Natural resources-environmental technology-ecological footprint nexus: Does natural resources rents diversification make a difference?

Researchers have shown a growing interest in investigating the environmental consequences of energy exploitation and green technologies, particularly in light of the escalating severity of climate change issues in recent times. However, these researches remain incomplete in terms of the various elements and mechanisms of impact. By assessing the novel facet of resource diversification, this study has assessed the direct and indirect effects of this feature on environmental quality. This study used the Moment quantile Regression technique to examine data from 31 OECD nations spanning the time frame of 2009-2019. The findings indicate that resource diversification has an adverse effect on environmental quality, however this effect is not homogeneously observed across all countries. Countries with favorable environmental conditions will encounter a more pronounced influence from the diversification of natural resources extraction. This study further demonstrates that expanding the variety of natural resource exploitation will amplify the negative effects of resource exploitation on environmental quality. Furthermore, the degree of environmental technology exerts a beneficial impact on environmental quality across various degrees of environmental quality. Our findings offer several insightful policies for natural resources management in the context of the ongoing industrial revolution.

Patterns of psychotropic drug use in veterans with epilepsy: Do drug interactions matter?

RATIONALE: Patients with epilepsy are likely to suffer from psychiatric comorbidities, including depression and anxiety. They often require treatment with multiple psychotropic drugs (PDs). While it is clear that CYP-inducing ASMs (EIASMs) can increase the oral clearance of multiple medications (thus lowering systemic exposure), it is less clear that all PK interactions are clinically meaningful (e.g. lower efficacy). As a first step in addressing this issue, this study sought to quantify the potential impact of ASM choice, whether EIASM or non-inducer (NIASM), on surrogate markers of suggestive of clinical use, including resultant antidepressant (AD) or antipsychotic (AP) dose, frequency of combination use of AD & AP, and number of multiple drug switches of PDs. Our hypothesis is that because of PK interactions, EIAED treatment would be associated with higher psychotropic drug doses, more frequent Rx adjustments and poly psychotropic comedication, all in order to optimize therapeutic response. METHODS: Using VA pharmacy and national encounter databases, veterans with epilepsy were identified based on having a seizure diagnosis and being prescribed concomitantly an ASM and a psychotropic drug for at least 365 days between 10/1/2010 and 9/30/2014. Patients for whom psychotropic drugs were prescribed any time between beginning and end prescriptions dates of ASMs were considered. Among those, patients receiving both an EIASM + NEIASM concomitantly were categorized with the EIASM group. Patients were evaluated for AD only, AP only and both (AD & AP). To compute average drug doses per day, averages for each patient were computed and averaged again. Multiple drug switches were defined to be for patients who had been prescribed more than three psychotropic drugs during the observation period. Pearson's Chi-Square test was used to compare relative proportions of AD, AP and AD + AP in both groups. RESULTS: In all, 16,188 patients were identified (57.0% on EIASM, 43.0% on NIASM) with a mean age of 58.7 years (91.2% male). A larger proportion of patients on EIASM received mono treatment with any psychotropic drug, as compared to NIASM (42.0% vs 36.1%). Among all, 59.6% received AD only, 6.5% received AP only, and 33.8% received both concurrently. Of EIASM, 62.5% were on AD, 5.9% on AP, and 31.7% on both AP & AD. For NIASM, 55.9% received AD, 7.4% AP, and 36.7% on AD & AP.Chi-square showed that the distribution of PD was statistically different between EIASM and NIASM groups. Z tests showed that each difference (AD, AP and both) in proportions was statistically significant (p values (4 tests, one Chi-square, 3 Z tests <0.001) between EIASM vs NIASM. Interestingly, mean doses of AD or AP did not appear to differ between ASM groups. CONCLUSIONS: Concurrent psychotropic drug use is quite common in the VA population with epilepsy, and a large number of patients still receive enzyme-inducing ASMs that may complicate other medical therapies. Interestingly, in seeming contradiction to our hypothesis, mean daily doses of either AD or AP did not appear to differ between inducers vs non-inducers. Similarly, use of polytherapy, and/or multiple trials of various psychotropic drugs did not appear increased in the CYP-induced group. In fact, combination therapy of AD + AP was higher in NIASM than EIASM. These data suggest that perhaps these types of PK interactions may not in fact result in meaningful clinical differences. Since the present analyses did not include clinical psychiatric measures, future analyses examining direct clinical outcomes are clearly warranted.

