Gut bacterial nutrient preferences quantified in vivo.

Great progress has been made in understanding gut microbiomes' products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here, we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate, and urea (but not glucose or amino acids) feed the gut microbiome. To determine the nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We found systematic differences in nutrient use: most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.

Personalized Mapping of Drug Metabolism by the Human Gut Microbiome.

The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Dozens of drugs have been shown to be metabolized by single isolates from the gut microbiome, but the extent of this phenomenon is rarely explored in the context of microbial communities. Here, we develop a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Included are a batch culturing system for sustained growth of subject-specific gut microbial communities, an ex vivo drug metabolism screen, and targeted and untargeted functional metagenomic screens to identify microbiome-encoded genes responsible for specific metabolic events. Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized medicine.

Application of Laser-Induced Acoustic Desorption for Molecular Rotational Resonance Spectroscopy.

Molecular Rotational Resonance (MRR) spectroscopy is a uniquely precise tool for the determination of molecular structures of volatile compounds in mixtures, as the characteristic rotational transition frequencies of a molecule are extremely sensitive to its 3D structure through the moments of inertia in a three-dimensional coordinate system. This enables identification of the compounds based on just a few parameters that can be calculated, as opposed to, for example, mass spectrometric data, which often require expert analysis of 10-20 different signals and the use of many standards/model compounds. This paper introduces a new sampling technique for MRR, laser-induced acoustic desorption (LIAD), to allow the vaporization of nonvolatile and thermally labile analytes without the need for excessive heating or derivatization. In this proof-of-concept study, LIAD was successfully coupled to an MRR instrument to conduct measurements on seven compounds with differing polarities, molecular weights, and melting and boiling points. Identification of three isomers in a mixture was also successfully performed using LIAD/MRR. Based on these results, LIAD/MRR is demonstrated to provide a powerful approach for the identification of nonvolatile and/or thermally labile analytes with molecular weights up to 600 Da in simple mixtures, which does not require the use of reference compounds. In the future, applications to more complex mixtures, such as those relevant to pharmaceutical research, and quantitative aspects of LIAD/MRR will be reported.

CD47-mediated immune evasion in early-stage lung cancer progression.

Alveolar and interstitial macrophages play crucial roles in eradicating pathogens and transformed cells in the lungs. The immune checkpoint CD47, found on normal and malignant cells, interacts with the SIRPα ligand on macrophages, inhibiting phagocytosis, antigen presentation, and promoting immune evasion. In this study, we demonstrated that CD47 is not only a transmembrane protein, but that it is also highly concentrated in extracellular vesicles from lung cancer cell lines and patient plasma. Abundant CD47 was observed in the cytoplasm of lung cancer cells, aligning with our finding that it was packed into extracellular vesicles for physiological and pathological functions. In our clinical cohort, extracellular vesicle CD47 was significantly higher in the patients with early-stage lung cancer, emphasizing innate immunity inactivation in early tumor progression. To validate our hypothesis, we established an orthotopic xenograft model mimicking lung cancer development, which showed increased serum soluble CD47 and elevated IL-10/TNF-α ratio, indicating an immune-suppressive tumor microenvironment. CD47 expression led to reduced tumor-infiltrating macrophages during progression, while there was a post-xenograft increase in tumor-associated macrophages. In conclusion, CD47 is pivotal in early lung cancer progression, with soluble CD47 emerging as a key pathological effector.

The Evolution of the Reconstructive Strategy for Elbow Flexion for Acute C5, C6 Brachial Plexus Injuries over Two Decades.

BACKGROUND: Over the course of the past two decades, improved outcomes following brachial plexus reconstruction have been attributed to newer nerve transfer techniques. However, key factors aside from surgical techniques have brought improved consistency to elbow flexion techniques in the latter decade. METHODS: One-hundred seventeen patients who underwent brachial plexus reconstruction from 1996 to 2006 were compared with 120 patients from 2007 to 2017. All patients were evaluated preoperatively and postoperatively to assess the recovery time and of elbow flexion strength. RESULTS: In the first decade, nerve reconstruction methods included proximal nerve grafting, intercostal nerve transfer, and Oberlin-I transfer. In the second decade, newer methods such as double fascicular transfer and ipsilateral C7 division transfer to the anterior division of upper trunk were introduced. About 78.6% of the first decade group versus 87.5% of the second decade group were able to reach M3 flexion strength (p = 0.04), with shorter time recovery to reach M3 in the 2nd decade. About 59.8% of the first decade group versus 65.0% of the second decade group were able to reach M4 (p = 0.28), but no significant difference in time of recovery. In both groups, the double fascicular nerve transfer had the highest impact when introduced in the second decade. More precise magnetic resonance imaging (MRI) techniques helped to diagnose the level of injury, the roots involved and evaluate the health of the donor nerves in preparation for intraplexus transfer. CONCLUSION: In addition to modified techniques in nerve transfers, (1) MRI-assisted evaluation and surgical exploration of the roots with (2) more judicious choice of donor nerves for primary nerve transfer were factors that ensured reliable and outcomes in the second decade.

