LOXL1 modulates the malignant progression of colorectal cancer by inhibiting the transcriptional activity of YAP.

BACKGROUND: LOX-like 1 (LOXL1) is a lysyl oxidase, and emerging evidence has revealed its effect on malignant cancer progression. However, its role in colorectal cancer (CRC) and the underlying molecular mechanisms have not yet been elucidated. METHODS: LOXL1 expression in colorectal cancer was detected by immunohistochemistry, western blotting and real-time PCR. In vitro, colony formation, wound healing, migration and invasion assays were performed to investigate the effects of LOXL1 on cell proliferation, migration and invasion. In vivo, metastasis models and mouse xenografts were used to assess tumorigenicity and metastasis ability. Molecular biology experiments were utilized to reveal the underlying mechanisms by which LOXL1 modulates the Hippo pathway. RESULTS: LOXL1 was highly expressed in normal colon tissues compared with cancer tissues. In vitro, silencing LOXL1 in CRC cell lines dramatically enhanced migration, invasion, and colony formation, while overexpression of LOXL1 exerted the opposite effects. The results of the in vivo experiments demonstrated that the overexpression of LOXL1 in CRC cell lines drastically inhibited metastatic progression and tumour growth. Mechanistically, LOXL1 inhibited the transcriptional activity of Yes-associated protein (YAP) by interacting with MST1/2 and increasing the phosphorylation of MST1/2. CONCLUSIONS: LOXL1 may function as an important tumour suppressor in regulating tumour growth, invasion and metastasis via negative regulation of YAP activity. Video abstract.

Mechanisms Suppressing Superheavy Element Yields in Cold Fusion Reactions.

Superheavy elements are formed in fusion reactions which are hindered by fast nonequilibrium processes. To quantify these, mass-angle distributions and cross sections have been measured, at beam energies from below-barrier to 25% above, for the reactions of ^{48}Ca, ^{50}Ti, and ^{54}Cr with ^{208}Pb. Moving from ^{48}Ca to ^{54}Cr leads to a drastic fall in the symmetric fission yield, which is reflected in the measured mass-angle distribution by the presence of competing fast nonequilibrium deep inelastic and quasifission processes. These are responsible for reduction of the compound nucleus formation probablity P_{CN} (as measured by the symmetric-peaked fission cross section), by a factor of 2.5 for ^{50}Ti and 15 for ^{54}Cr in comparison to ^{48}Ca. The energy dependence of P_{CN} indicates that cold fusion reactions (involving ^{208}Pb) are not driven by a diffusion process.

Evidence for the Role of Proton Shell Closure in Quasifission Reactions from X-Ray Fluorescence of Mass-Identified Fragments.

The atomic numbers and the masses of fragments formed in quasifission reactions are simultaneously measured at scission in ^{48}Ti+^{238}U reactions at a laboratory energy of 286 MeV. The atomic numbers are determined from measured characteristic fluorescence x rays, whereas the masses are obtained from the emission angles and times of flight of the two emerging fragments. For the first time, thanks to this full identification of the quasifission fragments on a broad angular range, the important role of the proton shell closure at Z=82 is evidenced by the associated maximum production yield, a maximum predicted by time-dependent Hartree-Fock calculations. This new experimental approach gives now access to precise studies of the time dependence of the N/Z (neutron over proton ratios of the fragments) evolution in quasifission reactions.

A bacteriorhodopsin-based biohybrid solar cell using carbon-based electrolyte and cathode components.

There is currently a high demand for energy production worldwide, mainly producing renewable and sustainable energy. Bio-sensitized solar cells (BSCs) are an excellent option in this field due to their optical and photoelectrical properties developed in recent years. One of the biosensitizers that shows promise in simplicity, stability and quantum efficiency is bacteriorhodopsin (bR), a photoactive, retinal-containing membrane protein. In the present work, we have utilized a mutant of bR, D96N, in a photoanode-sensitized TiO2 solar cell, integrating low-cost, carbon-based components, including a cathode composed of PEDOT (poly(3,4-ethylenedioxythiophene) functionalized with multi-walled carbon nanotubes (CNT) and a hydroquinone/benzoquinone (HQ/BQ) redox electrolyte. The photoanode and cathode were characterized morphologically and chemically (SEM, TEM, and Raman). The electrochemical performance of the bR-BSCs was investigated using linear sweep voltammetry (LSV), open circuit potential decay (VOC), and impedance spectroscopic analysis (EIS). The champion device yielded a current density (JSC) of 1.0 mA/cm2, VOC of -669 mV, a fill factor of ~24 %, and a power conversion efficiency (PCE) of 0.16 %. This bR device is one of the first bio-based solar cells utilizing carbon-based alternatives for the photoanode, cathode, and electrolyte. This may decrease the cost and significantly improve the device's sustainability.

