Computational prediction of interactions between Paxlovid and prescription drugs.

Pfizer's Paxlovid has recently been approved for the emergency use authorization (EUA) from the US Food and Drug Administration (FDA) for the treatment of mild-to-moderate COVID-19. Drug interactions can be a serious medical problem for COVID-19 patients with underlying medical conditions, such as hypertension and diabetes, who have likely been taking other drugs. Here, we use deep learning to predict potential drug-drug interactions between Paxlovid components (nirmatrelvir and ritonavir) and 2,248 prescription drugs for treating various diseases.

Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy.

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ+ and interleukin-10+ regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases.

Enteric Viruses Ameliorate Gut Inflammation via Toll-like Receptor 3 and Toll-like Receptor 7-Mediated Interferon-ß Production.

Metagenomic studies show that diverse resident viruses inhabit the healthy gut; however, little is known about the role of these viruses in the maintenance of gut homeostasis. We found that mice treated with antiviral cocktail displayed more severe dextran sulfate sodium (DSS)-induced colitis compared with untreated mice. DSS-induced colitis was associated with altered enteric viral abundance and composition. When wild-type mice were reconstituted with Toll-like receptor 3 (TLR3) or TLR7 agonists or inactivated rotavirus, colitis symptoms were significantly ameliorated. Mice deficient in both TLR3 and TLR7 were more susceptible to DSS-induced experimental colitis. In humans, combined TLR3 and TLR7 genetic variations significantly influenced the severity of ulcerative colitis. Plasmacytoid dendritic cells isolated from inflamed mouse colon produced interferon-ß in a TLR3 and TLR7-dependent manner. These results imply that recognition of resident viruses by TLR3 and TLR7 is required for protective immunity during gut inflammation.

SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.

Downregulation of otulin induces inflammasome activation in neutrophilic asthma.

BACKGROUND: Neutrophilic asthma (NA) is a severe asthma phenotype associated with steroid resistance and IL-1ß overproduction; however, the exact mechanism remains unclear. Moreover, the dysfunction of TNF-α signaling pathway, a regulator of IL-1ß production, was associated with the deficiency of ovarian tumor protease deubiquitinase with linear linkage specificity (otulin) in autoimmune patients. OBJECTIVE: We hypothesized that otulin downregulation in macrophages (Mφ) could trigger Mφ activation via the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling pathway. METHODS: We assessed the expressions of otulin in blood monocyte subsets from NA patients and in alveolar Mφ from NA mice. Additionally, we evaluated the functional consequences of otulin deficiency in bone marrow-derived Mφ. The effects of inhibiting receptor-interacting protein kinase (RIPK)-1 and RIPK-3 on neutrophils and group 3 innate lymphoid cells (ILC3s) were assessed in vitro and in vivo. RESULTS: When comparing nonclassical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients compared to healthy controls (P = .005). Moreover, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. After otulin knockdown in bone marrow-derived Mφ, we observed spontaneous IL-1ß production depending on NLRP3 inflammasome. Moreover, the infiltrated neutrophils and ILC3s were significantly decreased by combined treatment of RIPK-1 and RIPK-3 inhibitors through blocking IL-1ß release in NA. CONCLUSIONS: IL-1ß overproduction caused by a deficiency of otulin, an upstream triggering factor, could be a promising diagnostic and therapeutic target for NA.

Anti-inflammatory effect of Trichospira verticillata via suppression of the NLRP3 inflammasome in neutrophilic asthma.

Trichospira verticillata is an annual herb that belongs to the family Asteraceae. Trichospira verticillata extract (TVE) elicits anti-plasmodial activity; however, there has been no detailed report about its anti-inflammatory effects and molecular mechanisms. In addition, herbal plants exhibit anti-inflammatory effects by suppressing the NLRP3 inflammasome. Therefore, the primary goal of this study was to examine the effects of TVE on NLRP3 inflammasome activation by measuring interleukin-1ß (IL-1ß) secretion. We treated lipopolysaccharides (LPS)-primed J774A.1 and THP-1 cells with TVE, which attenuated NLRP3 inflammasome activation. Notably, TVE did not affect nuclear factor-kappa B (NF-κB) signalling or intracellular reactive oxygen species (ROS) production and potassium efflux, suggesting that it inactivates the NLRP3 inflammasome via other mechanisms. Moreover, TVE suppressed the formation of apoptosis-associated speck-like protein (ASC) speck and oligomerization. Immunoprecipitation data revealed that TVE reduced the binding of NLRP3 to NIMA-related kinase 7 (NEK7), resulting in reduced ASC oligomerization and speck formation. Moreover, TVE alleviated neutrophilic asthma (NA) symptoms in mice. This study demonstrates that TVE modulates the binding of NLPR3 to NEK7, thereby reporting novel insights into the mechanism by which TVE inhibits NLRP3 inflammasome. These findings suggest TVE as a potential therapeutic of NLRP3 inflammasome-mediated diseases, particularly NA.