Stromal Vascular Fraction and Mesenchymal Stem Cells from Human Adipose Tissue: A Comparison of Immune Modulation and Angiogenic Potential.

INTRODUCTION: In recent years, both stromal vascular fraction (SVF) from adipose tissue and mesenchymal stem cells (MSC) from adipose tissues were extensively used in both preclinical and clinical treatment for various diseases. Some studies reported differences in treatment efficacy between SVFs and MSCs in animals as well as in humans. Therefore, this study is aimed to evaluate the immune modulation and angiogenic potential of SVFs and MSCs from the same SVF samples to support an explanation when SVFs or MSCs should be used. METHODS: The adipose tissue samples from ten female donors with consent forms were collected. SVFs from these samples were isolated according to the published protocols. The existence of mesenchymal cells that positive with CD44, CD73, CD90, and CD105 and endothelial progenitor cells that positive with CD31 and CD34 was determined using flow cytometry. Three samples of SVFs with similar percentages of mesenchymal cell portion and endothelial progenitor cell portion were used to isolate MSCs. Obtained MSCs were confirmed as MSCs using the ISCT minimal criteria. To compare the immune modulation of SVF and MSCs, the mixed lymphocyte assay was used. The lymphocyte proliferation, as well as IFN-gamma and TNF-alpha concentrations, were determined. To compare the angiogenic potential, the angiogenesis in quail embryo assay was used. The angiogenesis efficacy was measured based on the vessel areas formed in the embryos after 7 days. RESULTS: The results showed that all SVF samples contained the portions of mesenchymal cells and endothelial progenitor cells. MSCs from SVFs meet all minimal criteria of MSCs that suggested by ISCT. MSCs from SVFs efficiently suppressed the immune cell proliferation compared to the SVFs, especially at ratios of 1:4 (1 MSCs: 4 immune cells). MSCs also inhibited the IFN-gamma and TNF-alpha production more efficiently than SVFs (p < 0.05). However, in quail embryo models, SVFs triggered the angiogenesis and neovessel formation better than MSCs with more significant vessel areas after 7 days (p < 0.05). CONCLUSION: This study suggested that SVFs and MSCs have different potentials for immune modulation and angiogenesis. SVFs help the angiogenesis better than MSCs, while MSCs displayed the more significant immune modulation. These results can guide the usage of SVFs or MSCs in disease treatment.

The impact of intensive laparoscopic training course with structured assessment and immediate feedback on residents' operative performance in animal lab.

INTRODUCTION: The objective of this study was to examine the impact of an intensive laparoscopic training course incorporating structured assessment and immediate feedback on residents' operative performance in animal lab. METHODS: Surgical residents participated in a 2-day intensive laparoscopic training course. They performed the same procedures on two consecutive days on live pigs. Junior residents (PGY1-2) performed laparoscopic cholecystectomy and incisional hernia repair and the senior residents (PGY3-5) performed laparoscopic Nissen fundoplication, splenectomy, and low anterior colon resection. Assessment tools with proven validity evidence (global and procedure-specific rating tools for operative assessment of laparoscopic skills) were used to assess their operative performance. Faculty assessment and self-assessments were completed immediately after each procedure on both days. The Wilcoxon rank test was used to examine the effect of training on resident performance after one repetition. RESULTS: Forty surgical residents (20 junior and 20 senior residents) participated. There was a significant improvement in general laparoscopic skills during incisional hernia repair and Nissen fundoplication using global rating scales (p < 0.05). Moreover, there was an improvement in their performance during cholecystectomy, incisional hernia repair, and low anterior colectomy when procedure-specific skills assessments were used (p < 0.05). There was a positive correlation between residents' self-reported confidences and their operative performance CONCLUSION: Trainees showed significant improvements in performance in general and procedure-specific laparoscopic skills in a wide range of procedures after an intensive training course. This study demonstrates the benefit of a structured training curriculum in improving operative performance in basic and advanced laparoscopic skills in a simulated environment. Future studies are needed to examine the duration of training required to achieve skill retention and competency.

