Miracle-dz/UniFAR-FTUs huggingface dataset:
Memantine and Ketamine Differentially Alter NMDA Receptor Desensitization

Memantine and ketamine are clinically useful NMDA receptor (NMDAR) open channel blockers that inhibit NMDARs with similar potency and kinetics, but display vastly different clinical profiles. This discrepancy has been hypothesized to result from inhibition by memantine and ketamine of overlapping but distinct NMDAR subpopulations. For example, memantine but not ketamine may inhibit extrasynaptic NMDARs more effectively than synaptic NMDARs. However, the basis for preferential NMDAR inhibition depending on subcellular location has not been investigated systematically. We integrated recordings from heterologously expressed single NMDAR subtypes, kinetic modeling, and recordings of synaptically evoked NMDAR responses in acute brain slices to investigate mechanisms by which channel blockers may distinguish NMDAR subpopulations. We found that memantine and ketamine differentially alter NMDAR desensitization and that memantine stabilizes a Ca2+-dependent desensitized state. As a result, inhibition by memantine of GluN1/2A receptors in tsA201 cells and of native synaptic NMDARs in cortical pyramidal neurons from mice of either sex increased in conditions that enhanced intracellular Ca2+ accumulation. Therefore, differential inhibition by memantine and ketamine based on NMDAR location is likely to result from location dependence of the intensity and duration of NMDAR activation. Modulation of Ca2+-dependent NMDAR desensitization is an unexplored mechanism of inhibitory action with the potential to endow drugs with NMDAR selectivity that leads to superior clinical profiles. Our results suggest that designing compounds to target specific receptor states, rather than specific receptor types, may be a viable strategy for future drug development. SIGNIFICANCE STATEMENT Memantine and ketamine are NMDA receptor (NMDAR) channel-blocking drugs with divergent clinical effects. Understanding mechanistically their differential actions may advance our understanding of nervous system disorders and suggest strategies for the design of more effective drugs. Here, we show that memantine and ketamine have contrasting effects on NMDAR desensitization. Ketamine binding decreases occupancy of desensitized states of the GluN1/2B NMDAR subtype. In contrast, memantine binding increases occupancy of GluN1/2A and native NMDAR desensitized states entered after accumulation of intracellular Ca2+, a novel inhibitory mechanism. These properties may contribute to inhibition of distinct NMDAR subpopulations by memantine and ketamine and help to explain their differential clinical effects. Our results suggest stabilization of Ca2+-dependent desensitized states as a new strategy for pharmaceutical neuroprotection.
Alcohol Biomarkers Associated with Obstructive Sleep Apnea

ABSTRACT The views expressed in this presentation are those of the author and do not reflect the official policy of the Department of the Army/Navy/Air Force or the Department of Defense The identification of specific products or scientific instrumentation does not constitute an endorsement or implied endorsement on the part of the authors, DoD, or any component agency. While we generally excise references to products, companies, manufacturers, organizations, etc. in government produced works, the abstracts produced and other similarly situated researchers presents a special circumstance when such product inclusions become an integral part of the scientific endeavor.
Peptostreptococcus anaerobius Induces Intracellular Cholesterol Biosynthesis in Colon Cells to Induce Proliferation and Causes Dysplasia in Mice.