Apoptosis pathways and osteoporosis: An approach to genomic analysis.

BACKGROUND: Osteoporosis is a disease of the bone system that causes a decrease in skeletal density and degrades skeletal tissue. Decreased bone quality, so that bones are easily broken, damaged and fractured, is an important public health problem. Previous studies have shown that the maintenance of adult bone mass is not only due to changes in bone marrow and bone cells. By regulating apoptosis, they change the lifespan of each individual. This study influences understanding of the function of apoptosis in the pathogenesis of osteoporosis and the importance of controlling the mechanisms of osteoporosis. METHODS: On the National Institute of Biotechnology Information website, Gene Expression Omnibus (GEO) microarray data and GSE551495 GEO profiles were collected. The gene set enrichment analysis tool was used to confirm the enrichment of genetic sets in relation to the gene set. The collection of C2 gene sets is compiled from the KEGG (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://www.kegg.jp/kegg/) online database and REACTOME (https://www.gsea-msigdb.org/gsea/msigdb/human/search.jsp and https://reactome.org/) pathway analysis. The Search Tool for the Retrieval of Interaction Genes (STRING) website was used to construct and select proteins and genes. The comparative toxicological genomic database (CTD) tools can be used to predict the relationship between apoptosis, osteoporosis-related genes and interactions between central genes and osteoporosis. RESULTS: These results generally expand our understanding of the path of apoptosis in osteoporosis. We have discovered genes CASP9, CASP8, CASP3, BAX and TP53 associated with osteoporosis. In activation of KEGG apoptosis and REACTOME, caspase activation through the extrinsic apoptotic signaling pathway is characterized by the identification of a subcollection of C2. Other STRINGs show the formation of protein networks and central gene selection, and CTD can accurately predict the relationship between these apoptosis pathways and central genes. CONCLUSIONS: Our research has highlighted the importance of the osteoporosis pathway associated with osteoporosis apoptosis with several analytical approaches. These results have broadened our understanding of the pathways of osteoporosis apoptosis. It is particularly possible to predict the sensitivity and vulnerability to osteoporosis.

Early detection of myocardial ischemia in resting ECG: analysis by HHT.

BACKGROUND: Exercise electrocardiography (ECG) is a noninvasive test aiming at producing ischemic changes. However, resting ECG cannot be adopted in diagnosing myocardial ischemia till ST-segment depressions. Therefore, this study aimed to detect myocardial energy defects in resting ECG using the Hilbert-Huang transformation (HHT) in patients with angina pectoris. METHODS: Electrocardiographic recordings of positive exercise ECG by performing coronary imaging test (n = 26) and negative exercise ECG (n = 47) were collected. Based on the coronary stenoses severity, patients were divided into three categories: normal, < 50%, and ≥ 50%. During the resting phase of the exercise ECG, all 10-s ECG signals are decomposed by HHT. The RT intensity index, composed of the power spectral density of the P, QRS, and T components, is used to estimate the myocardial energy defect. RESULTS: After analyzing the resting ECG using HHT, the RT intensity index was significantly higher in patients with positive exercise ECG (27.96%) than in those with negative exercise ECG (22.30%) (p < 0.001). In patients with positive exercise ECG, the RT intensity index was gradually increasing with the severity of coronary stenoses: 25.25% (normal, n = 4), 27.14% (stenoses < 50%, n = 14), and 30.75% (stenoses ≥ 50%, n = 8). The RT intensity index of different coronary stenoses was significantly higher in patients with negative exercise ECG, except for the normal coronary imaging test. CONCLUSIONS: Patients with coronary stenoses had a higher RT index at the resting stage of exercise ECG. Resting ECG analyzed using HHT could be a method for the early detection of myocardial ischemia.