Survival after traumatic out-of-hospital cardiac arrest in Vietnam: a multicenter prospective cohort study.

BACKGROUND: Pre-hospital services are not well developed in Vietnam, especially the lack of a trauma system of care. Thus, the prognosis of traumatic out-of-hospital cardiac arrest (OHCA) might differ from that of other countries. Although the outcome in cardiac arrest following trauma is dismal, pre-hospital resuscitation efforts are not futile and seem worthwhile. Understanding the country-specific causes, risk, and prognosis of traumatic OHCA is important to reduce mortality in Vietnam. Therefore, this study aimed to investigate the survival rate from traumatic OHCA and to measure the critical components of the chain of survival following a traumatic OHCA in the country. METHODS: We performed a multicenter prospective observational study of patients (> 16 years) presenting with traumatic OHCA to three central hospitals throughout Vietnam from February 2014 to December 2018. We collected data on characteristics, management, and outcomes of patients, and compared these data between patients who died before hospital discharge and patients who survived to discharge from the hospital. RESULTS: Of 111 eligible patients with traumatic OHCA, 92 (82.9%) were male and the mean age was 39.27 years (standard deviation: 16.38). Only 5.4% (6/111) survived to discharge from the hospital. Most cardiac arrests (62.2%; 69/111) occurred on the street or highway, 31.2% (29/93) were witnessed by bystanders, and 33.7% (32/95) were given cardiopulmonary resuscitation (CPR) by a bystander. Only 29 of 111 patients (26.1%) were taken by the emergency medical services (EMS), 27 of 30 patients (90%) received pre-hospital advanced airway management, and 29 of 53 patients (54.7%) were given resuscitation attempts by EMS or private ambulance. No significant difference between patients who died before hospital discharge and patients who survived to discharge from the hospital was found for bystander CPR (33.7%, 30/89 and 33.3%, 2/6, P > 0.999; respectively) and resuscitation attempts (56.3%, 27/48, and 40.0%, 2/5, P = 0.649; respectively). CONCLUSION: In this study, patients with traumatic OHCA presented to the ED with a low rate of EMS utilization and low survival rates. The poor outcomes emphasize the need for increasing bystander first-aid, developing an organized trauma system of care, and developing a standard emergency first-aid program for both healthcare personnel and the community.

Suspected heparin-induced thrombocytopenia in a COVID-19 patient on extracorporeal membrane oxygenation support: a case report.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) support can be life-saving in critically ill COVID-19 patients. However, there are many complications associated with this procedure, including Heparin-induced thrombocytopenia (HIT.) Despite its rarity in ECMO cases, HIT can lead to devastating consequences and is difficult to manage. CASE PRESENTATION: In this report, we present a case of a COVID-19 patient on ECMO support who was diagnosed with HIT and required intensive treatment. Initially, HIT was only suspected due to newly-developed thrombocytopenia and oxygenator dysfunction, with thrombi observed later. Regarding his treatment, since there was no recommended replacement to heparin available to us at the time of diagnosis, we decided to use rivaroxaban temporarily. No adverse events were recorded during that period. The patient was able to make a full recovery. CONCLUSION: HIT may jeopardize patient's care during ECMO. As COVID-19 may bring about a surge in the number of patients requiring ECMO support, we need consented guidance to optimize treatment in this specific situation.

Self-management of Epilepsy: A Systematic Review.