BACKGROUND & AIMS Stool samples from patients with colorectal cancer (CRC) have a higher abundance of Peptostreptococcus anaerobius than stool from individuals without CRC, based on metagenome sequencing. We investigated whether P anaerobius contributes to colon tumor formation in mice and its possible mechanisms of carcinogenesis. METHODS We performed quantitative polymerase chain reaction analyses to measure P anaerobius in 112 stool samples and 255 colon biopsies from patients with CRC or advanced adenoma and from healthy individuals (controls) undergoing colonoscopy examination at hospitals in Hong Kong and Beijing. C57BL/6 mice were given broad-spectrum antibiotics, followed by a single dose of azoxymethane, to induce colon tumor formation. Three days later, mice were given P anaerobius or Esherichia coli MG1655 (control bacteria), via gavage, for 6 weeks. Some mice were also given the nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin. Intestine tissues were collected and analyzed histologically. The colon epithelial cell line NCM460 and colon cancer cell lines HT-29 and Caco-2 were exposed to P anaerobius or control bacteria; cells were analyzed by immunoblot, proliferation, and bacterial attachment analyses and compared in gene expression profiling studies. Gene expression was knocked down in these cell lines with small interfering RNAs. RESULTS P anaerobius was significantly enriched in stool samples from patients with CRC and in biopsies from patients with colorectal adenoma or CRC compared with controls. Mice depleted of bacteria and exposed to azoxymethane and P anaerobius had a higher incidence of intestinal dysplasia (63%) compared with mice not given the bacteria (8.3%; P < .01). P anaerobius mainly colonized the colon compared with the rest of the intestine. Colon cells exposed to P anaerobius had significantly higher levels of proliferation than control cells. We found genes that regulate cholesterol biosynthesis, Toll-like receptor (TLR) signaling, and AMP-activated protein kinase signaling to be significantly up-regulated in cells exposed to P anaerobius. Total cholesterol levels were significantly increased in colon cell lines exposed to P anaerobius via activation of sterol regulatory element-binding protein 2. P anaerobius interacted with TLR2 and TLR4 to increase intracellular levels of reactive oxidative species, which promoted cholesterol synthesis and cell proliferation. Depletion of reactive oxidative species by knockdown of TLR2 or TLR4, or incubation of cells with an antioxidant, prevented P anaerobius from inducing cholesterol biosynthesis and proliferation. CONCLUSIONS Levels of P anaerobius are increased in human colon tumor tissues and adenomas compared with non-tumor tissues; this bacteria increases colon dysplasia in a mouse model of CRC. P anaerobius interacts with TLR2 and TLR4 on colon cells to increase levels of reactive oxidative species, which promotes cholesterol synthesis and cell proliferation.
Mechanism of gating by calcium in connexin hemichannels

Significance Connexin channels are ubiquitous, providing pathways for movement of molecules between cells (junctional channels) and for release of molecular effectors into the extracellular environment (plasma membrane hemichannels). To maintain an adequate permeability barrier, hemichannels are tightly regulated by normal extracellular Ca2+ to be closed under most conditions. Connexin mutations that disrupt hemichannel regulation by Ca2+ cause human pathologies due to aberrantly open hemichannels. Here we elucidate molecular mechanisms of gating by Ca2+ in hemichannels: Ca2+ binding causes a reorganization of specific interactions within the connexin protein that lead to a closed channel. Further, we show that the actual “gate” is deeper into the pore from where Ca2+ binds. The interactions involved are conserved across connexins, pointing to a general mechanism. Aberrant opening of nonjunctional connexin hemichannels at the plasma membrane is associated with many diseases, including ischemia and muscular dystrophy. Proper control of hemichannel opening is essential to maintain cell viability and is achieved by physiological levels of extracellular Ca2+, which drastically reduce hemichannel activity. Here we examined the role of conserved charged residues that form electrostatic networks near the extracellular entrance of the connexin pore, a region thought to be involved in gating rearrangements of hemichannels. Molecular dynamics simulations indicate discrete sites for Ca2+ interaction and consequent disruption of salt bridges in the open hemichannels. Experimentally, we found that disruption of these salt bridges by mutations facilitates hemichannel closing. Two negatively charged residues in these networks are putative Ca2+ binding sites, forming a Ca2+-gating ring near the extracellular entrance of the pore. Accessibility studies showed that this Ca2+-bound gating ring does not prevent access of ions or small molecules to positions deeper into the pore, indicating that the physical gate is below the Ca2+-gating ring. We conclude that intra- and intersubunit electrostatic networks at the extracellular entrance of the hemichannel pore play critical roles in hemichannel gating reactions and are tightly controlled by extracellular Ca2+. Our findings provide a general mechanism for Ca2+ gating among different connexin hemichannel isoforms.
Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study