Epstein Barr Virus Reactivation during COVID-19 Hospitalization Significantly Increased Mortality/Death in SARS-CoV-2(+)/EBV(+) than SARS-CoV-2(+)/EBV(-) Patients: A Comparative Meta-Analysis.

Epstein-Barr virus (EBV) reactivation in acute-phase of COVID-19 disease was recently discovered but it is not clear in terms of degree of mortality caused, and this was the aim of the current study. Six databases and three non-databases were thoroughly searched, independently. The articles related to non-human study (abstract, in vitro, in vivo, in silico, case study, poster, and review articles) were excluded for main analysis. Four articles related to mortality linked to EBV reactivation were systematically identified and included in the qualitative and quantitative analyses. Based on proportional meta-analysis of 4 studies, 34.3% or 0.343 (95% CI: 0.189-0.516; I 2 = 74.6) mortality related to EBV reactivation was identified. To address high heterogeneity, subgroup meta-analysis was carried out. Based on subgroup analysis, 26.6% or 0.266 (95% CI: 0.191-0.348; I 2 = 0) with no heterogeneity was identified. Interestingly, in comparative meta-analysis, EBV(-)/SARS-CoV-2(+) patients had statistically lesser mortality (9.9%) than EBV(+)/SARS-CoV-2(+) patients (23.6%) where RR = 2.31 (95% CI: 1.34-3.99; p = 0.003; I 2 = 6%). This finding is equivalent to the absolute mortality effect of 130 more per 1000 COVID-19 patients (95% CI: 34-296). Furthermore, based on statistical analysis, D-dimer was not statistically significantly different (p > 0.05) between the groups although studies have shown that D-dimer was statistically significantly different (p < 0.05) between these groups. Based on the inclusion and analysis of low risk of bias and high quality of articles graded with Newcastle-Ottawa Scale (NOS), when COVID-19 patients' health state is gradually worsening, EBV reactivation needs to be suspected because EBV reactivation is a possible marker for COVID-19 disease severity.

Piperlongumine Induces Cellular Apoptosis and Autophagy via the ROS/Akt Signaling Pathway in Human Follicular Thyroid Cancer Cells.

Thyroid cancer (TC) is the most common endocrine malignancy. Recently, the global incidence of TC has increased rapidly. Differentiated thyroid cancer includes papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), which are the most common types of TC. Although PTCs and FTCs exert good prognoses and high survival rates, FTCs tend to be more aggressive than PTCs. There is an urgent need to improve patient outcomes by developing effective therapeutic agents for FTCs. Piperlongumine exerts anti-cancer effects in various human carcinomas, including human anaplastic TCs and PTCs. However, the anti-cancer effects of piperlongumine in FTCs and the underlying mechanisms are yet to be elucidated. Therefore, in the present study, we evaluated the effect of piperlongumine on cell proliferation, cell cycle, apoptosis, and autophagy in FTC cells with flowcytometry and Western blot. We observed that piperlongumine caused growth inhibition, cell cycle arrest, apoptosis induction, and autophagy elevation in FTC cells. Activities of reactive oxygen species and the downstream PI3K/Akt pathway were the underlying mechanisms involved in piperlongumine mediated anti-FTC effects. Advancements in our understanding of the effects of piperlongumine in FTC hold promise for the development of novel therapeutic strategies.

Cracks that Let the Light in: Collective Reflections on Integrating Lived Experience of Psychosis in Research and Policy in the Context of a Global Commission.

Within psychiatric research fields, there has been a marked uptick of interest in service user involvement in recent years. Nevertheless, it is often unclear how robust or impactful common forms of inclusion are, and the extent to which they have included individuals with psychosis. Using collective auto-ethnography, this paper describes the experiences of 8 academic and non-academic members of the 'lived experience' and participatory research workgroup of a global psychosis Commission and our navigation of power and power hierarchies, differences in background and training, and multiple vectors of identity, diversity, and privilege. We conclude that the realities of "involvement" are much messier, more fraught, and less intrinsically empowering than often signaled in calls for involvement and co-production. We nevertheless stress the power of collective dialogue and support-between and among a pluralistic group-and of honesty and transparency about challenges, barriers, and the colonial underpinnings and geopolitics of global mental health.

YAP maintains the production of intermediate progenitor cells and upper-layer projection neurons in the mouse cerebral cortex.

