Kv7/M-type potassium channels in rat skin keratinocytes

Skin keratinocytes fulfil important signalling and protective functions. Immunocytochemical experiments revealed the unexpected presence of immunoreactivity for the M-type potassium channel subunit Kv7.2 in the keratinocyte layer of intact rat paw skin and in keratinocytes isolated from the skin of 1-day-old rats and cultured in vitro for 3–10 days. Application of the M-channel enhancer retigabine (3–10 μM) to isolated cultured rat keratinocytes: (a) increased outward membrane currents recorded under voltage clamp, (b) produced ~3 mV hyperpolarization at rest, (c) enhanced ~3-fold the release of ATP induced by the TRPV3 agonist carvacrol (1 mM) and (d) increased the amplitude of the carvacrol-induced intracellular Ca²⁺ transient measured with Fura-2. The effect of retigabine on ATP release was prevented by the M-channel blocking agent XE991. We conclude that rat skin keratinocytes possess M-channels that, when activated, can modify their physiological properties, with potential significance for their sensory and other biological functions.     

Complete genome sequences of infectious spleen and kidney necrosis virus isolated from farmed albino rainbow sharks Epalzeorhynchos frenatum in the United States

Virus Genes - The genus Megalocytivirus includes viruses known to cause significant disease in aquacultured fish stocks. Herein, we report the complete genome sequences of two megalocytiviruses...     

cheML.io: an online database of ML-generated molecules

Several recent ML algorithms for de novo molecule generation have been utilized to create an open-access database of virtual molecules. The algorithms were trained on samples from ZINC, a free database of commercially available compounds. Generated molecules, stemming from 10 different ML frameworks, along with their calculated properties were merged into a database and coupled to a web interface, which allows users to browse the data in a user friendly and convenient manner. ML-generated molecules with desired structures and properties can be retrieved with the help of a drawing widget. For the case of a specific search leading to insufficient results, users are able to create new molecules on demand. These newly created molecules will be added to the existing database and as a result, the content as well as the diversity of the database keeps growing in line with the user''s requirements.

Several recent ML algorithms for de novo molecule generation have been utilized to create an open-access database of virtual molecules.     

COVID-19 Impact on Kazakhstan University Student Fear,Mental Health,and Substance Use

International Journal of Mental Health and Addiction -     

Differences in sleep-induced hypoxia between A/J and DBA/2J mouse strains

In obstructive sleep apnea, hypoxic ventilatory sensitivity may affect the degree of hypoxic stress and sleep disruption that occurs in response to upper airway obstruction. We induced (1) sleep-induced hypoxia (SIH) or (2) sleep fragmentation (SF) without hypoxia for 5 days (12-hour light/dark cycle) in two inbred mouse strains with low (A/J) and high (DBA/2J) hypoxic ventilatory sensitivities. During SIH, the time to arousal (26.4 +/- 1.1 vs. 21.3 +/- 1.5 seconds, p<0.025) and the severity of hypoxic exposure (nadir FIO2: 11.5 +/- 0.4 vs. 13.6 +/- 0.1%, p<0.002) was greater in A/J than DBA/2J mice. Furthermore, A/J mice had a greater frequency of hypoxic events (640 +/- 29 vs. 368 +/- 33 events per 24 hours, p<0.001) and total sleep time (47.5 +/- 2.8% vs. 26.5 +/- 2.4% per 24 hours, p<0.0001) during SIH than DBA/2J mice. In contrast, the event characteristics and total sleep time during SF were the same in both strains. Furthermore, in the light phase, both strains showed a longer (p<0.01) time to arousal during SIH and SF compared with the dark phase. We conclude that genetic background can influence respiratory events and sleep architecture during SIH and that the arousal threshold is subject to circadian variation. Our data imply that individuals with low hypoxic sensitivity may be at a greater risk for hypoxia-related complications of obstructive sleep apnea.     

Collagen/Chitosan Gels Cross-Linked with Genipin for Wound Healing in Mice with Induced Diabetes

Diabetes mellitus continues to be one of the most common diseases often associated with diabetic ulcers. Chitosan is an attractive biopolymer for wound healing due to its biodegradability, biocompatibility, mucoadhesiveness, low toxicity, and hemostatic effect. A panel of hydrogels based on chitosan, collagen, and silver nanoparticels were produced to treat diabetic wounds. The antibacterial activity, cytotoxicity, swelling, rheological properties, and longitudinal sections of hydrogels were studied. The ability of the gels for wound healing was studied in CD1 mice with alloxan-induced diabetes. Application of the gels resulted in an increase in VEGF, TGF-b1, IL-1b, and TIMP1 gene expression and earlier wound closure in a comparison with control untreated wounds. All gels increased collagen deposition, hair follicle repair, and sebaceous glands formation. The results of these tests show that the obtained hydrogels have good mechanical properties and biological activity and have potential applications in the field of wound healing. However, clinical studies are required to compare the efficacy of the gels as animal models do not reproduce full diabetes pathology.     

