Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based ...transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer. In the first method, we used limited proteolysis to assess the protein folding stability of each of the mutants compared with the wild-type. In the second method, we used a phosphopeptide pull-down assay to assess the ability of each of the variants to specifically interact with a peptide containing a pSer-X-X-Phe motif, a known functional target of the BRCA1 BRCT domain. Finally, we used transcriptional assays to assess the ability of each BRCT variant to act as a transcriptional activation domain in human cells. Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk.
The BRCT repeats in BRCA1 are essential for its tumor suppressor activity and interact with phosphorylated protein targets containing the sequence pSer-X-X-Phe, where X indicates any residue. The ...structure of the tandem BRCA1 BRCT repeats bound to an optimized phosphopeptide reveals that the N-terminal repeat harbors a conserved BRCT phosphoserine-binding pocket, while the interface between the repeats forms a hydrophobic groove that recognizes the phenylalanine. Crystallographic and biochemical data suggest that the structural integrity of both binding sites is essential for peptide recognition. The diminished peptide-binding capacity observed for cancer-associated BRCA1-BRCT variants may explain the enhanced cancer risks associated with these mutations.
Modification of proteins by post-translational covalent attachment of a single, or chain, of ubiquitin molecules serves as a signaling mechanism for a number of regulatory functions in eukaryotic ...cells. For example, proteins tagged with lysine-63 linked polyubiquitin chains are involved in error-free DNA repair. The catalysis of lysine-63 linked polyubiquitin chains involves the sequential activity of three enzymes (E1, E2, and E3) that ultimately transfer a ubiquitin thiolester intermediate to a protein target. The E2 responsible for catalysis of lysine-63 linked polyubiquitination is a protein heterodimer consisting of a canonical E2 known as Ubc13, and an E2-like protein, or ubiquitin conjugating enzyme variant (UEV), known as Mms2. We have determined the solution structure of the complex formed by human Mms2 and ubiquitin using high resolution, solution state nuclear magnetic resonance (NMR) spectroscopy. The structure of the Mms2-Ub complex provides important insights into the molecular basis underlying the catalysis of lysine-63 linked polyubiquitin chains.
A key step in the signaling cascade responsible for activation of the transcription factor NF‐κB involves Lys63‐linked polyubiquitination of TRAF6. Covalent attachment of ubiquitin (Ub) to TRAF6, and ...subsequent poly(Ub) chain synthesis, is catalyzed by the hUev1a–hUbc13 heterodimer. hUbc13 is a catalytically competent E2 enzyme, and hUev1a is an E2‐like protein that binds substrate Ub. The hUev1a–hUbc13 heterodimer is targeted to TRAF6 through interactions between hUbc13 and the N‐terminal RING domain from TRAF6. Nuclear magnetic resonance (NMR) spectroscopy was used to determine the solution state structure of the RING domain from human TRAF6, and the interaction between hUbc13 and TRAF6 was characterized using NMR chemical shift mapping. The main‐chain dynamics of the RING domain from TRAF6 were studied using 15N NMR relaxation. Analysis of the main‐chain dynamics data indicates that residues within the α‐helix and β‐sheet of the RING domain are as rigid as regions of canonical secondary structure in larger proteins, consistent with the biological role of RING‐domain E3 proteins, which requires that the E3 contain a recognition site for recruitment of E2 ubiquitin conjugation enzymes.
Lys63-linked polyubiquitination of TRAF2 or TRAF6 is an essential step within the signal transduction cascade responsible for activation of p38, c-Jun N-terminal kinase, and the transcription factor ...NF-κB. Attachment of ubiquitin (Ub) to a TRAF, and conjugation of Ub molecules to form a polyUb chain, is catalyzed by a heterodimer composed of a catalytically active E2 (hUbc13), involved in covalent bond transfer, and hUev1a, an E2-like protein involved in substrate Ub binding. Given the key biochemical processes in which hUev1a is involved, it is important to determine the molecular basis of the catalytic mechanism for Lys63-linked protein ubiquitination. Nuclear magnetic resonance (NMR) spectroscopy was used to determine the structure of hUev1a and its interactions with Ub and hUbc13. A structural model for the Ub-hUev1a-hUbc13∼Ub tetramer was developed to gain chemical insight into the synthesis of Lys63-linked Ub chains. We propose that a network of hydrogen bonds involving hUbc13-Asp81 and Ub-Glu64 positions Ub-Lys63 proximal to the active site. Interestingly, restrained molecular dynamics simulations in implicit solvent indicate that deprotonation of Ub-Lys63 does not involve a general Asp or Glu base and may occur when the amino group approaches the thioester carbonyl carbon near the Bürgi−Dunitz trajectory.
The ingested foreign body is a very unusual etiology of liver abscess. This clinical scenario is infrequently reported in the literature. A 66-year-old male patient presented to the hospital because ...of abdominal pain along with 7 days of right upper quadrant pain and intermittent low-grade fever. He was living in an epidemiological area of Fasciola infection. Physical examination showed right hypochondria tenderness without guarding or rebounding. Laboratory results were significant for leukocytosis, predominant neutrophils, and increased inflammatory markers. The liver function tests were within normal limits. Abdominal ultrasonography and CT scan were consistent with a hepatic abscess spread from segment 4B to segment 3. The patient was preliminarily diagnosed with a parasitic hepatic abscess. After management with fluid infusion and antibiotics, the patient was discharged in stable condition. Two weeks later, on the follow-up visit, the patient reported intermittent low-grade fever had persisted. After consulting the CT scan, an abnormal high-attenuation linear structure was identified inside the liver lesion, which is suspected of being a foreign body. Laparoscopic surgery was performed, and a fishbone was removed from the abscess cavity. Perforation was not found in the stomach, duodenum, or in the bowel. One week later, their condition was fully resolved. Liver abscess due to a foreign body should be suspected when a patient has radiology findings suggestive of an abscess, but the clinical presentation does not indicate the common etiologies. Meticulous observation on abdominal CT scans or ultrasonography can help with diagnosis and guide treatment.
