Metabolic bifunctionality of Rv0812 couples folate and peptidoglycan biosynthesis in Mycobacterium tuberculosis

Comparative sequence analysis has enabled the annotation of millions of genes from organisms across the evolutionary tree. However, this approach has inherently biased the annotation of phylogenetically ubiquitous, rather than species-specific, functions. The ecologically unusual pathogen Mycobacterium tuberculosis (Mtb) has evolved in humans as its sole reservoir and emerged as the leading bacterial cause of death worldwide. However, the physiological factors that define Mtb’s pathogenicity are poorly understood. Here, we report the structure and function of a protein that is required for optimal in vitro fitness and bears homology to two distinct enzymes, Rv0812. Despite diversification of related orthologues into biochemically distinct enzyme families, rv0812 encodes a single active site with aminodeoxychorismate lyase and D–amino acid transaminase activities. The mutual exclusivity of substrate occupancy in this active site mediates coupling between nucleic acid and cell wall biosynthesis, prioritizing PABA over D-Ala/D-Glu biosynthesis. This bifunctionality reveals a novel, enzymatically encoded fail-safe mechanism that may help Mtb and other bacteria couple replication and division.     

Combating an invisible enemy:The American military response to global pandemics

The present moment is not the first time that America has found itself at war with a pathogen during a time of international conflict.Between crowded barracks at home and trenches abroad,wartime conditions helped enable the spread of influenza in the fall of 1918 during World War Ⅰ such that an estimated 20％-40％ of U.S.military members were infected.While the coronavirus disease 2019 (COVID-19) pandemic is unparalleled for most of today's population,it is essential to not view it as unprecedented lest the lessons of past pandemics and their effect on the American military be forgotten.This article provides a historical perspective on the effect of the most notable antecedent pandemic,the Spanish Influenza epidemic,on American forces with the goal of understanding the interrelationship of global pandemics and the military,highlighting the unique challenges of the current pandemic,and examining how the American military has fought back against pandemics both at home and abroad,both 100 years ago and today.     

To tell or not to tell – what to do about p.C282Y heterozygotes identified by HFE screening

Hereditary hemochromatosis (HH) is a common preventable disorder of iron overload that can result in liver cirrhosis and reduced lifespan. Most HH is due to homozygosity for the HFE p.C282Y substitution. We conducted a study of screening for p.C282Y in high schools where p.C282Y heterozygotes (CY) individuals were informed of their genotype by letter. We studied whether these individuals understood the implications of their genotype, whether this resulted in anxiety or reduced health perception and whether cascade testing was higher in families of CY than wild‐type homozygous (CC) individuals. We found 586 of 5757 (1 in 10) screened individuals were CY. One month after receiving their result, 83% correctly answered that they have one copy of p.C282Y. There was no adverse change in anxiety or health perception from prior to screening to 1 month after receiving results. Significantly more family members of CY individuals than CC individuals were informed about HH and had testing for HH. In conclusion, we found that informing CY individuals of their genotype does not increase anxiety and the implications are generally well understood. This leads to cascade testing in a minority of families. CY individuals should be informed of their genetic status when identified by population screening.     

Clinical Significance of Serum CA-125 in Korean Females with Ascites

Purpose

Mycobacterium tuberculosis is endemic in Korea. Because tuberculous peritonitis is characterized by ascites, abdominal pain, abdominal mass and elevation of serum CA-125, it can be confused with ovarian malignancies. The aim of this study was to evaluate the significance of serum CA-125 level in the differential diagnosis of tuberculous peritonitis and ovarian malignancy in a Mycobacterium tuberculosis-endemic area.

Materials and Methods

The medical records of patients diagnosed with tuberculous peritonitis (n=48) or epithelial ovarian malignancy (n=370) at Samsung Medical Center from January 2000 to October 2009 were retrospectively reviewed.

