Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant

The New Delhi Metallo-β-lactamase (NDM-1) was first reported in 2009 in a Swedish patient. A recent study reported that Klebsiella pneumonia NDM-1 positive strain or Escherichia coli NDM-1 positive strain was highly resistant to all antibiotics tested except tigecycline and colistin. These can no longer be relied on to treat infections and therefore, NDM-1 now becomes potentially a major global health threat

Investigation of the Acetylation Mechanism by GCN5 Histone Acetyltransferase

The histone acetylation of post-translational modification can be highly dynamic and play a crucial role in regulating cellular proliferation, survival, differentiation and motility. Of the enzymes that mediate post-translation modifications, the GCN5 of the histone acetyltransferase (HAT) proteins family that add acetyl groups to target lysine residues within histones, has been most extensively studied. According to the mechanism studies of GCN5 related proteins, two key processes, deprotonation and acetylation, must be involved. However, as a fundamental issue, the structure of hGCN5/AcCoA/pH3 remains elusive. Although biological experiments have proved that GCN5 mediates the acetylation process through the sequential mechanism pathway, a dynamic view of the catalytic process and the molecular basis for hGCN5/AcCoA/pH3 are still not available and none of theoretical studies has been reported to other related enzymes in HAT family. To explore the molecular basis for the catalytic mechanism, computational approaches including molecular modeling, molecular dynamic (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) simulation were carried out. The initial hGCN5/AcCoA/pH3 complex structure was modeled and a reasonable snapshot was extracted from the trajectory of a 20 ns MD simulation, with considering post-MD analysis and reported experimental results. Those residues playing crucial roles in binding affinity and acetylation reaction were comprehensively investigated. It demonstrated Glu80 acted as the general base for deprotonation of Lys171 from H3. Furthermore, the two-dimensional QM/MM potential energy surface was employed to study the sequential pathway acetylation mechanism. Energy barriers of addition-elimination reaction in acetylation obtained from QM/MM calculation indicated the point of the intermediate ternary complex. Our study may provide insights into the detailed mechanism for acetylation reaction of GCN5, and has important implications for the discovery of regulators against GCN5 enzymes and related HAT family enzymes

Prediction and Control of Focal Seizure Spread: Random Walk with Restart on Heterogeneous Brain Networks

Whole-brain models offer a promising method of predicting seizure spread, which is critical for successful surgery treatment of focal epilepsy. Existing methods are largely based on structural connectome, which ignores the effects of heterogeneity in regional excitability of brains. In this study, we used a whole-brain model to show that heterogeneity in nodal excitability had a significant impact on seizure propagation in the networks, and compromised the prediction accuracy with structural connections. We then addressed this problem with an algorithm based on random walk with restart on graphs. We demonstrated that by establishing a relationship between the restarting probability and the excitability for each node, this algorithm could significantly improve the seizure spread prediction accuracy in heterogeneous networks, and was more robust against the extent of heterogeneity. We also strategized surgical seizure control as a process to identify and remove the key nodes (connections) responsible for the early spread of seizures from the focal region. Compared to strategies based on structural connections, virtual surgery with a strategy based on mRWER generated outcomes with a high success rate while maintaining low damage to the brain by removing fewer anatomical connections. These findings may have potential applications in developing personalized surgery strategies for epilepsy

A Modified Flexor Tendon Suture Technique Combining Kessler and Loop Lock Flexor Tendon Sutures

OBJECTIVES: In the present study, a novel single knot tenorrhaphy was developed by combining the modified Kessler flexor tendon suture (MK) with the loop lock technique. METHODS: A total of 48 porcine flexor digitorum profundus tendons were collected and randomly divided into six groups. The tendons were transversely cut and then repaired using six different techniques, the MK method, double knot Kessler-loop lock flexor tendon suture (DK), and single knot Kessler-loop lock flexor tendon suture (SK), each in combination with the epitendinous suture (P), and the same three techniques without P. Furthermore, by performing the load-to-failure tests, the biomechanical properties and the time taken to complete a repair, for each tenorrhaphy, were assessed. RESULTS: Compared to the MK+P method, DK+P was more improved, thereby enhancing the ultimate tensile strength. The SK+P method, which required fewer knots than DK+P, was easier to perform. Moreover, the SK+P repair increased the force at a 2-mm gap formation, while requiring lesser knots than DK+P. CONCLUSION: As opposed to the traditional MK+P method, the SK+P method was improved and exhibited better biomechanical properties, which may facilitate early mobilization after the repair

Integrated analysis reveals important differences in the gut and oropharyngeal microbiota between children with mild and severe hand, foot, and mouth disease

ABSTRACTLittle is known about alternation and difference in gut microbiota between patients with mild and severe hand, foot, and mouth disease (HFMD). We investigated the differences in gut and oropharynx microbiota between mild and severe HFMD in young children and changes in bacterial profiles as the disease progresses from acute to convalescent phase. Forty-two patients with confirmed HFMD were studied, among which 32 had severe HFMD and 10 had mild HFMD. First rectal swabs were collected from all patients at an average of 2 days (acute phase) after the onset of symptoms, and second rectal swabs were collected from 8 severe patients at day 9 (convalescent phase) after the onset. Oropharyngeal swabs were obtained from 10 patients in the acute phase and 6 in the convalescent phase. 16S rRNA sequencing was performed for all 70 samples. Compared with mild HFMD, severe HFMD exhibited significantly decreased diversity and richness of gut microbiota. Gut microbiota bacterial profiles observed in the acute and convalescent phases resembled each other but differed from those in mild cases. Additionally, 50% of patients with severe HFMD in the acute phase harboured a dominant pathobiontic bacterial genus. However, none of the patients with mild HFMD had such bacteria. Similar bacterial compositions in oropharynx microbiota were detected between mild and severe cases. Our findings indicate that severe HFMD exhibits significantly impaired diversity of gut microbiota and frequent gut and oropharyngeal inflammation-inducing bacteria. However, the results should be interpreted with caution as the number of subjects was limited