BACKGROUND: The Hippo pathway is conserved through evolution and plays critical roles in development, tissue homeostasis and tumorigenesis. Yes-associated protein (YAP) is a transcriptional coactivator downstream of the Hippo pathway. Previous studies have demonstrated that activation of YAP promotes proliferation in the developing brain. Whether YAP is required for the production of neural progenitor cells or neurons in vivo remains unclear. RESULTS: We demonstrated that SATB homeobox 2 (SATB2)-positive projection neurons (PNs) in upper layers, but not T-box brain transcription factor 1-positive and Coup-TF interacting protein 2-positive PNs in deep layers, were decreased in the neonatal cerebral cortex of Yap conditional knockout (cKO) mice driven by Nestin-Cre. Cell proliferation was reduced in the developing cerebral cortex of Yap-cKO. SATB2-positive PNs are largely generated from intermediate progenitor cells (IPCs), which are derived from radial glial cells (RGCs) during cortical development. Among these progenitor cells, IPCs but not RGCs were decreased in Yap-cKO. We further demonstrated that cell cycle re-entry was reduced in progenitor cells of Yap-cKO, suggesting that fewer IPCs were generated in Yap-cKO. CONCLUSION: YAP is required for the production of IPCs and upper-layer SATB2-positive PNs during development of the cerebral cortex in mice.

Measuring self-regulation in everyday life: Reliability and validity of smartphone-based experiments in alcohol use disorder.

Self-regulation, the ability to guide behavior according to one's goals, plays an integral role in understanding loss of control over unwanted behaviors, for example in alcohol use disorder (AUD). Yet, experimental tasks that measure processes underlying self-regulation are not easy to deploy in contexts where such behaviors usually occur, namely outside the laboratory, and in clinical populations such as people with AUD. Moreover, lab-based tasks have been criticized for poor test-retest reliability and lack of construct validity. Smartphones can be used to deploy tasks in the field, but often require shorter versions of tasks, which may further decrease reliability. Here, we show that combining smartphone-based tasks with joint hierarchical modeling of longitudinal data can overcome at least some of these shortcomings. We test four short smartphone-based tasks outside the laboratory in a large sample (N = 488) of participants with AUD. Although task measures indeed have low reliability when data are analyzed traditionally by modeling each session separately, joint modeling of longitudinal data increases reliability to good and oftentimes excellent levels. We next test the measures' construct validity and show that extracted latent factors are indeed in line with theoretical accounts of cognitive control and decision-making. Finally, we demonstrate that a resulting cognitive control factor relates to a real-life measure of drinking behavior and yields stronger correlations than single measures based on traditional analyses. Our findings demonstrate how short, smartphone-based task measures, when analyzed with joint hierarchical modeling and latent factor analysis, can overcome frequently reported shortcomings of experimental tasks.

Optimal Heart Rate Control Improves Long-Term Prognosis of Decompensated Heart Failure with Reduced Ejection Fraction.

Background and Objectives: An elevated heart rate is an independent risk factor for cardiovascular disease; however, the relationship between heart rate control and the long-term outcomes of patients with heart failure with reduced ejection fraction (HFrEF) remains unclear. This study explored the long-term prognostic importance of heart rate control in patients hospitalized with HFrEF. Materials and Methods: We retrieved the records of patients admitted for decompensated heart failure with a left ventricular ejection fraction (LVEF) of ≤40%, from 1 January 2005 to 31 December 2019. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure (HHF) during follow-up. We analyzed the outcomes using Cox proportional hazard ratios calculated using the patients' heart rates, as measured at baseline and approximately 3 months later. The mean follow-up duration was 49.0 ± 38.1 months. Results: We identified 5236 eligible patients, and divided them into five groups on the basis of changes in their heart rates. The mean LVEFs of the groups ranged from 29.1% to 30.6%. After adjustment for all covariates, the results demonstrated that lesser heart rate reductions at the 3-month screening period were associated with long-term cardiovascular death, HHF, and all-cause mortality (p for linear trend = 0.033, 0.042, and 0.003, respectively). The restricted cubic spline model revealed a linear relationship between reduction in heart rate and risk of outcomes (p for nonlinearity > 0.2). Conclusions: Greater reductions in heart rate were associated with a lower risk of long-term cardiovascular death, HHF, and all-cause mortality among patients discharged after hospitalization for decompensated HFrEF.

The Removal, Excision, Sterilization, and Quarantine (RESQ) Method is a Feasible Alternative Treatment for Cardiac Implantable Electronic Device Infections.