Abstract Objective: To assess the prognostic influence of pre-morbid type 2 diabetes mellitus, arterial hypertension and cardiovascular (CV) risk profile on ALS phenotype and outcome in a population-based cohort of Italian patients. Methods: A total of 650 ALS patients from the Piemonte/Valle d’Aosta Register for ALS, incident in the 2007–2011 period, were recruited. Information about premorbid presence of type 2 diabetes mellitus, arterial hypertension was collected at the time of diagnosis. Patients’ CV risk profile was calculated according to the Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice (JBS2). Results: At the univariate analysis, the presence of pre-morbid arterial hypertension was associated with a higher age at onset of ALS and a shorter survival, and patients with a high CV risk profile had a worse prognosis than those with a low CV risk profile. The Cox multivariable analysis did not confirm such findings. Type 2 diabetes mellitus did not modify either the phenotype or the prognosis of ALS patients. Conclusions: This study performed on a large population-based cohort of ALS patients has demonstrated that arterial hypertension, type 2 diabetes and CV risk factors, calculated using the Framingham equation, do not influence ALS phenotype and prognosis.
Multidrug-Resistant Salmonella enterica 4,[5],12:i:- Sequence Type 34, New South Wales, Australia, 2016–2017

Multidrug- and colistin-resistant Salmonella enterica serotype 4,[5],12:i:- sequence type 34 is present in Europe and Asia. Using genomic surveillance, we determined that this sequence type is also endemic to Australia. Our findings highlight the public health benefits of genome sequencing–guided surveillance for monitoring the spread of multidrug-resistant mobile genes and isolates.
Monte Carlo modelling of photodynamic therapy treatments comparing clustered three dimensional tumour structures with homogeneous tissue structures

We explore the effects of three dimensional (3D) tumour structures on depth dependent fluence rates, photodynamic doses (PDD) and fluorescence images through Monte Carlo radiation transfer modelling of photodynamic therapy. The aim with this work was to compare the commonly used uniform tumour densities with non-uniform densities to determine the importance of including 3D models in theoretical investigations. It was found that fractal 3D models resulted in deeper penetration on average of therapeutic radiation and higher PDD. An increase in effective treatment depth of 1 mm was observed for one of the investigated fractal structures, when comparing to the equivalent smooth model. Wide field fluorescence images were simulated, revealing information about the relationship between tumour structure and the appearance of the fluorescence intensity. Our models indicate that the 3D tumour structure strongly affects the spatial distribution of therapeutic light, the PDD and the wide field appearance of surface fluorescence images.
Speech intelligibility benefits of frequency-lowering algorithms in adult hearing aid users: a systematic review and meta-analysis

Abstract Objective: This systematic review evaluated the effectiveness of two frequency-lowering schemes, non-linear frequency compression and frequency transposition, at improving speech intelligibility for adult hearing-impaired populations. Design: A systematic search of 10 electronic databases was carried out using pre-defined inclusion criteria. Accepted articles were then critically appraised using the Effective Public Health Practice Project (EPHPP) Critical Appraisal Tool. Outcome results were further synthesised where possible using random effects meta-analysis to provide overall combined estimates of the treatment differences along with 95% confidence intervals. Study sample: A total of 20 articles were accepted for final review. Results: Overall, study quality was of moderate strength. Meta-analysis found a statistically significant benefit in favour of frequency-lowering for consonant recognition testing in quiet across 145 participants with both algorithms providing comparable gains. Equivalent results were found between frequency-lowering and conventional processing on all other speech measures. Conclusions: Based on the available data, frequency-lowering does seem to provide some improvement in an individual’s speech intelligibility dependant on the stimulus type, although the benefits were modest. This improvement was not seen across all measures, however those who do not benefit from the technology will also not be harmed by trialling it.
Microwave-Assisted Extraction of Natural Antioxidants from the Exotic Gordonia axillaris Fruit: Optimization and Identification of Phenolic Compounds