Background: Although self-management is recommended for persons with epilepsy, its optimal strategies and effects are uncertain. Purpose: To evaluate the components and efficacy of self-management interventions in the treatment of epilepsy in community-dwelling persons. Data Sources: English-language searches of MEDLINE, Cochrane Central Register of Controlled Trials, PsycINFO, and CINAHL in April 2018; the MEDLINE search was updated in March 2019. Study Selection: Randomized and nonrandomized comparative studies of self-management interventions for adults with epilepsy. Data Extraction: An investigator assessed study characteristics; intervention details, including 6 components of self-management; and outcomes, which were verified by a second reviewer. Risk of bias (ROB) was assessed independently by 2 investigators. Data Synthesis: 13 randomized and 2 nonrandomized studies (2514 patients) evaluated self-management interventions. Interventions were delivered primarily in group settings, used a median of 4 components, and followed 2 general strategies: 1 based on education and the other on psychosocial therapy. Education-based approaches improved self-management behaviors (standardized mean difference, 0.52 [95% CI, 0.0 to 1.04]), and psychosocial therapy-based approaches improved quality of life (mean difference, 6.64 [CI, 2.51 to 10.77]). Overall, self-management interventions did not reduce seizure rates, but 1 educational intervention decreased a composite of seizures, emergency department visits, and hospitalizations. Limitation: High ROB in most studies, incomplete intervention descriptions, and studies limited to English-language publications. Conclusion: There is limited evidence that self-management strategies modestly improve some patient outcomes that are important to persons with epilepsy. Overall, self-management research in epilepsy is limited by the range of interventions tested, the small number of studies using self-monitoring technology, and uncertainty about components and strategies associated with benefit. Primary Funding Source: U.S. Department of Veterans Affairs. (PROSPERO: CRD42018098604).

Confirm or refute?: A comparative study on citation sentiment classification in clinical research publications.

Quantifying scientific impact of researchers and journals relies largely on citation counts, despite the acknowledged limitations of this approach. The need for more suitable alternatives has prompted research into developing advanced metrics, such as h-index and Relative Citation Ratio (RCR), as well as better citation categorization schemes to capture the various functions that citations serve in a publication. One such scheme involves citation sentiment: whether a reference paper is cited positively (agreement with the findings of the reference paper), negatively (disagreement), or neutrally. The ability to classify citation function in this manner can be viewed as a first step toward a more fine-grained bibliometrics. In this study, we compared several approaches, varying in complexity, for classification of citation sentiment in clinical trial publications. Using a corpus of 285 discussion sections from as many publications (a total of 4,182 citations), we developed a rule-based method as well as supervised machine learning models based on support vector machines (SVM) and two variants of deep neural networks; namely, convolutional neural network (CNN) and bidirectional long short-term memory (BiLSTM). A CNN model augmented with hand-crafted features yielded the best performance (0.882 accuracy and 0.721 macro-F1 on held-out set). Our results show that baseline performances of traditional supervised learning algorithms and deep neural network architectures are similar and that hand-crafted features based on sentiment dictionaries and rhetorical structure allow neural network approaches to outperform traditional machine learning approaches for this task. We make the rule-based method and the best-performing neural network model publicly available at: https://github.com/kilicogluh/clinical-citation-sentiment.

Quantum Chiral Higher Spin Gravity.

An example of a higher spin gravity in four-dimensional flat space has recently been constructed by D. Ponomarev and E. D. Skvortsov, J. Phys. A, 50, 095401(2017). This theory is chiral and the action is written in the light-cone gauge. The theory has certain stringy features, e.g., admits Chan-Paton factors. We show that the theory is consistent, both at the classical and quantum level. Even though the interactions are nontrivial, due to the coupling conspiracy all tree level amplitudes vanish on shell. The loop corrections also vanish. Therefore, the full quantum S matrix is one and the theory is consistent with the numerous no-go theorems. This provides the first example of a (quantum) interacting higher spin gravity with an action. We argue that higher spin gravities in anti-de Sitter space should display the same features.

Child Desire Among Men and Women Living with HIV/AIDS in the Traditional Culture of Vietnam.