Current Therapies in Clinical Trials of Parkinson's Disease: A 2021 Update.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that currently has no cure, but treatments are available to improve PD symptoms and maintain quality of life. In 2020, about 10 million people worldwide were living with PD. In 1970, the United States Food and Drug Administration approved the drug levodopa as a dopamine replacement to manage PD motor symptoms; levodopa-carbidopa combination became commercialized in 1975. After over 50 years of use, levodopa is still the gold standard for PD treatment. Unfortunately, levodopa therapy-induced dyskinesia and OFF symptoms remain unresolved. Therefore, we urgently need to analyze each current clinical trial's status and therapeutic strategy to discover new therapeutic approaches for PD treatment. We surveyed 293 registered clinical trials on ClinicalTrials.gov from 2008 to 16 June 2021. After excluded levodopa/carbidopa derivative add-on therapies, we identified 47 trials as PD treatment drugs or therapies. Among them, 19 trials are in phase I (41%), 25 trials are in phase II (53%), and 3 trials are in phase III (6%). The three phase-III trials use embryonic dopamine cell implant, 5-HT1A receptor agonist (sarizotan), and adenosine A2A receptor antagonist (caffeine). The therapeutic strategy of each trial shows 29, 5, 1, 5, 5, and 2 trials use small molecules, monoclonal antibodies, plasma therapy, cell therapy, gene therapy, and herbal extract, respectively. Additionally, we discuss the most potent drug or therapy among these trials. By systematically updating the current trial status and analyzing the therapeutic strategies, we hope this review can provide new ideas and insights for PD therapy development.

Hold the Chemo! Leukostasis, a Presentation of Brown Recluse Spider Bite: A Case Report.

Brown recluse spiders, also known as Loxosceles reclusa, are endemic to the Southwest and Central Midwestern United States. A bite from this spider can cause a range of clinical manifestations, anywhere from a painless papular lesion to life-threatening reactions. We report a possible spider bite presenting as leukostasis initially suspected to be acute leukemia. A 22-year-old female patient presented to the emergency department with confusion and right upper arm pain, redness, and swelling after a suspected spider bite. Initial labs showed WBC count of 103.5x10e3/µL, hemoglobin of 3.3 g/dL, positive Direct Coombs' test, creatinine of 1.8 mg/dL, transaminitis, and lactic acid of 20 mmol/L. Acute leukemia with leukostasis was suspected. She was started emergently on hydroxyurea in conjunction with prophylaxis for tumor lysis syndrome. However, peripheral smear showed left-shifted granulocytosis with lymphocytosis, monocytosis, and no blast cells or evidence of myelodysplasia. Bone marrow aspirate showed mildly hypercellular marrow with myeloid hyperplasia and no myelodysplasia. Flow cytometry analysis confirmed a left-shifted myeloid maturation pattern with 0.3% myeloblasts. BCR-ABL1 and JAK2 testing was negative. Hence, she had no evidence of leukemia but rather had leukostasis from a spider bite. Hydroxyurea was stopped and follow-up labs normalized. Sphingomyelinase D in the brown recluse spider venom is unique to Loxosceles and Sicarius and may be responsible for the unique clinical presentation of loxoscelism. The presentation of hyperleukocytosis complicated by shock with an unclear history poses a diagnostic challenge. In diagnostic uncertainty, consider delaying chemotherapy until a diagnosis can be confirmed to avoid potential harm.

Development of a time of flight spectrometer based on position sensitive multi-wire proportional counters for fission fragment mass distribution studies.

Characteristics and performance of a time of flight (TOF) spectrometer developed for performing fission mass distribution studies are presented. The spectrometer contains two TOF arms based on multi-wire proportional counters (MWPCs). Each arm has two MWPCs to form a start-stop detection system for TOF measurements. The start detector has an active area of 4 × 4 cm2. The stop detector is a two-dimensional position sensitive MWPC with an active area of 16 × 11 cm2. Salient features of the MWPCs are the use of reduced sub-millimeter wire pitches of 0.635 and 0.317 mm in the electrodes along with the use of gold plated tungsten wires of diameters 10 and 20 µm. A delay line for position electrodes is prepared using chip inductors and capacitors. Ten different configurations of MWPC were investigated for the start detector, which involved the use of three and four electrode geometries, use of different wire pitches, and use of aluminized mylar for timing electrodes. Performance results close to micro-channel plate detectors have been observed with some designs of MWPC, displaying rise times better than 2 ns with an estimated inherent time resolution of ∼100 ps FWHM. A position resolution of ∼1 mm (FWHM) has been observed. Design features of the MWPCs and their test performance results are described in this article.

