Zinc finger protein-440 promotes cartilage degenerative mechanisms in human facet and knee osteoarthritis chondrocytes.

OBJECTIVES: To investigate the role of zinc finger protein 440 (ZNF440) in the pathophysiology of cartilage degeneration during facet joint (FJ) and knee osteoarthritis (OA). METHODS: Expression of ZNF440 in FJ and knee cartilage was determined by immunohistochemistry, quantitative (q)PCR, and Western blotting (WB). Human chondrocytes isolated from FJ and knee OA cartilage were cultured and transduced with ZNF440 or control plasmid, or transfected with ZNF440 or control small interfering RNA (siRNA), with/without interleukin (IL)-1ß. Gene and protein levels of catabolic, anabolic and apoptosis markers were determined by qPCR or WB, respectively. In silico analyses were performed to determine compounds with potential to inhibit expression of ZNF440. RESULTS: ZNF440 expression was increased in both FJ and knee OA cartilage compared to control cartilage. In vitro, overexpression of ZNF440 significantly increased expression of MMP13 and PARP p85, and decreased expression of COL2A1. Knockdown of ZNF440 with siRNA partially reversed the catabolic and cell death phenotype of human knee and FJ OA chondrocytes stimulated with IL-1ß. In silico analysis followed by validation assays identified scriptaid as a compound with potential to downregulate the expression of ZNF440. Validation experiments showed that scriptaid reduced the expression of ZNF440 in OA chondrocytes and concomitantly reduced the expression of MMP13 and PARP p85 in human knee OA chondrocytes overexpressing ZNF440. CONCLUSIONS: The expression of ZNF440 is significantly increased in human FJ and knee OA cartilage and may regulate cartilage degenerative mechanisms. Furthermore, scriptaid reduces the expression of ZNF440 and inhibits its destructive effects in OA chondrocytes.

The IMEx coronavirus interactome: an evolving map of Coronaviridae-host molecular interactions.

The current coronavirus disease of 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2, has spurred a wave of research of nearly unprecedented scale. Among the different strategies that are being used to understand the disease and develop effective treatments, the study of physical molecular interactions can provide fine-grained resolution of the mechanisms behind the virus biology and the human organism response. We present a curated dataset of physical molecular interactions focused on proteins from SARS-CoV-2, SARS-CoV-1 and other members of the Coronaviridae family that has been manually extracted by International Molecular Exchange (IMEx) Consortium curators. Currently, the dataset comprises over 4400 binarized interactions extracted from 151 publications. The dataset can be accessed in the standard formats recommended by the Proteomics Standards Initiative (HUPO-PSI) at the IntAct database website (https://www.ebi.ac.uk/intact) and will be continuously updated as research on COVID-19 progresses.

The IMEx Coronavirus interactome: an evolving map of Coronaviridae-Host molecular interactions.

The current Coronavirus Disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has spurred a wave of research of nearly unprecedented scale. Among the different strategies that are being used to understand the disease and develop effective treatments, the study of physical molecular interactions enables studying fine-grained resolution of the mechanisms behind the virus biology and the human organism response. Here we present a curated dataset of physical molecular interactions, manually extracted by IMEx Consortium curators focused on proteins from SARS-CoV-2, SARS-CoV-1 and other members of the Coronaviridae family. Currently, the dataset comprises over 2,200 binarized interactions extracted from 86 publications. The dataset can be accessed in the standard formats recommended by the Proteomics Standards Initiative (HUPO-PSI) at the IntAct database website ( www.ebi.ac.uk/intact ), and will be continuously updated as research on COVID-19 progresses.

Publisher Correction: Capturing variation impact on molecular interactions in the IMEx Consortium mutations data set.

In the original HTML version of this Article, the order of authors within the author list was incorrect. The IMEx Consortium contributing authors were incorrectly listed as the last author and should have been listed as the first author. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.

Capturing variation impact on molecular interactions in the IMEx Consortium mutations data set.

The current wealth of genomic variation data identified at nucleotide level presents the challenge of understanding by which mechanisms amino acid variation affects cellular processes. These effects may manifest as distinct phenotypic differences between individuals or result in the development of disease. Physical interactions between molecules are the linking steps underlying most, if not all, cellular processes. Understanding the effects that sequence variation has on a molecule's interactions is a key step towards connecting mechanistic characterization of nonsynonymous variation to phenotype. We present an open access resource created over 14 years by IMEx database curators, featuring 28,000 annotations describing the effect of small sequence changes on physical protein interactions. We describe how this resource was built, the formats in which the data is provided and offer a descriptive analysis of the data set. The data set is publicly available through the IntAct website and is enhanced with every monthly release.

Tight focusing of laser light using a chromium Fresnel zone plate.

Using near-field scanning microscopy, we demonstrate that a 15-µm zone plate fabricated in a 70-nm chromium film sputtered on a glass substrate and having a focal length and outermost zone's width equal to the incident wavelength λ = 532 nm, focuses a circularly polarized Gaussian beam into a circular subwavelength focal spot whose diameter at the full-width of half-maximum intensity is FWHM = 0.47λ. This value is in near-accurate agreement with the FDTD-aided numerical estimate of FWHM = 0.46λ. When focusing a Gaussian beam linearly polarized along the y-axis, an elliptic subwavelength focal spot is experimentally found to measure FWHMx = 0.42λ (estimated value FWHMx = 0.40λ) and FWHMy = 0.64λ. The subwavelength focal spots presented here are the tightest among all attained so far for homogeneously polarized beams by use of non-immersion amplitude zone plates.

Thin high numerical aperture metalens.