Background: Current guidelines recommend that all infected cardiac implantable electronic devices (CIEDs) should be removed. However, financial or anatomical concerns can lead to management of infection with simple debridement, as opposed to complete removal. In this observational study, we report the outcomes of our modified procedure for this real-world dilemma. Methods and Results: The Quarantine (RESQ) method is characterized as follows: the removal (R) of all non-essential foreign materials, including old sutures and leads; the excision (E) of all non-viable, chronically inflamed, granulation, or scar tissue; the sterilization (S) of the remaining generator; and the quarantine (Q) of a new pocket in the sub-muscular layer for reimplantation. From a review of electronic medical records, 30 patients were selected and divided into three groups according to the intervention used: RESQ (n = 9) in group A, simple debridement (n = 16) in group B, and guideline-recommended replacement (n = 5) in group C. Patient baseline characteristics were similar between the groups. After analyzing the proportion of patients that were free from infection one year following their respective interventions, we found that group A performed better than group B (100% and 31.2% infection-free, respectively, p = 0.001), and was comparable to group C (both 100% infection-free, p = not applicable). Conclusions: The RESQ method is a feasible and beneficial alternative for selected patients with CIED infections who are unable to receive a generator replacement according to the recommended guideline.

Loss of CPAP in developing mouse brain and its functional implication for human primary microcephaly.

Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by small brain size with mental retardation. CPAP (also known as CENPJ), a known microcephaly-associated gene, plays a key role in centriole biogenesis. Here, we generated a previously unreported conditional knockout allele in the mouse Cpap gene. Our results showed that conditional Cpap deletion in the central nervous system preferentially induces formation of monopolar spindles in radial glia progenitors (RGPs) at around embryonic day 14.5 and causes robust apoptosis that severely disrupts embryonic brains. Interestingly, microcephalic brains with reduced apoptosis are detected in conditional Cpap gene-deleted mice that lose only one allele of p53 (also known as Trp53), while simultaneous removal of p53 and Cpap rescues RGP death. Furthermore, Cpap deletion leads to cilia loss, RGP mislocalization, junctional integrity disruption, massive heterotopia and severe cerebellar hypoplasia. Together, these findings indicate that complete CPAP loss leads to severe and complex phenotypes in developing mouse brain, and provide new insights into the causes of MCPH.

Regulation of innate immune signaling pathways by autophagy in dengue virus infection.

Autophagy is not only an intracellular recycling degradation system that maintains cellular homeostasis but is also a component of innate immunity that contributes to host defense against viral infection. The viral components as well as viral particles trapped in autophagosomes can be delivered to lysosomes for degradation. Abundant evidence indicates that dengue virus (DENV) has evolved the potent ability to hijack or subvert autophagy process for escaping host immunity and promoting viral replication. Moreover, autophagy is often required to deliver viral components to pattern recognition receptors signaling for interferon (IFN)-mediated viral elimination. Hence, this review summarizes DENV-induced autophagy, which exhibits dual effects on proviral activity of promoting replication and antiviral activity to eliminating viral particles.

Preprocedural features of patients under antihypertensive drugs may help identify responders to renal denervation: a hypothesis-generating study.

BACKGROUND: Renal denervation (RDN) is effective to lower systolic blood pressure (SBP) in essential hypertension. However, patient selection under medications remains an important unmet clinical need. METHODS: This multicenter study aimed at observing whether preprocedural features associated with increased renin-angiotensin-aldosterone activity influence RDN response. This study enrolled the patients who underwent RDN for uncontrolled hypertension. Medical records were reviewd and patients were divided into 2 groups depending by meeting any of the following conditions prior to RDN: (1) >10 mmHg of office SBP reduction after aldosterone inhibition, (2) aldosterone-renin ratio >30 or (3) slow flow on the renal angiogram. RDN responders were defined by a reduction in 24-hour mean ≥6 mmHg or by ≥1 class of antihypertensive drug withdraw. RESULTS: A total of 46 patients were enrolled, of which 27 (59%) were in control group A and 19 (41%) in group B. The baseline age, gender, office and 24-hour SBP (mean 140.0 ± 12.8 mmHg vs. 144.0 ± 16.5 mmHg, p = 0.577) were comparable, while the number of prescribed drug classes was fewer in group A (4.0 ± 1.3 vs. 4.9 ± 0.9, p = 0.014). The proportion patients with prescribed aldosterone antagonist or high aldosterone-renin ratios were higher in group B. At 12 months post RDN, the results were significantly better in group B in terms of mean change in office SBP (12.4 ± 23.5 mmHg vs. 29.9 ± 25.5 mmHg, p = 0.046) and the proportion of RDN responders (51.9% vs. 89.5%, p < 0.001). CONCLUSION: RDN was more effective in patients with any of 3 clinical indices.