The role of the microbiota in myelopoiesis during homeostasis and inflammation.

The microbiota engages in the development and maintenance of the host immune system. The microbiota affects not only mucosal tissues where it localizes but also the distal organs. Myeloid cells are essential for host defense as first responders of the host immune system. Their generation, called myelopoiesis, is regulated by environmental signals, including commensal microbiota. Hematopoietic stem and progenitor cells in bone marrow can directly or indirectly sense microbiota-derived signals, thereby giving rise to myeloid cell lineages at steady-state and during inflammation. In this review, we discuss the role of commensal microorganisms in the homeostatic regulation of myelopoiesis in the bone marrow. We also outline the effects of microbial signals on myelopoiesis during inflammation and infection, with a particular focus on the development of innate immune memory. Studying the relationship between the microbiota and myelopoiesis will help us understand how the microbiota regulates immune responses at a systemic level beyond the local mucosa.

Synthetic ShK-like Peptide from the Jellyfish Nemopilema nomurai Has Human Voltage-Gated Potassium-Channel-Blocking Activity.

We identified a new human voltage-gated potassium channel blocker, NnK-1, in the jellyfish Nemopilema nomurai based on its genomic information. The gene sequence encoding NnK-1 contains 5408 base pairs, with five introns and six exons. The coding sequence of the NnK-1 precursor is 894 nucleotides long and encodes 297 amino acids containing five presumptive ShK-like peptides. An electrophysiological assay demonstrated that the fifth peptide, NnK-1, which was chemically synthesized, is an effective blocker of hKv1.3, hKv1.4, and hKv1.5. Multiple-sequence alignment with cnidarian Shk-like peptides, which have Kv1.3-blocking activity, revealed that three residues (3Asp, 25Lys, and 34Thr) of NnK-1, together with six cysteine residues, were conserved. Therefore, we hypothesized that these three residues are crucial for the binding of the toxin to voltage-gated potassium channels. This notion was confirmed by an electrophysiological assay with a synthetic peptide (NnK-1 mu) where these three peptides were substituted with 3Glu, 25Arg, and 34Met. In conclusion, we successfully identified and characterized a new voltage-gated potassium channel blocker in jellyfish that interacts with three different voltage-gated potassium channels. A peptide that interacts with multiple voltage-gated potassium channels has many therapeutic applications in various physiological and pathophysiological contexts.

Does prior rotator cuff surgery influence the outcomes and complications after reverse total shoulder arthroplasty in patients with cuff tear arthropathy or massive rotator cuff tear? A propensity score-matched study.

BACKGROUND: The aim of this study was to compare outcomes and complications in patients with and without a history of prior rotator cuff surgery who underwent reverse total shoulder arthroplasty (RTSA). METHODS: Two-hundred and nine consecutive patients who had undergone RTSA for rotator cuff insufficiency with a minimum 12-months follow-up period were reviewed. A total of 35 patients with a history of prior rotator cuff surgery were made the study group (PS group). Using propensity score matching for age and sex, these patients were matched 1:3 with a control group of 105 patients with no history of prior surgery (NPS group). The mean follow-up period was 41.4 months. RESULTS: Both groups showed a significant improvement of clinical scores and range of motion after RTSA. The PS group showed a significantly higher final visual analog scale (VAS) pain score compared with the NPS group (P = 0.020). The PS group showed a significantly higher incidence of acromial stress fracture compared with the NPS group (17.1% vs 4.8%, P = 0.018), but no significant difference in the overall complication rate was observed (25.7% vs 13.3%, P > 0.05). The PS group showed a significantly higher reoperation rate compared with the NPS group (14.3% vs 1.9%, P = 0.004). CONCLUSIONS: Our study demonstrated that a history of prior rotator cuff surgery was associated with a high incidence of acromial stress fracture and reoperation after RTSA as well as a high final VAS pain score, although satisfactory clinical outcomes after RTSA were achieved in both groups.