In various settings, heterogeneity in fertility rates among HIV-affected couples highlights the importance of understanding contextual factors to inform program planning and implementation. We interviewed 1016 patients with HIV/AIDS at seven clinics in Vietnam to assess their desire to have a(nother) child and willingness to pay (WTP) for prevention of mother to child transmission (PMTCT) services. One-fifth of participants reported their desire for a(another) child and this was slightly higher among men than women. Factors associated with the desire to have a(nother) child of HIV/AIDS patients included (1) not yet have a child or a son, (2) provincial and district-level service, (3) income per capita, (4) marital status and (5) history of drug injection. The average WTP for PMTCT service was US $179 (95% CI 161-197). The study highlights the need for interventions on social, cultural barriers, improved accessibility and outcomes of counseling, and better care and treatment services for couples and child affected by HIV/AIDS.

Quality of life profile of general Vietnamese population using EQ-5D-5L.

BACKGROUND: Health-related quality of life (HRQOL) is a vital benchmark to assess the effects of health interventions and policies. Measuring HRQOL of the general population is essential to establish a reference for health outcomes evaluations. However, evidence on HRQOL of general populations in low and middle income countries is very limited. This study aimed to measure HRQOL of the Vietnamese population by using the EuroQol-5 dimensions-5 levels (EQ-5D-5L) instrument and determine its associated factors. METHODS: A cross-sectional study was performed in Hanoi with 1571 residences in Hanoi, the capital city of Vietnam. EQ-5D-5L and EQ- visual analogue scale (EQ-VAS) were used to assess HRQOL. Potential covariates included socio-demographic characteristics, having acute symptoms in the last four weeks, chronic diseases in the last three months, having multiple health issues, and health service utilisation in the last twelve months. A generalized linear model was employed to identify the association between HRQOL and covariates. RESULTS: Overall, the mean EQ-5D utility index was 0.91 (SD = 0.15), and the mean EQ-VAS score was 87.4 (SD = 14.3). The highest proportion of respondents reporting any problems was in Usual activities (24.3%), followed by Anxiety/Depression (15.2%) and Pain/Discomfort (10.0%), while the lowest percentage was in Self-care (2.5%). Lower HRQOL composite scores were related to unemployment, lower income, higher education, living in urban areas, having chronic diseases, having multiple health issues and using health service. For any health problem self-reported by respondents, the health utility reduced by 0.02 (respiratory diseases) to 0.15 (musculoskeletal diseases). CONCLUSIONS: Health utility of the general population and reductions for self-reported health problems in this study are useful for future population health evaluations and comparisons. It also informs the development of interventions to reduce health problems of the general population.

Predicting mental conditions based on "history of present illness" in psychiatric notes with deep neural networks.

BACKGROUND: Applications of natural language processing to mental health notes are not common given the sensitive nature of the associated narratives. The CEGS N-GRID 2016 Shared Task in Clinical Natural Language Processing (NLP) changed this scenario by providing the first set of neuropsychiatric notes to participants. This study summarizes our efforts and results in proposing a novel data use case for this dataset as part of the third track in this shared task. OBJECTIVE: We explore the feasibility and effectiveness of predicting a set of common mental conditions a patient has based on the short textual description of patient's history of present illness typically occurring in the beginning of a psychiatric initial evaluation note. MATERIALS AND METHODS: We clean and process the 1000 records made available through the N-GRID clinical NLP task into a key-value dictionary and build a dataset of 986 examples for which there is a narrative for history of present illness as well as Yes/No responses with regards to presence of specific mental conditions. We propose two independent deep neural network models: one based on convolutional neural networks (CNN) and another based on recurrent neural networks with hierarchical attention (ReHAN), the latter of which allows for interpretation of model decisions. We conduct experiments to compare these methods to each other and to baselines based on linear models and named entity recognition (NER). RESULTS: Our CNN model with optimized thresholding of output probability estimates achieves best overall mean micro-F score of 63.144% for 11 common mental conditions with statistically significant gains (p<0.05) over all other models. The ReHAN model with interpretable attention mechanism scored 61.904% mean micro-F1 score. Both models' improvements over baseline models (support vector machines and NER) are statistically significant. The ReHAN model additionally aids in interpretation of the results by surfacing important words and sentences that lead to a particular prediction for each instance. CONCLUSIONS: Although the history of present illness is a short text segment averaging 300 words, it is a good predictor for a few conditions such as anxiety, depression, panic disorder, and attention deficit hyperactivity disorder. Proposed CNN and RNN models outperform baseline approaches and complement each other when evaluating on a per-label basis.