Our previous study reported that the fruit of Gordonia axillaris, an edible wild fruit, possessed strong antioxidant activity. In this study, a microwave-assisted extraction (MAE) method was established to extract antioxidants from the fruit of Gordonia axillaris. The influence of five parameters, including ethanol concentration, solvent/material ratio, extraction time, extraction temperature and microwave power, was investigated by single-factor experiments. Three factors, namely ethanol concentration, solvent/material ratio, extraction time, were found to exert a major influence on extraction efficacy, and were further studied by response surface methodology to investigate their interactions. Ethanol concentration of 36.89%, solvent/material ratio of 29.56 mL/g, extraction time of 71.04 min, temperature of 40 °C, and microwave power of 400 W were found to be the optimal condition. The TEAC value was 198.16 ± 5.47 µmol Trolox/g DW under the optimal conditions, which was in conformity to the predicted value (200.28 µmol Trolox/g DW). In addition, the MAE method was compared with two conventional methods (Soxhlet extraction and maceration extraction). Results showed that the antioxidant capacity of the extract obtained by MAE method was stronger than that obtained by maceration (168.67 ± 3.88 µmol Trolox/g DW) or Soxhlet extraction (114.09 ± 2.01 µmol Trolox/g DW). Finally, several phenolic compounds in the extract were identified and quantified by UPLC-MS/MS, which were rutin, gallic acid, protocatechuic acid, epicatechin, epicatechin gallate, 2-hydrocinnamic acid, p-coumaric acid, quercetin, chlorogenic acid and ferulic acid.
Permeation of macromolecules into the renal glomerular basement membrane and capture by the tubules

Significance Human kidneys contain ∼2 x 106 glomeruli that produce ∼180 L per day of primary filtrate. Downstream tubules reabsorb most of the water, salt, and desirable low-molecular weight substances, leaving 1 to 2 L per day of urine containing undesirable waste products. Currently, most investigators think that the primary filtrate is low in protein because fluid exiting the glomerulus passes through slits spanned by a diaphragm that acts as a low-porosity molecular sieve. Our experiments challenge this view; they show that size-dependent permeation into the glomerular basement membrane and into a gel-like coat that covers the slits, together with saturable tubular reabsorption, determines which macromolecules reach the urine. The slit diaphragm is essential for capillary structure but may not directly determine glomerular size selectivity. How the kidney prevents urinary excretion of plasma proteins continues to be debated. Here, using unfixed whole-mount mouse kidneys, we show that fluorescent-tagged proteins and neutral dextrans permeate into the glomerular basement membrane (GBM), in general agreement with Ogston's 1958 equation describing how permeation into gels is related to molecular size. Electron-microscopic analyses of kidneys fixed seconds to hours after injecting gold-tagged albumin, negatively charged gold nanoparticles, and stable oligoclusters of gold nanoparticles show that permeation into the lamina densa of the GBM is size-sensitive. Nanoparticles comparable in size with IgG dimers do not permeate into it. IgG monomer-sized particles permeate to some extent. Albumin-sized particles permeate extensively into the lamina densa. Particles traversing the lamina densa tend to accumulate upstream of the podocyte glycocalyx that spans the slit, but none are observed upstream of the slit diaphragm. At low concentrations, ovalbumin-sized nanoparticles reach the primary filtrate, are captured by proximal tubule cells, and are endocytosed. At higher concentrations, tubular capture is saturated, and they reach the urine. In mouse models of Pierson’s or Alport’s proteinuric syndromes resulting from defects in GBM structural proteins (laminin β2 or collagen α3 IV), the GBM is irregularly swollen, the lamina densa is absent, and permeation is increased. Our observations indicate that size-dependent permeation into the lamina densa of the GBM and the podocyte glycocalyx, together with saturable tubular capture, determines which macromolecules reach the urine without the need to invoke direct size selection by the slit diaphragm.
Four-Stage Procedure for Keratoconus: ICRS Implantation, Corneal Cross-linking, Toric Phakic Intraocular Lens Implantation, and Topography-Guided Photorefractive Keratectomy.