Clinical characteristics of Coronavirus Disease 2019 patients in Beijing, China

The outbreak of Coronavirus Disease (COVID-19) in Wuhan have affected more than 250 countries and regions worldwide. However, most of the clinical studies have been focused on Wuhan, and little is known about the disease outside of Wuhan in China. In this retrospective cohort study, we report the early clinical features of 80 patients with COVID-19 admitted to the hospital in Beijing. The results show that 27 (33.8%) patients had severe illness. Six (7.5%) patients were admitted to the ICU, and 3 (3.8%) patients died. Forty-eight percent (39/80) of the patients had a history of living/traveling in Wuhan. Patients with severe- illness were significantly older (average age, 71 years old vs 44 years old) and had a high incidence of expectoration (59.3% vs 34.0%), shortness of breath (92.6% vs 9.4%), anorexia (51.9% vs 18.9%) and confusion(18.5% vs 0%) compared with nonsevere patients. The systolic blood pressure (median, 130 mmHg vs 120 mmHg) was higher and the oxygen saturation (median, 98.3% vs 92.0%) was significantly lower in severe patients than nonsevere patients. In addition, myoglobin (median, 56.0 ng/mL vs 35.0 ng/mL), troponin I (median, 0.02 pg/mL vs 0.01 pg/mL), C-reactive protein (median, 69.7 mg/L vs 12.9 mg/L) and neutrophils (median, 3.3×109/L vs 2.2×109/L) were significantly increased, while lymphocytes (median, 0.8×109/L vs 1.2×109/L), albumin (mean, 32.8 g/L vs 36.8 g/L) and the creatinine clearance rate (median, 91.2 vs 108.2 ml/min/1.73m2) were significantly decreased among severe patients. Our study revealed that older patients with high levels of C-reactive protein, myoglobin, troponin I, and neutrophil and high systolic blood pressure as well as low levels of lymphocytes, and albumin and a low creatinine clearance rate and oxygen saturation were more likely to have severe disease

Faded Critical Dynamics in Adult Moyamoya Disease Revealed by EEG and fMRI

Criticality is considered a dynamic signature of healthy brain activity that can be measured on the short-term timescale with neural avalanches and long-term timescale with long-range temporal correlation (LRTC). It is unclear how the brain dynamics change in adult moyamoya disease (MMD). We used BOLD-fMRI for LRTC analysis from 16 hemorrhagic (HMMD) and 34 ischemic (IMMD) patients and 25 healthy controls. Afterwards, they were examined by EEG recordings in the eyes-closed (EC), eyes-open (EO), and working memory (WM) states. The EEG data of 11 HMMD and 13 IMMD patients and 21 healthy controls were in good quality for analysis. Regarding the 4 metrics of neural avalanches (e.g., size (α), duration (β), κ value, and branching parameter (σ)), both MMD subtypes exhibited subcritical states in the EC state. When switching to the WM state, HMMD remained inactive, while IMMD surpassed controls and became supercritical (p<0.05). Regarding LRTC, the amplitude envelope in the EC state was more analogous to random noise in the MMD patients than in controls. During state transitions, LRTC decreased sharply in the controls but remained chaotic in the MMD individuals (p<0.05). The spatial LRTC reduction distribution based on both EEG and fMRI in the EC state implied that, compared with controls, the two MMD subtypes might exhibit mutually independent but partially overlapping patterns. The regions showing decreased LRTC in both EEG and fMRI were the left supplemental motor area of HMMD and right pre-/postcentral gyrus and right inferior temporal gyrus of IMMD. This study not only sheds light on the decayed critical dynamics of MMD in both the resting and task states for the first time but also proposes several EEG and fMRI features to identify its two subtypes

Detection of ABCC1 expression in classical Hodgkin lymphoma is associated with increased risk of treatment failure using standard chemotherapy protocols

BACKGROUND: The mechanisms responsible for chemoresistance in patients with refractory classical Hodgkin lymphoma (CHL) are unknown. ATP-binding cassette (ABC) transporters confer multidrug resistance in various cancers and ABCC1 overexpression has been shown to contribute to drug resistance in the CHL cell line, KMH2. FINDINGS: We analyzed for expression of five ABC transporters ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2 using immunohistochemistry in 103 pre-treatment tumor specimens obtained from patients with CHL. All patients received first-line standard chemotherapy with doxorubicin (Adriamycin®), bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens. ABCC1 was expressed in Hodgkin and Reed-Sternberg (HRS) cells in 16 of 82 cases (19.5%) and ABCG2 was expressed by HRS cells in 25 of 77 cases (32.5%). All tumors were negative for ABCB1, ABCC2 and ABCC3. ABCC1 expression was associated with refractory disease (p = 0.01) and was marginally associated with poorer failure-free survival (p = 0.06). Multivariate analysis after adjusting for hemoglobin and albumin levels and age showed that patients with CHL with HRS cells positive for ABCC1 had a higher risk of not responding to treatment (HR = 2.84, 95%, CI: 1.12-7.19 p = 0.028). CONCLUSIONS: Expression of ABCC1 by HRS cells in CHL patients predicts a higher risk of treatment failure and is marginally associated with poorer failure-free survival using standard frontline chemotherapy regimens