High-copy bacterial plasmids diffuse in the nucleoid-free space, replicate stochastically and are randomly partitioned at cell division.

Bacterial plasmids play important roles in the metabolism, pathogenesis and bacterial evolution and are highly versatile biotechnological tools. Stable inheritance of plasmids depends on their autonomous replication and efficient partition to daughter cells at cell division. Active partition systems have not been identified for high-copy number plasmids, and it has been generally believed that they are partitioned randomly at cell division. Nevertheless, direct evidence for the cellular location of replicating and nonreplicating plasmids, and the partition mechanism has been lacking. We used as model pJHCMW1, a plasmid isolated from Klebsiella pneumoniae that includes two ß-lactamase and two aminoglycoside resistance genes. Here we report that individual ColE1-type plasmid molecules are mobile and tend to be excluded from the nucleoid, mainly localizing at the cell poles but occasionally moving between poles along the long axis of the cell. As a consequence, at the moment of cell division, most plasmid molecules are located at the poles, resulting in efficient random partition to the daughter cells. Complete replication of individual molecules occurred stochastically and independently in the nucleoid-free space throughout the cell cycle, with a constant probability of initiation per plasmid.

Isolation and proliferation of umbilical cord tissue derived mesenchymal stem cells for clinical applications.

Umbilical cord (UC) is a rich source of rapidly proliferating mesenchymal stem cells (MSCs) that are easily cultured on a large-scale. Clinical applications of UC-MSCs include graft-versus-host disease, and diabetes mellitus types 1 and 2. UC-MSCs should be isolated and proliferated according to good manufacturing practice (GMP) with animal component-free medium, quality assurance, and quality control for their use in clinical applications. This study developed a GMP standard protocol for UC-MSC isolation and culture. UC blood and UC were collected from the same donors. Blood vasculature was removed from UC. UC blood was used as a source of activated platelet rich plasma (aPRP). Small fragments (1-2 mm(2)) of UC membrane and Wharton's jelly were cut and cultured in DMEM/F12 medium containing 1 % antibiotic-antimycotic, aPRP (2.5, 5, 7.5 and 10 %) at 37 °C in 5 % CO2. The MSC properties of UC-MSCs at passage 5 such as osteoblast, chondroblast and adipocyte differentiation, and markers including CD13, CD14, CD29, CD34, CD44, CD45, CD73, CD90, CD105, and HLA-DR were confirmed. UC-MSCs also were analyzed for karyotype, expression of tumorigenesis related genes, cell cycle, doubling time as well as in vivo tumor formation in NOD/SCID mice. Control cells consisted of UC-MSCs cultured in DMEM/F12 plus 1 % antibiotic-antimycotic, and 10 % fetal bovine serum (FBS). All UC-MSC (n = 30) samples were successfully cultured in medium containing 7.5 and 10 % aPRP, 92 % of samples grew in 5.0 % aPRP, 86 % of samples in 2.5 % aPRP, and 72 % grew in 10 % FBS. UC-MSCs in these four groups exhibited similar marker profiles. Moreover, the proliferation rates in medium with PRP, especially 7.5 and 10 %, were significantly quicker compared with 2.5 and 5 % aPRP or 10 % FBS. These cells maintained a normal karyotype for 15 sub-cultures, and differentiated into osteoblasts, chondroblasts, and adipocytes. The analysis of pluripotent cell markers showed UC-MSCs maintained the expression of the oncogenes Nanog and Oct4 after long term culture but failed to transfer tumors in NOD/SCID mice. Replacing FBS with aPRP in the culture medium for UC tissues allowed the successful isolation of UC-MSCs that satisfy the minimum standards for clinical applications.

Inhibition of aminoglycoside 6'-N-acetyltransferase type Ib-mediated amikacin resistance in Klebsiella pneumoniae by zinc and copper pyrithione.