PURPOSE To evaluate a four-stage combined treatment for keratoconus including intrastromal corneal ring segment (ICRS) implantation followed by corneal cross-linking (CXL), toric phakic intraocular lens (IOL) implantation, and topography-guided photorefractive keratectomy (TG-PRK). METHODS In this retrospective interventional case series, 11 eyes of 7 patients with progressive keratoconus were treated with a four-stage procedure including the following: Keraring ICRS (Mediphacos Ltda, Belo Horizonte, Brazil) implantation followed by CXL, phakic IOL implantation, and TG-PRK (minimum 6 months between each stage). Minimum follow-up was 12 months after TG-PRK. RESULTS Both mean uncorrected distance visual acuity and corrected distance visual acuity (CDVA) improved from 0.025 decimal (20/800 Snellen) and 0.093 decimal (20/215 Snellen) preoperatively to 0.68 decimal (20/30 Snellen) and 0.73 decimal (20/27 Snellen), respectively, after the combined treatment (P < .0001). Mean postoperative CDVA of 0.73 decimal (20/27 Snellen) was similar to preoperative contact lens CDVA of 0.72 decimal (20/28 Snellen). Mean manifest refraction spherical equivalent reduced from 16.78 ± 3.58 to 0.59 ± 0.89 diopters (P < .0001) and mean refractive astigmatism reduced from 5.16 ± 1.86 to 0.82 ± 0.28 diopters (P < .0001). CONCLUSIONS This four-stage procedure appears to be an effective and safe approach for corneal stabilization and improvement of functional vision in patients with keratoconus. Larger case series with a longer follow-up are required to thoroughly evaluate the efficacy, safety, and stability of this combined approach. [J Refract Surg. 2017;33(10):683-689. ].
Pulsed-High Intensity Focused Ultrasound and Low Temperature–Sensitive Liposomes for Enhanced Targeted Drug Delivery and Antitumor Effect

Purpose: To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. Experimental Design: Comparisons in vitro and in vivo were carried out between non–thermosensitive liposomes (NTSL) and low temperature–sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. Results:In vitro incubations simulating the pulsed-HIFU thermal dose (42°C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.
Neuropsychological investigation of "the amazing memory man".

OBJECTIVE Mnemonists, memory champions, and persons with highly superior autobiographical memory (HSAM) are apparently rare breeds, with no more than a few dozen cases of each described in the neuroscientific literature. This report describes a newly discovered HSAM case who has extraordinary memory for a wider range of material than has heretofore been described. METHOD Subject MM was interviewed about his personal life and administered standard clinical tests of cognition and personality, as well as experimental tasks assessing personal and generic episodic and semantic memory. Finally, he was studied with high resolution structural MRI of the medial temporal lobes, as well as brain connectivity analysis using resting-state functional MRI. RESULTS MM's ability to recall general factual information, historical facts and dates, sports statistics, and popular culture, as well as personal life experiences, is exceptional, even though he performs in only the average range on tests of intellect and new learning ability. Unlike most mnemonists, he denies using any specific mnemonic strategy and, unlike many other HSAM cases, is unable to recall highly specific details of days in his adult life. Structural brain imaging in MM reveals atypical anatomy in his left temporal lobe, and functional neuroimaging suggests greater than usual connectivity of the left hippocampus with premotor, prefrontal and retrosplenial cingulate cortex. CONCLUSIONS These observations are discussed in the context of previous studies of mnemonists and HSAM cases, some of which implicate hyperconnectivity among components of an expanded memory network in extraordinary memory retrieval. (PsycINFO Database Record
Fentanyl novel derivative‐related deaths

Fentanyl (FEN) is a potent, synthetic narcotic used as an anaesthetic and a pain reliever, but also illegally manufactured. For diversion purpose, it is being steadily modified to produce new analogous compounds and derivatives (FENS), categorised as novel psychoactive substances. While potential FEN abuse is already known, even in the absence of a clear lethal dosage, there is still a shortage of data on its derivatives.