Results

Median serum CA-125 level in the epithelial ovarian cancer group was significantly higher than that in the tuberculous peritonitis group (p≤0.01). Only one patient (2.1%) in the tuberculous peritonitis group had a serum CA-125 level over 2000 U/mL. However, 109 patients (29.5%) in the epithelial ovarian cancer group had a serum CA-125 level over 2000 U/mL. At the CA-125 ranges of 400 to 599 and 600 to 799, the proportions of those with tuberculous peritonitis were 24% and 21.9%, respectively. At a serum CA-125 level over 1000 U/mL, however, the proportion of tuberculous peritonitis was much lower (2.1%).

Conclusion

Tuberculous peritonitis should be considered in the evaluation of female patients with ascites and high serum CA-125.     

Gastric Autoantigenic Proteins in Helicobacter Pylori Infection

Purpose

This study tried to identify novel gastric autoimmune antigens that might be involved in aggravating the atrophic gastritis among patients with Helicobacter pylori infection using two-dimensional immunoblotting analysis.

Materials and Methods

Proteins from gastric mucosal antrectomy specimens and AGS cells (gastric adenocarcinoma cell lines derived from a Caucasian patient who had received no prior therapy) were 2-dimensionally immunoblotted separately with a pool of 300 sera from H. pylroi-infected patients at Gyeongsang National University Hospital.

Results

Thirty-eight autoantigenic proteins including alcohol dehydrogenase [NADP+], alpha enolase, gastrokine-1, gastric triacylglycerol lipase, heat shock 70 kDa protein 1, and peroxiredoxin-2 were identified in the gastric mucosal tissue. Fourteen autoantigenic proteins including programmed cell death 6-interacting protein, serum albumin and T-complex protein 1 subunit gamma were identified in the AGS cells. Albumin, alpha-enolase, annexin A3, cytoplasmic actin 1, heat shock cognate 71 kDa protein and leukocyte elastase inhibitor were commonly observed autoantigenic proteins in both gastric mucosal tissue and AGS cells. Alpha-enolase, glutathione S-transferase P, heat shock cognate 71 kDa protein, heat shock 70 kDa protein 1, human mitochondrial adenosine triphosphate synthase (ATP) subunit beta, mitochondrial 60 kDa heat shock protein, peroxiredoxin-2, 78 kDa glucose-regulated protein precursor, tyrosine-protein phosphatase non-receptor type 11 and Tryptophan-Aspartic acid (WD) repeat-containing protein 1 showed 60% or higher amino acid positivity.

Conclusion

These newly identified gastric autoimmune antigens might be useful in the control and prevention of gastroduodenal disorders, and might be valuable in breaking the vicious circle that exists in gastroduodenal disorders if their pathophysiological roles could be understood in the progress of chronic atrophic gastritis, gastroduodenal ulcers, intestinal metaplasia, and gastric carcinogenesis.     

Age-dependent neurological phenotypes in a mouse model of PRRT2-related diseases

Paroxysmal kinesigenic dyskinesia is an episodic movement disorder caused by dominant mutations in the proline-rich transmembrane protein PRRT2, with onset in childhood and typically with improvement or resolution by middle age. Mutations in the same gene may also cause benign infantile seizures, which begin in the first year of life and typically remit by the age of 2 years. Many details of PRRT2 function at the synapse, and the effects of mutations on neuronal excitability in the pathophysiology of epilepsy and dyskinesia, have emerged through the work of several groups over the last decade. However, the age dependence of the phenotypes has not been explored in detail in transgenic models. Here, we report our findings in heterozygous and homozygous Prrt2 knockout mice that recapitulate the age dependence of dyskinesia seen in the human disease. We show that Prrt2 deletion reduces the levels of synaptic proteins in a dose-dependent manner that is most pronounced at postnatal day 5 (P5), attenuates at P60, and disappears by P180. In a test for foot slippage while crossing a balance beam, transient loss of coordination was most pronounced at P60 and less prominent at age extremes. Slower traverse time was noted in homozygous knockout mice only, consistent with the ataxia seen in rare individuals with biallelic loss of function mutations in Prrt2. We thus identify three age-dependent phenotypic windows in the mouse model, which recapitulate the pattern seen in humans with PRRT2-related diseases.