The in vitro activity of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] was inhibited by CuCl2 with a 50% inhibitory concentration (IC50) of 2.8 µM. The growth of an amikacin-resistant Klebsiella pneumoniae strain isolated from a neonate with meningitis was inhibited when amikacin was supplemented by the addition of Zn(2+) or Cu(2+) in complex with the ionophore pyrithione. Coordination complexes between cations and ionophores could be developed for their use, in combination with aminoglycosides, to treat resistant infections.

Inhibition of aminoglycoside 6'-N-acetyltransferase type Ib by zinc: reversal of amikacin resistance in Acinetobacter baumannii and Escherichia coli by a zinc ionophore.

In vitro activity of the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] was inhibited by ZnCl2 with a 50% inhibitory concentration (IC50) of 15 µM. Growth of Acinetobacter baumannii or Escherichia coli harboring aac(6')-Ib in cultures containing 8 µg/ml amikacin was significantly inhibited by the addition of 2 µM Zn(2+) in complex with the ionophore pyrithione (ZnPT).

A new species of the Cyrtodactyluschauquangensis species group (Squamata, Gekkonidae) from Lao Cai Province, Vietnam.

We describe a new species of the genus Cyrtodactylus based on five adult specimens from Bac Ha District, Lao Cai Province, northern Vietnam. Cyrtodactyluslucisp. nov. is distinguished from the remaining Indochinese bent-toed geckos by a combination of the following morphological characteristics: medium size (SVL up to 89.5 mm); dorsal tubercles in 17-19 irregular transverse rows; ventral scales in 32-34 longitudinal rows at midbody; precloacal pores present in both sexes, 9 or 10 in males, 8 or 9 in females; 12-15 enlarged femoral scales on each thigh; femoral pores 9-12 in males, 5-10 in females; postcloacal tubercles 2-4; lamellae under toe IV 21-23; dorsal pattern consisting of 5 or 6 irregular dark bands, a thin neckband without V-shape or triangle shape in the middle, top of head with dark brown blotches; subcaudal scales transversely enlarged. Molecular phylogenetic analyses recovered the new species as the sister taxon to C.gulinqingensis from Yunnan Province, China, with strong support from all analyses and the two taxa are separated by approximately 8.87-9.22% genetic divergence based on a fragment of the mitochondrial ND2 gene. This is the first representative of Cyrtodactylus known from Lao Cai Province.

Structure-Activity Relationship of Pyrrolidine Pentamine Derivatives as Inhibitors of the Aminoglycoside 6'-N-Acetyltransferase Type Ib.

Resistance to amikacin and other major aminoglycosides is commonly due to enzymatic acetylation by the aminoglycoside 6'-N-acetyltransferase type I enzyme, of which type Ib [AAC(6')-Ib] is the most widespread among Gram-negative pathogens. Finding enzymatic inhibitors could be an effective way to overcome resistance and extend the useful life of amikacin. Small molecules possess multiple properties that make them attractive for drug development. Mixture-based combinatorial libraries and positional scanning strategy have led to the identification of a chemical scaffold, pyrrolidine pentamine, that, when substituted with the appropriate functionalities at five locations (R1-R5), inhibits AAC(6')-Ib-mediated inactivation of amikacin. Structure-activity relationship studies have shown that while truncations to the molecule result in loss of inhibitory activity, modifications of functionalities and stereochemistry have different effects on the inhibitory properties. In this study, we show that alterations at position R1 of the two most active compounds, 2700.001 and 2700.003, reduced inhibition levels, demonstrating the essential nature not only of the presence of an S-phenyl moiety at this location but also the distance to the scaffold. On the other hand, modifications on the R3, R4, and R5 positions had varied effects, demonstrating the potential for optimization. A correlation analysis between molecular docking values (ΔG) and the dose required for two-fold potentiation of the compounds described in this and the previous studies showed a significant correlation between ΔG values and inhibitory activity.

Structure-activity relationship of pyrrolidine pentamine derivatives as inhibitors of the aminoglycoside 6'- N -acetyltransferase type Ib.