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson's Disease.

Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson's disease (PD) is the second-leading cause of neurodegenerative disorder after Alzheimer's disease. In PD, continuous loss of dopaminergic neurons in the substantia nigra causes dopamine depletion in the striatum, promotes the primary motor symptoms of resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors of PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, and hereditary defects. The pathologic features of PD include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, and neuroinflammation, but the interaction of these factors contributing to PD is not fully understood. In neurotoxin-induced PD models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, and permethrin mainly impair the mitochondrial respiratory chain, activate microglia, and generate reactive oxygen species to induce autooxidation and dopaminergic neuronal apoptosis. Since no current treatment can cure PD, using a suitable PD animal model to evaluate PD motor symptoms' treatment efficacy and identify therapeutic targets and drugs are still needed. Hence, the present review focuses on the latest scientific developments in different neurotoxin-induced PD animal models with their mechanisms of pathogenesis and evaluation methods of PD motor symptoms.

An Electronic and Optically Controlled Bifunctional Transistor Based on a Bio-Nano Hybrid Complex.

We report an electronically and optically controlled bioelectronic field-effect transistor (FET) based on the hybrid film of photoactive bacteriorhodopsin and electronically conducting single-walled carbon nanotubes (SWNTs). Two-dimensional (2D) crystals of bacteriorhodopsin form the photoactive center of the bio-nano complex, whereas one-dimensional (1D) pure SWNTs provide the required electronic support. The redshift in the Raman spectra indicates the electronic doping with an estimated charge density of 3 × 106 cm-2. The hybrid structure shows a conductivity of 19 µS/m and semiconducting characteristics due to preferential binding with selective diameters of semiconducting SWNTs. The bioelectronic transistor fabricated using direct laser lithography shows both optical and electronic gating with a significant on/off switch ratio of 8.5 and a photoconductivity of 13.15 µS/m. An n-type FET shows complementary p-type characteristics under light due to optically controlled, electronic doping by the "proton-pumping" bacteriorhodopsin. The fabricated bioelectronic transistor exhibits both electronically and optically well-controlled bifunctionality based on the functionalized hybrid electronic material.

Epigallocatechin gallate suppresses inflammation in human coronary artery endothelial cells by inhibiting NF-κB.

The endothelium is a critical regulator of vascular homeostasis, controlling vascular tone and permeability as well as interactions of leukocytes and platelets with blood vessel walls. Consequently, endothelial dysfunction featuring inflammation and reduced vasodilation are considered central to cardiovascular disease (CVD) pathogenesis and have become a therapeutic area of focus. Type II endothelial cell (EC) activation by stress-related stimuli such as tumor necrosis factor-α (TNF-α) initiates the nuclear factor-κB (NF-κB) signaling pathway, a master regulator of inflammatory responses. Because dysregulated NF-κB signaling has been tightly linked to several CVDs, EC-specific inhibition of NF-κB represents an attractive pharmacological strategy. As accumulating evidence highlights the clinical benefits of tea catechin for multiple diseases including CVDs, we sought to determine whether the tea catechin epigallocatechin gallate (EGCG) that displays antioxidative, anti-inflammatory, hypolipidemic, anti-thrombogenic, and anti-hypertensive properties offers protection against CVDs by suppressing the canonical NF-κB pathway. Our findings indicate that EGCG downregulates multiple components of the TNF-α-induced NF-κB signaling pathway and thereby reduces the consequent increase in inflammatory gene transcription and protein expression. Furthermore, EGCG blocked type II EC activation, evidenced by diminished EC leakage and monocyte adhesion in EGCG-treated cells. In summary, our study advances knowledge of EGCG's anti-inflammatory effects on the NF-κB pathway and hence its benefits on endothelial health, supporting its therapeutic potential for CVDs.

MicroRNA Signatures in Blood or Bone Marrow Distinguish Subtypes of Pediatric Acute Lymphoblastic Leukemia.