Nha Trang Coast is located in the South Central Vietnam and the coastal erosion has occurred rapidly in recent years. Hence it is crucial to accurately monitor the shoreline changes for better ...coastal management and reduction of risks for communities. In this paper, we explored a statistical forecasting model, Seasonal Auto-regressive Integrated Moving Average (SARIMA), and two Machine Learning (ML) models, Neural Network Auto-Regression (NNAR) and Long Short-Term Memory (LSTM), to predict the shoreline variations from surveillance camera images. Compared to the Empirical Orthogonal Function (EOF), the most common method used for predicting shoreline changes from cameras, we demonstrate that the SARIMA, NNAR and LSTM models outperform the EOF model significantly in terms of prediction accuracy. The forecasting performance of the SARIMA model, NNAR model and LSTM model is comparable in both long and short-term predictions. The results suggest that these models are highly effective in detecting shoreline changes from video cameras under extreme weather conditions.
•HPV infection in men having sex with men (MSM) was studied in two cities of Vietnam•Prevalence of any HPV and HPV16/18 among MSM was 32.3% and 11.0%, respectively•High-risk HPV infections in MSM ...were associated with risky sexual behaviours•A targeted HPV vaccination strategy would be beneficial for MSM in Vietnam
Men who have sex with men (MSM) are at risk of human papillomavirus (HPV)-related cancers, while published data are scarce. This study determined HPV prevalence and risk factors in MSM in Vietnam to inform HPV prevention strategies in this key population.
A cross-sectional study of 799 MSM aged 16-50 years was conducted in Vietnam in 2017-2018. Information was collected on risk behaviours, and knowledge of HPV and anal cancer; rectal swabs were taken to detect anal HPV infection. An in-house polymerase chain reaction and Genoflow HPV array test kit were used for HPV detection and genotyping.
The median age of the study participants was 25 years (range 18-52). Overall prevalence of any HPV and HPV16/18 infection was 32.3% and 11.0%, respectively. A higher prevalence of high-risk HPV infection to all 14 types tested was found in Ho Chi Minh City (30.9%) than in Hanoi (18.4%). High-risk HPV infection was associated with inconsistent condom use and history of engaging in sex under the influence of drugs (adjusted odds ratio (aOR), 2.27; 95% CI, 1.48-10.67), as well as having multiple sexual partners (aOR, 1.01; 95% CI, 1.00–1.02).
High-risk anal HPV infections in Vietnamese MSM were significantly associated with risky sexual behaviours. A targeted HPV vaccination strategy would have substantial benefit for MSM in Vietnam.
BACKGROUND/AIMThe aim of this study was to evaluate the safety and efficacy of AFree oral spray, in combination with Standard of Care, in treating mild to moderate COVID-19 patients. This was an ...open-label, single-blinded, and controlled randomized clinical trial.PATIENTS AND METHODSThe study involved 1,252 patients, who were randomly assigned to either the control or study group, with 626 patients in each group. Patients in the control group were treated with Standard of Care recommended by the Ministry of Health of Vietnam, while patients in the study group received AFree oral spray in addition to Standard of Care for a period of 10 days. The clinical progression and outcomes of both groups were compared.RESULTSThe results showed that the proportion of patients with clinical symptoms on the 5th, 7th and 10th days were significantly lower in the study group (45.05%, 3.19% and 0%, respectively) compared to the control group (86.10%, 67.73% and 22.84%, respectively). Additionally, the rate of Real-time PCR test positivity for COVID-19 was significantly lower in the study group compared to the control group on the 4th, 7th, and 10th days (82.75% vs. 98.72%, 9.27% vs. 92.97%, and 1.12% vs. 50.48%, respectively). Furthermore, no side effects or complications related to AFree oral spray were recorded in the study group.CONCLUSIONThe use of AFree oral spray resulted in significant improvements in clinical symptoms, recovery time, and viral clearance in COVID-19 patients with mild to moderate symptoms. This therapy has been shown to be safe and can be used as an adjuvant treatment for COVID-19 as well as other respiratory viral infections.
A prospective randomized, open-label, single-blinded clinical trial was conducted to evaluate the efficacy of AFree on the symptoms and course of moderate and severe COVID-19 in the field hospital.
...Two hundred hospitalized patients diagnosed with COVID-19 were enrolled. The patients were randomized into 100 patients in the interventional AFree group and 100 in the control group. The AFree group patients were treated with AFree oral spray in conjunction with the standard COVID-19 treatment protocol, while the control group of patients were treated with only standard care.
Patients of the AFree group demonstrated a remarkedly faster improvement in all COVID-19-related symptoms, resulting in a shorter time for complete recovery than the control group. More importantly, they showed a shorter time for complete viral clearance. Adding AFree to the standard of care protocol also significantly improved the restoration of taste and smell and reduced lung infiltration. Additionally, the patients in the AFree group also exhibited fewer adverse effects related to treatment.
AFree oral spray is a simple-to-use, safe, and effective adjunctive treatment for moderate and severe COVID-19 cases. AFree oral spray was demonstrated to potentially be effective for COVID-19 prevention.
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