The autonomic balance of heart rhythm complexity after renal artery denervation: insight from entropy of entropy and average entropy analysis.

BACKGROUND: The current method to evaluate the autonomic balance after renal denervation (RDN) relies on heart rate variability (HRV). However, parameters of HRV were not always predictive of response to RDN. Therefore, the complexity and disorder of heart rhythm, measured by entropy of entropy (EoE) and average entropy (AE), have been used to analyze autonomic dysfunction. This study evaluated the dynamic changes in autonomic status after RDN via EoE and AE analysis. METHODS: Five patients were prospectively enrolled in the Global SYMPLICITY Registry from 2020 to 2021. 24-h Holter and ambulatory blood pressure monitoring (ABPM) was performed at baseline and 3 months after RDN procedures. The autonomic status was analyzed using the entropy-based AE and EoE analysis and the conventional HRV-based low frequency (LF), high frequency (HF), and LF/HF. RESULTS: After RDN, the ABPM of all patients showed a significant reduction in blood pressure (BP) and heart rate. Only AE and HF values of all patients had consistent changes after RDN (p < 0.05). The spearman rank-order correlation coefficient of AE vs. HF was 0.86, but AE had a lower coefficient of variation than HF. CONCLUSIONS: Monitoring the AE and EoE analysis could be an alternative to interpreting autonomic status. In addition, a relative change of autonomic tone, especially an increasing parasympathetic activity, could restore autonomic balance after RDN.

Ivermectin induces cell cycle arrest and caspase-dependent apoptosis in human urothelial carcinoma cells.

Bladder carcinoma is one of the most common malignancies worldwide, and >90% of all bladder cancers are classified as urothelial carcinomas (UC). Surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy are evidence-based treatments that are administered depending on the clinical stage of UC. All these treatments exhibited limited effects in cases of metastatic UC, and UC with specific location, invasiveness, and recurrence. Therefore, a new therapeutic strategy for UC is urgently needed. Ivermectin, an avermectin derivative, has been reported to be effective against various parasites, and its pharmacokinetic and pharmacodynamic properties as well as safety are well understood in humans. Recently, ivermectin was shown to exhibit therapeutic benefits against various virus infections in vitro, and anticancer activity against various human cancer cells. This study aimed to investigate the anticancer effects of ivermectin in human UC cells. Ivermectin inhibited growth, regulated the cell cycle, and induced apoptosis in human UC cells. It also induced the activation of both extrinsic and intrinsic caspase-dependent apoptotic pathways. Further investigation revealed that ivermectin induced apoptosis in UC cells is mediated via c-Jun N-terminal kinase signaling. Herein, we demonstrated that ivermectin can be used as a new therapeutic agent for treating UC cells.

Assessing the synergies and trade-offs of development projects in response to climate change in an urban region.

A synthesis of the complex relationships, including synergies and trade-offs, between urban development projects and climate change mitigation and adaptation objectives can ensure that all these relationships are taken into consideration. We used a systems approach and applied an impact matrix and chain effect analysis methods to projects in the highly urbanized Taipei metropolitan region to identify the influences and effects between urban development projects and climate change objectives. Three types of urban plans and projects were analyzed: flood control, transportation, and urban planning. The magnitudes of the influences and effects between these projects and plans were derived through interviews with experts familiar with Taipei's urban development. This pilot study found no synergy in the response to climate change mitigation and adaptation for the urban development projects analyzed. The current standalone policies and plans related to urbanization in Taipei have resulted in trade-offs for flood control and public transit projects because they contribute positively toward one climate objective but negatively impact another. A high-level policymaking mechanism that ensures coordination and collaboration between different sectors is needed to supervise sectoral policies. Prior to the approval and implementation of a plan, policymakers should request the assessment of synergies and trade-offs between plans and projects to ensure a synergistic effect to climate change issues. This study confirms that the strategy from individual sector in a metropolitan region will result in trade-off between climate change issues is a global problem. This paper also strengthens the concept that the assessment of synergy/trade-offs between policy and plans should be conducted using systemic approach.