OncomiRs are microRNAs that are associated with early onset of specific cancers. To identify microRNAs involved in pediatric acute lymphoblastic leukemia (ALL) subtypes T-ALL and B-ALL, peripheral blood and bone marrow samples were independently subjected to microarray analysis using two different high-fidelity array platforms. The unique and common gene signatures from both arrays were validated by TaqMan individual assays in 100 pediatric ALL samples. Survival studies were carried out in the test set and validation set with 50 randomly selected samples in each set. MicroRNA expression profile revealed characteristic signatures for distinguishing T and B lineages and identified 51 novel microRNAs in pediatric ALL. Interestingly, the present study also revealed endogenous similarities and differences between blood and bone marrow within each ALL subtype. When Cox regression analysis was carried out with these identified microRNAs, 11 of them exhibited expression levels significantly correlated with survival. Validation of some of the common and relevant microRNAs from both arrays showed that their targets are involved in key oncogenic signaling pathways. Thus, this study suggests that microRNAs have the potential to become important diagnostic tools for identification and monitoring clinical outcomes in ALL patients.

Inhibitors from pigeonpea active against lepidopteran gut proteinases.

The proteinase inhibitors (PIs) active against bovine pancreatic trypsin, chymotrypsin, and insect midgut trypsin-like proteinases were found in the seeds of 14 cultivars and eight wild types of pigeonpea, Cajanus cajan L.. The inhibitory activity of PIs against trypsin and chymotrypsin, as well as their activity profile on gelatin-polyacrylamide gel electrophoresis (PAGE) were identical among the various cultivars. In contrast to cultivars, the wild types showed differences in inhibitory activity of PIs and their activity profile on gelatin-PAGE. The PIs from all cultivars and few wild types showed 10- to 50-fold higher activity against midgut trypsin-like proteinases of Achaea janata (L.) (Lepidoptera: Noctuidae), compared with bovine pancreatic trypsin. However, the PIs from both cultivars and wild types showed three- to nine-fold less activity against Spodoptera litura (F.) (Lepidoptera: Noctuidae) midgut trypsin-like proteinases, compared with bovine pancreatic trypsin. This inhibitory potential of PIs from cultivars and wild types, toward midgut trypsin-like proteinases from A. janata was further evident by the strong activity profile visualized on gelatin-PAGE. These results further suggest that the inhibitory potential of PIs from pigeonpea cultivars and wild types could be exploited in management of nonhost insects.

Pinocembrin Protects Against Dextran Sulfate Sodium-Induced Rats Colitis by Ameliorating Inflammation, Improving Barrier Function and Modulating Gut Microbiota.

Pinocembrin (PIN) is a natural flavonoid widely found in bee propolis with potent gastrointestinal protective effects. In consequence, PIN has great potential in preventing inflammatory bowel diseases (IBDs) while scant information is available. In this study, a dextran sulfate sodium (DSS)-induced rats ulcerative colitis model (3.5% DSS in drinking water for 7 days) was applied to explore the protective effects of PIN on macroscopic colitis symptoms, inflammation, intestinal epithelial barrier function, and gut microbiota homeostasis. While DSS-treated rats showed severe colitis clinical symptoms and histological changes (colonic pathological damages and intestinal goblet cells loss), pre-administration of PIN (5 and 10 mg/kg, p.o.) for a week alleviated these symptoms. Pre-administration of PIN also suppressed the pro-inflammatory gene expressions and improved tight junction functions of colonic epithelial cells. Additionally, PIN administration reversed DSS-induced short chain fatty acid loss, and improved the gut microbial diversity assessed by 16S rRNA phylogenetic sequencing. Overall, our results suggest a wide spectrum of protective effects of PIN in preventing IBDs.

Cardioprotective effect of Vitex negundo on isoproterenol-induced myocardial necrosis in wistar rats: A dual approach study.

Cardiovascular diseases (CVDs) are becoming the major cause of deaths worldwide, and their treatment demands novel therapeutic strategies. In this connection, we have identified p21 activated kinase 1 (PAK1) as a novel therapeutic target for the treatment of myocardial infarction (MI), where its expression is decreased when MI is induced with isoproterenol (ISO), which was brought back normal with pretreatment of Vitex negundo leaf ethanolic extract (VNE). These results were also supported by histopathological studies, cardiac markers, antioxidants, and inflammatory cytokines (NF-κB and IL-1ß). Further studies with GC-MS analysis of VNE and in silico experiments confirmed 5,7-dihydroxy-6,4',-dimethoxy flavonone and 3',5-dihydroxy-6,7,4',-trimethoxyflavone are responsible for either maintaining or inducing the expression of PAK1 to protect from MI. Our findings for the first time revealed the use of phytoconstituents in the treatment of MI.

