzing their panoramic and cephalometric film. We measured the angulations of articular eminence, cranio-cervical angle, and the percentage of the occlusal plane passing through the first and second cervical vertebrae with other morphologic geometric data. The angle of articular eminence inclination was higher in the non-missing teeth group than the missing teeth group (46.66° and 42.28°, respectively). The cranio-cervical angle was smaller in the missing posterior teeth group than the non-missing posterior teeth group (99.81° and 103.27°, respectively). The missing teeth group also showed fewer occlusal planes passing through the intersection of the first and second cervical vertebrae compared to the non-missing teeth group (28.9% and 65%, respectively). Individuals with unilateral missing teeth had lower articular eminence inclination, smaller cranio-cervical angle, and a lower percentage of the occlusal plane passing through the intersection of the first and second cervical vertebrae

The Effect and Safety of Rapid and Gradual Urinary Decompression in Urine Retention: A Systematic Review and Meta-Analysis

Background and objectives: Trials to evaluate the effect and safety of rapid and gradual urinary decompression have been published for decades. Due to inconclusive results, this study aimed to assess whether rapid bladder decompression increased complications in adults with acute urinary retention. Materials and Methods: We searched the Cochrane Library, EMBASE, Google Scholar, and PubMed databases for articles published from the database inception to 31 August 2021. Studies that compared the effects and complication rates of rapid and gradual urinary decompression in adults with acute urinary retention were included. The primary outcome was post-decompression hematuria, while the secondary outcome was circulatory collapse. Meta-analyses were conducted using random effects models. Sensitivity analyses, tests for publication bias, and trial sequential analyses were conducted. The PROSPERO registration number is CRD42021233457. Results: Overall, four articles were included in the comprehensive analysis, and 435 participants met all the eligibility criteria. In the primary meta-analysis of all four study groups, rapid urinary decompression did not increase the risk of post-decompression hematuria (RR = 0.91; 95% CI: 0.62 to 1.35; p = 0.642). The I2 statistic was 0.0% (p = 0.732), indicating no substantial heterogeneity. In the meta-analysis of randomized controlled studies, the result did not change (RR = 0.89; 95% CI: 0.31 to 2.52; p = 0.824). The Egger’s test and Begg test (p = 0.339 and 0.497, respectively) indicated the absence of statistical evidence of publication bias. Leave-one-out sensitivity analysis was conducted and showed the pooled results were robust. In secondary outcome, there were no reported events of circulatory collapse in the current studies. Conclusions: The currently available data suggest that rapid urinary decompression is an effective and safe method with a complication rate similar to that of gradual decompression in an acute urinary retention population. Further large-scale randomized studies are required