We designed, fabricated, and characterized a thin metalens in an amorphous silicon film of diameter 30 µm, focal length equal to the incident wavelength 633 nm. The lens is capable of simultaneously manipulating the state of polarization and phase of incident light. The lens converts a linearly polarized beam into radially polarized light, producing a subwavelength focus. When illuminated with a linearly polarized Gaussian beam, the lens produces a focal spot whose size at full-width half-maximum intensity is 0.49λ and 0.55λ (λ is incident wavelength). The experimental results are in good agreement with the numerical simulation, with the simulated focal spot measuring 0.46λ and 0.52λ. This focal spot is less than all other focal spots obtained using metalenses.

Microlens-aided focusing of linearly and azimuthally polarized laser light.

We have investigated a four-sector transmission polarization converter (4-SPC) for a wavelength of 633 nm, that enables the conversion of a linearly polarized incident beam into a mixture of linearly and azimuthally polarized beams. It was numerically shown that by placing a Fresnel zone plate of focal length 532 nm immediately after the 4-SPC, the incident light can be focused into an oblong subwavelength focal spot whose size is smaller than the diffraction limit (with width and breadth, respectively, measuring FWHM = 0.28λ and FWHM = 0.45λ, where λ is the incident wavelength and FWHM stands for full-width at half maximum of the intensity). After passing through the 4-SPC, light propagates in free space over a distance of 300 µm before being focused by a Fresnel zone plate (ZP), resulting in focal spot measuring 0.42λ and 0.81λ. The focal spot was measured by a near-field microscope SNOM, and the transverse E-field component of the focal spot was calculated to be 0.42λ and 0.59λ. This numerical result was verified experimentally, giving a focal spot of smaller and larger size, respectively, measuring 0.46λ and 0.57λ. To our knowledge, this is the first implementation of polarization conversion and subwavelength focusing of light using a pair of transmission micro-optic elements.

Self-collimating photonic crystal polarization beam splitter.

We present theoretical and experimental results of a polarization splitter device that consists of a photonic crystal (PhC) slab, which exhibits a large reflection coefficient for TE and a high transmission coefficient for TM polarization. The slab is embedded in a PhC tile operating in the self-collimation mode. Embedding the polarization-discriminating slab in a PhC with identical lattice symmetry suppresses the in-plane diffraction losses at the PhC-non-PhC interface. The optimization of the PhC-non-PhC interface is thereby decoupled from the optimization of the polarizing function. Transmissions as high as 35% for TM- and 30% for TE-polarized light are reported.

An unusual presentation of sertraline and trazodone overdose.

OBJECTIVE: To report an unusual and life-threatening presentation of an overdose of sertraline and trazodone. CASE SUMMARY: A patient with a history of depression ingested sertraline 6,000 mg and trazodone 1,300 mg in a suicide attempt. Twenty-four hours after antidepressant administration, the patient presented with symptoms of selective serotonin-reuptake inhibitor (SSRI) overdose and serotonin syndrome, and later developed an enlarged tongue consistent with angioedema. A compromised airway resulted and endotracheal intubation was necessary. After intubation, the symptoms subsided and the patient recovered. DISCUSSION: Although SSRIs and trazodone are generally considered to be relatively safe in single-agent overdose, serious delayed reactions can occur, especially if several agents are involved. In this case the patient initially presented with symptoms typical of an SSRI overdose that did not appear to be exceptionally dangerous. Over time, symptoms consistent with angioedema appeared that necessitated intubation. Although previous reports of angioedema have been reported with SSRIs, this is the first report, to our knowledge, of a presentation this severe. CONCLUSIONS: This case demonstrates that overdose with the newer antidepressants can result in unusual and delayed presentations and must be treated with caution.

Effect of nonnicotine pharmacotherapy on smoking behavior.

Smoking-related disease is the single biggest preventable cause of morbidity and mortality in the United States, yet approximately 25% of Americans continue to smoke. Various dosage forms of nicotine replacement therapy increase smoking quit rates relative to placebo, but they generally do not result in 1-year quit rates of over 20%. To increase these rates, a number of nonnicotine agents have been investigated. Drugs that modulate noradrenergic neurotransmission (bupropion, nortriptyline, moclobemide) are more effective than those affecting serotonin (selective serotonin reuptake inhibitors, buspirone, ondansetron) or other neurotransmitters.

Effects of obesity on the cytochrome P450 enzyme system.

OBJECTIVE: This review evaluates the effect of obesity on the various isozymes of the cytochrome P450 enzyme system. MATERIALS AND METHOD: A Medline search of the international literature on drug metabolism and obesity from 1966 to early 1998 was conducted. All English language studies in humans that compared the pharmacokinetics of a given medication between obese and non-obese subjects were evaluated. Any study in which the substrate examined is excreted unchanged, not metabolized primarily by a single cytochrome P450 isozyme or which is considered a high extraction compound was excluded from this review. RESULTS: Despite the prevalence of obesity, the known health consequences of obesity and the increase of medication usage in the obese population, very few studies have attempted to establish the effect of this condition on the cytochrome P450 enzyme system. Numerous studies, however, have compared pharmacokinetic parameters between obese and non-obese subjects for individual drugs. By examining those trials in which the agents studied all undergo biotransformation via the same CYP450 isozyme, a preliminary appreciation of the effect of obesity on the activity of that particular isozyme can be attained. CONCLUSIONS: The effect of obesity on CYP450 appears to be isozyme-specific with the activity of cytochrome P450 3A4 decreasing and that of cytochrome P450 2E1 increasing. The effect of obesity on the cytochrome P450 1A2, 2C9, 2C19, and 2D6 isozymes is inconclusive.