Resistance to amikacin and other major aminoglycosides is commonly due to enzymatic acetylation by aminoglycoside 6'- N -acetyltransferase type I enzyme, of which type Ib [AAC(6')-Ib] is the most widespread among Gram-negative pathogens. Finding enzymatic inhibitors could be an effective way to overcome resistance and extend the useful life of amikacin. Small molecules possess multiple properties that make them attractive compounds to be developed as drugs. Mixture-based combinatorial libraries and positional scanning strategy led to the identification of a chemical scaffold, pyrrolidine pentamine, that, when substituted with the appropriate functionalities at five locations (R1 - R5), inhibits AAC(6')-Ib-mediated inactivation of amikacin. Structure-activity relationship (SAR) studies showed that while truncations to the molecule result in loss of inhibitory activity, modifications of functionalities and stereochemistry have different effects on the inhibitory properties. In this study, we show that alterations at position R1 of the two most active compounds, 2700.001 and 2700.003 , reduced inhibition levels, demonstrating the essential nature not only of the presence of an S -phenyl moiety at this location but also the distance to the scaffold. On the other hand, modifications on the R3, R4, and R5 positions have varied effects, demonstrating the potential for optimization. A correlation analysis between molecular docking values (ΔG) and the dose required for two-fold potentiation of compounds described in this and the previous studies showed a significant correlation between ΔG values and inhibitory activity. Highlights: Amikacin resistance in Gram-negatives is mostly caused by the AAC(6')-Ib enzymeAAC(6')-Ib has been identified in most Gram-negative pathogensInhibitors of AAC(6')-Ib could be used to treat resistant infectionsCombinatorial libraries and positional scanning identified an inhibitorThe lead compound can be optimized by structure activity relationship studies.

Dynamics and quantitative contribution of the aminoglycoside 6'-N-acetyltransferase type Ib to amikacin resistance.

Aminoglycosides are essential components in the available armamentarium to treat bacterial infections. The surge and rapid dissemination of resistance genes strongly reduce their efficiency, compromising public health. Among the multitude of modifying enzymes that confer resistance to aminoglycosides, the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib] is the most prevalent and relevant in the clinical setting as it can inactivate numerous aminoglycosides, such as amikacin. Although the mechanism of action, structure, and biochemical properties of the AAC(6')-Ib protein have been extensively studied, the contribution of the intracellular milieu to its activity remains unclear. In this work, we used a fluorescent-based system to quantify the number of AAC(6')-Ib per cell in Escherichia coli, and we modulated this copy number with the CRISPR interference method. These tools were then used to correlate enzyme concentrations with amikacin resistance levels. Our results show that resistance to amikacin increases linearly with a higher concentration of AAC(6')-Ib until it reaches a plateau at a specific protein concentration. In vivo imaging of this protein shows that it diffuses freely within the cytoplasm of the cell, but it tends to form inclusion bodies at higher concentrations in rich culture media. Addition of a chelating agent completely dissolves these aggregates and partially prevents the plateau in the resistance level, suggesting that AAC(6')-Ib aggregation lowers resistance to amikacin. These results provide the first step in understanding the cellular impact of each AAC(6')-Ib molecule on aminoglycoside resistance. They also highlight the importance of studying its dynamic behavior within the cell.IMPORTANCEAntibiotic resistance is a growing threat to human health. Understanding antibiotic resistance mechanisms can serve as foundation for developing innovative treatment strategies to counter this threat. While numerous studies clarified the genetics and dissemination of resistance genes and explored biochemical and structural features of resistance enzymes, their molecular dynamics and individual contribution to resistance within the cellular context remain unknown. Here, we examined this relationship modulating expression levels of aminoglycoside 6'-N-acetyltransferase type Ib, an enzyme of clinical relevance. We show a linear correlation between copy number of the enzyme per cell and amikacin resistance levels up to a threshold where resistance plateaus. We propose that at concentrations below the threshold, the enzyme diffuses freely in the cytoplasm but aggregates at the cell poles at concentrations over the threshold. This research opens promising avenues for studying enzyme solubility's impact on resistance, creating opportunities for future approaches to counter resistance.