Structural basis for substrate discrimination by E. coli repair enzyme,AlkB

E. coli AlkB, a repair enzyme of the dioxygenase family, catalyses the removal of mutagenic methylated nucleotides from the genome. Known for substrate promiscuity, AlkB''s catalytic mechanism and conformational changes accompanying substrate binding have been extensively dissected. However, the structural parameters of various substrates governing their recognition by AlkB still remain elusive. In this work, through solution-state vibrational spectra of methylated substrates bound to AlkB in combination with computational analysis, we show that the recognition specificity is dictated by the protonation states of the substrates. Specificity is conferred predominantly through hydrogen bonding and cation–π interactions. Furthermore, we report on the interaction of AlkB with normal, unmodified nucleotides, wherein the presence of an exocyclic amino group serves as an essential criterion for the initial process of substrate recognition. Taken together, these results provide a rationale for structural determinants of substrate specificity as well as mode of lesion discrimination employed by AlkB.

Positive charge on methylated nucleotides is a prime criterion for substrate recognition by E. coli AlkB.     

The Diagnosis of Concussion in Pediatric Emergency Departments: A Prospective Multicenter Study

Background

The accurate identification of children with a concussion by emergency physicians is important to initiate appropriate anticipatory guidance and management.

A genome-wide association study of antidepressant response in Koreans

We conducted a three-stage genome-wide association study (GWAS) of response to antidepressant drugs in an ethnically homogeneous sample of Korean patients in untreated episodes of nonpsychotic unipolar depression, mostly of mature onset. Strict quality control was maintained in case selection, diagnosis, verification of adherence and outcome assessments. Analyzed cases completed 6 weeks of treatment with adequate plasma drug concentrations. The overall successful completion rate was 85.5%. Four candidate single-nucleotide polymorphisms (SNPs) on three chromosomes were identified by genome-wide search in the discovery sample of 481 patients who received one of four allowed selective serotonin reuptake inhibitor (SSRI) antidepressant drugs (Stage 1). In a focused replication study of 230 SSRI-treated patients, two of these four SNP candidates were confirmed (Stage 2). Analysis of the Stage 1 and Stage 2 samples combined (n=711) revealed GWAS significance (P=1.60 × 10^-8) for these two SNP candidates, which were in perfect linkage disequilibrium. These two significant SNPs were confirmed also in a focused cross-replication study of 159 patients treated with the non-SSRI antidepressant drug mirtazapine (Stage 3). Analysis of the Stage 1, Stage 2 and Stage 3 samples combined (n=870) also revealed GWAS significance for these two SNPs, which was sustained after controlling for gender, age, number of previous episodes, age at onset and baseline severity (P=3.57 × 10^-8). For each SNP, the response rate decreased (odds ratio=0.31, 95% confidence interval: 0.20–0.47) as a function of the number of minor alleles (non-response alleles). The two SNPs significantly associated with antidepressant response are rs7785360 and rs12698828 of the AUTS2 gene, located on chromosome 7 in 7q11.22. This gene has multiple known linkages to human psychological functions and neurobehavioral disorders. Rigorous replication efforts in other ethnic populations are recommended.     

Oxidative stress and antioxidant capacity in patients with chronic pancreatitis with and without diabetes mellitus

Aim

To determine oxidant stress and antioxidant capacity in chronic pancreatitis (CP) patients with and without diabetes mellitus.

Methods

This study is a secondary data analysis of our earlier study on 127 (male?=?86) patients with CP, grouped as those with diabetes (case; n?=?23) and those without diabetes (control). Markers of antioxidant status included vitamins A and E, total antioxidant capacity (TAC; measured as ferric-reducing ability of plasma [FRAP]), and total glutathione (T-GSH). Markers for oxidative stress included lipid peroxidation, measured as thiobarbituric acid reactive substances (TBARS) and serum superoxide dismutase (s-SOD).

Results

Patients with diabetes were older (mean [SD] age 36.4 [9.7] vs. 29.3 [10.0] years; p?=?0.032), had longer duration of CP [4 (0.3?C21) vs. 3 (0.3?C24) years; p?=?0.07), and had a lower TAC (269.8 [92.4] vs. 355.5 [128.6] ??moles Fe⁺² liberated; p?=?0.003) compared to those without diabetes. In multiple logistic regression analysis taking all exploratory variables, FRAP (<270 ??moles Fe⁺² liberated) was associated with diabetes independent of duration of CP, age of patients, and TBARS levels. However, oxidative stress levels were not different between diabetic and nondiabetic patients.

Conclusions

Diabetes was found to be associated with longer duration of CP and with low antioxidant capacity. Further studies will be needed to evaluate a causal association.     

COVID-19 and Eye: A Review of Ophthalmic Manifestations of COVID-19

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had health implications of unprecedented magnitude. The infection can range from asymptomatic, mild to life threatening respiratory distress. It can affect almost every organ of the body. Ophthalmologists world over are reporting various manifestations of the infection in the eye. This review was undertaken to help ophthalmologists recognize the possible manifestations and the stage of the viral disease when they commonly appear. Literature search was performed for the publications on ophthalmic manifestations of coronavirus disease-19 (COVID-19) between January 1, 2020 and January 31, 2021. 46 case reports, 8 case series, 11 cross sectional/cohort observational studies, 5 prospective interventional studies, 3 animal models/autopsy studies and 6 reviews/meta-analysis were included. Conjunctivitis is the most common manifestation and can develop at any stage of the disease. Direct effect due to virus, immune mediated tissue damage, activation of the coagulation cascade and prothrombotic state induced by the viral infection, the associated comorbidities and drugs used in the management are responsible for the findings in the eye. The viral ribonucleic acid (RNA) has been isolated from ocular tissues but the role of eye as a route for infection is yet to be substantiated. Ophthalmic manifestations may be the presenting feature of COVID-19 infection or they may develop several weeks after recovery. Ophthalmologists should be aware of the possible associations of ocular diseases with SARS-CoV-2 in order to ask relevant history, look for specific signs, advise appropriate tests and thereby mitigate the spread of infection as well as diagnose and initiate early treatment for life and vision threatening complications.     

Coexistence of salivary gland cysticercosis with squamous cell carcinoma of the mandible

Cysticercosis is a parasitic infestation caused by the pork tapeworm larval stage, Cysticercus cellulosae. The majority of the cases present in ocular, cerebral, and subcutaneous locations. We report the presence of cysticercosis inside the submandibular gland in association with squamous cell carcinoma of the inferior alveolar ramus of the mandible. To the best of our knowledge, this is the first case report documenting cysticercosis inside a salivary gland. A 65-year-old male presented with complaints of an ulcerative lesion on the inferior alveolar ramus present for 2 months. Histological examination revealed a keratinizing well-differentiated squamous cell carcinoma involving the alveolar margin and mandible. The histopathological examination of the submandibular gland revealed cysticercosis. This case emphasizes the importance of adequate sampling of all the tissues obtained for associated infectious disorders, more so in immunosuppressed patients, which will help the clinician to manage the case appropriately.