Development of the Critical Care Pharmacotherapy Trials Network.

PURPOSE: The development of the Critical Care Pharmacotherapy Trials Network (CCPTN) as a model for practice-based pharmacotherapy research is described. SUMMARY: The CCPTN was formed in 2010 as a collaborative research network dedicated to scientific investigation in the field of critical care pharmacotherapy. The CCPTN organizational structure is consistent with many professional pharmacy and interdisciplinary organizations and organized into 3 primary domains: executive committee, working committees, and network membership. The network membership consists of critical care investigators dedicated to the mission and vision of the CCPTN and is open to anyone expressing an interest in contributing to high-level research. Network member sites represent the breadth of U.S. critical care practice environments. In addition, network members include individuals with demonstrated expertise in patient safety, administration, research design, grantsmanship, database management, peer review, and scientific writing. In 2015, there were more than 100 site investigators from around the United States and Canada. Projects to date have yielded numerous abstracts, platform presentations, and peer-reviewed publications in high-impact journals. The CCPTN has expanded to form collaborations with researchers in the United Kingdom, Australia, and New Zealand. The CCPTN has identified new potential partnerships and field-based areas for inquiry. Numerous opportunities for continued growth and scientific inquiry in the field of critical care pharmacotherapy research exist for the CCPTN to foster in the coming years. CONCLUSION: The CCPTN has been a successful model for practice-based pharmacotherapy research and assists its members in expanding critical care pharmacotherapy knowledge.

In vitro activity of rifaximin, a topical rifamycin derivative, against Chlamydia trachomatis.

Rifaximin is a rifamycin derivative that possesses in vitro activity against a wide range of bacteria. Its antimicrobial spectrum plus poor intestinal absorption have led to consideration of this compound as a topical agent. We evaluated its in vitro activity against clinical and laboratory strains of Chlamydia trachomatis and found that rifaximin exhibits minimum inhibitory concentrations (MICs) at concentrations that would be greatly exceeded in a topical preparation.

An algorithm to detect Chlamydia trachomatis by polymerase chain reaction on specimens extracted for enzyme immunoassay.

Amplification assays for detecting Chlamydia trachomatis have been shown to be more sensitive than enzyme immunoassay (EIA) by many investigators. In this study, we have developed an algorithm for performing PCR (COBAS AMPLICOR) on selected specimens extracted for EIA (ACCESS) with sample-to-cutoff (s/co) values between 0.25 and 0.99. Furthermore, we have shown that these specimens can be utilized for PCR without encountering any inhibition problems. In our investigation, 230 out of 6,558 urethral and cervical swabs submitted for C. trachomatis screening by EIA over a period of 9 months, had s/co values ranging between of 0.25 and 0.99. Ninety (39.1%) of these specimens tested positive by PCR. These specimens were stable and gave reproducible PCR results before and after storage for a period of 9 months. This testing algorithm offers an effective way of detecting C. trachomatis with selective use of PCR while increasing the sensitivity of the EIA screening system.

In vitro activity of dirithromycin, a new macrolide antibiotic, against Mycoplasma species.

Dirithromycin is a new macrolide antibiotic that achieves high tissue concentration. We compared its in vitro activity against Mycoplasma species with that of erythromycin and tetracycline. Clinical isolates of M. pneumoniae (40), M. hominis (40), and Ureaplasma urealyticum (40) were tested against serial dilutions of three antibiotics using a microtiter plate method. Minimum inhibitory concentrations (MIC) were read as the lowest concentration of antibiotic yielding no color change in the broth. Neither macrolide antibiotic exhibited antimicrobial activity against M. hominis; MIC50 and MIC90 for tetracycline were 0.6 and 32 micrograms/ml, respectively. MIC50 for U. urealyticum was 4.0 micrograms/ml for dirithromycin, 2.0 micrograms/ml for erythromycin, and 1.0 micrograms/ml for tetracycline. MIC90 for U. urealyticum was > 128 micrograms/ml for all three agents. Against M. pneumoniae dirithromycin exhibited MIC50 of 0.1 micrograms/ml and MIC90 of 0.1 micrograms/ml. Both values for erythromycin were 0.2 micrograms/ml; for tetracycline they were 0.1 and 1.0 micrograms/ml, respectively. These results demonstrate the high in vitro activity of dirithromycin against M. pneumoniae and suggest that this agent may have a role in the treatment of respiratory Mycoplasma infections.