Facing successfully high mental workload and stressors: An fMRI study

The present fMRI study aimed at highlighting patterns of brain activations and autonomic activity when confronted with high mental workload and the threat of auditory stressors. Twenty participants performed a complex cognitive task in either safe or aversive conditions. Our results showed that increased mental workload induced recruitment of the lateral frontoparietal executive control network (ECN), along with disengagement of medial prefrontal and posterior cingulate regions of the default mode network (DMN). Mental workload also elicited an increase in heart rate and pupil diameter. Task performance did not decrease under the threat of stressors, most likely due to efficient inhibition of auditory regions, as reflected by a large decrement of activity in the superior temporal gyri. The threat of stressors was also accompanied with deactivations of limbic regions of the salience network (SN), possibly reflecting emotional regulation mechanisms through control from dorsal medial prefrontal and parietal regions, as indicated by functional connectivity analyses. Meanwhile, the threat of stressors induced enhanced ECN activity, likely for improved attentional and cognitive processes toward the task, as suggested by increased lateral prefrontal and parietal activations. These fMRI results suggest that measuring the balance between ECN, SN, and DMN recruitment could be used for objective mental state assessment. In this sense, an extra recruitment of task‐related regions and a high ratio of lateral versus medial prefrontal activity may represent a relevant marker of increased but efficient mental effort, while the opposite may indicate a disengagement from the task due to mental overload and/or stressors.     

Arrestin Facilitates Rhodopsin Dephosphorylation in Vivo

Deactivation of G-protein-coupled receptors (GPCRs) involves multiple phosphorylations followed by arrestin binding, which uncouples the GPCR from G-protein activation. Some GPCRs, such as rhodopsin, are reused many times. Arrestin dissociation and GPCR dephosphorylation are key steps in the recycling process. In vitro evidence suggests that visual arrestin (ARR1) binding to light-activated, phosphorylated rhodopsin hinders dephosphorylation. Whether ARR1 binding also affects rhodopsin dephosphorylation in vivo is not known. We investigated this using both male and female mice lacking ARR1. Mice were exposed to bright light and placed in darkness for different periods of time, and differently phosphorylated species of rhodopsin were assayed by isoelectric focusing. For WT mice, rhodopsin dephosphorylation was nearly complete by 1 h in darkness. Surprisingly, we observed that, in the Arr1 KO rods, rhodopsin remained phosphorylated even after 3 h. Delayed dephosphorylation in Arr1 KO rods cannot be explained by cell stress induced by persistent signaling, since it is not prevented by the removal of transducin, the visual G-protein, nor can it be explained by downregulation of protein phosphatase 2A, the putative rhodopsin phosphatase. We further show that cone arrestin (ARR4), which binds light-activated, phosphorylated rhodopsin poorly, had little effect in enhancing rhodopsin dephosphorylation, whereas mice expressing binding-competent mutant ARR1-3A showed a similar time course of rhodopsin dephosphorylation as WT. Together, these results reveal a novel role of ARR1 in facilitating rhodopsin dephosphorylation in vivo.SIGNIFICANCE STATEMENT G-protein-coupled receptors (GPCRs) are transmembrane proteins used by cells to receive and respond to a broad range of extracellular signals that include neurotransmitters, hormones, odorants, and light (photons). GPCR signaling is terminated by two sequential steps: phosphorylation and arrestin binding. Both steps must be reversed when GPCRs are recycled and reused. Dephosphorylation, which is required for recycling, is an understudied process. Using rhodopsin as a prototypical GPCR, we discovered that arrestin facilitated rhodopsin dephosphorylation in living mice.     

Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase

Obstructive sleep apnea leads to chronic intermittent hypoxia (CIH) and is associated with atherosclerosis. We have previously shown that C57BL/6J mice exposed to CIH and a high-cholesterol diet develop dyslipidemia, atherosclerosis of the aorta, and upregulation of a hepatic enzyme of lipoprotein secretion, stearoyl coenzyme A desaturase 1 (SCD-1). We hypothesized that (1) SCD-1 deficiency will prevent dyslipidemia and atherosclerosis during CIH; and (2) human OSA is associated with dyslipidemia and upregulation of hepatic SCD. C57BL/6J mice were exposed to CIH or normoxia for 10 weeks while being treated with either SCD-1 or control antisense oligonucleotides. Obese human subjects underwent sleep study and bariatric surgery with intraoperative liver biopsy. In mice, hypoxia increased hepatic SCD-1 and plasma very-low-density lipoprotein cholesterol levels and induced atherosclerosis lesions in the ascending aorta (the cross-section area of 156514+/-57408 microm(2)), and descending aorta (7.0+/-1.2% of the total aortic surface). In mice exposed to CIH and treated with SCD-1 antisense oligonucleotides, dyslipidemia and atherosclerosis in the ascending aorta were abolished, whereas lesions in the descending aorta showed 56% reduction. None of the mice exposed to normoxia developed atherosclerosis. In human subjects, hepatic SCD mRNA levels correlated with the degree of nocturnal hypoxemia (r=0.68, P=0.001). Patients exhibiting oxyhemoglobin desaturations at night showed higher plasma triglyceride and low-density lipoprotein cholesterol levels, compared to subjects without hypoxemia. In conclusion, CIH is associated with dyslipidemia and overexpression of hepatic SCD in both humans and mice alike; SCD-1 deficiency attenuates CIH-induced dyslipidemia and atherosclerosis in mice.