Reliability of self-reported dispositional mindfulness scales and their association with working memory performance and functional connectivity.

We systematically investigated the link between trait mindfulness scores and functional connectivity (FC) features or behavioral data, to emphasize the importance of the reliability of self-report mindfulness scores. Sixty healthy young male participants underwent two functional MRI runs with three mindfulness or mind-wandering task blocks with an N-back task (NBT) block. The data from 49 participants (age: 23.3 ± 2.8) for whom two sets of the self-reported Mindfulness Attention Awareness Scale (MAAS) and NBT performance were available were analyzed. We divided participants into two groups based on the consistency level of their MAAS scores (i.e., a "consistent" and an "inconsistent" group). Then, the association between the MAAS scores and FC features or NBT performance was investigated using linear regression analysis with p-value correction and bootstrapping. Meaningful associations (a) between MAAS and NBT accuracy (slope = 0.41, CI = [0.10, 0.73], corrected p < 0.05), (b) between MAAS and the FC edges in the frontoparietal network, and (c) between the FC edges and NBT performance were only observed in the consistent group (n = 26). Our findings demonstrate the importance of appropriate screening mechanisms for self-report-based dispositional mindfulness scores when trait mindfulness scores are combined with neuronal features and behavioral data.

Human METTL18 is a histidine-specific methyltransferase that targets RPL3 and affects ribosome biogenesis and function.

Protein methylation occurs primarily on lysine and arginine, but also on some other residues, such as histidine. METTL18 is the last uncharacterized member of a group of human methyltransferases (MTases) that mainly exert lysine methylation, and here we set out to elucidate its function. We found METTL18 to be a nuclear protein that contains a functional nuclear localization signal and accumulates in nucleoli. Recombinant METTL18 methylated a single protein in nuclear extracts and in isolated ribosomes from METTL18 knockout (KO) cells, identified as 60S ribosomal protein L3 (RPL3). We also performed an RPL3 interactomics screen and identified METTL18 as the most significantly enriched MTase. We found that His-245 in RPL3 carries a 3-methylhistidine (3MH; τ-methylhistidine) modification, which was absent in METTL18 KO cells. In addition, both recombinant and endogenous METTL18 were found to be automethylated at His-154, thus further corroborating METTL18 as a histidine-specific MTase. Finally, METTL18 KO cells displayed altered pre-rRNA processing, decreased polysome formation and codon-specific changes in mRNA translation, indicating that METTL18-mediated methylation of RPL3 is important for optimal ribosome biogenesis and function. In conclusion, we have here established METTL18 as the second human histidine-specific protein MTase, and demonstrated its functional relevance.

Indoor particulate matter induces epigenetic changes in companion atopic dogs.

The prevalence of atopic dermatitis (AD) is increasing and environmental factors are receiving attention as contributing causes. Indoor air pollutants (IAPs), especially particulate matter (PM) can alter epigenetic markers, DNA methylation (DNAm). Although DNAm-mediated epigenetic changes have been reported to modulate the pathogenesis of AD, their role at high risk of exposure to PM is still unclear. The study investigated the effects of exposure to IAPs in the development of AD and epigenetic changes through DNAm in companion atopic dogs that share indoor environment with their owners. Dogs were divided into two groups: AD (n = 47) and controls (n = 21). The IAPs concentration in each household was measured for 48 h, and a questionnaire on the residential environment was completed in all dogs. Eighteen dogs with AD and 12 healthy dogs were selected for DNAm analysis. In addition, clinical and immunological evaluations were conducted. The concentrations of PM2.5, PM10, and volatile organic compounds (VOCs) were significantly higher in the AD group. Moreover, there were more significant methylation differences in the LDLRAD4, KHSRP, and CTDSP2 genes in connection with PM10 in AD group compared to the controls. The degree of methylation of the LDLRAD4 and CTDSP2 genes was also correlated with related protein productions. The present study revealed that exposure to high indoor PM can cause epigenetic development of AD by methylation of the LDLRAD4, KHSRP, and CTDSP2 genes in dogs. Under the concept of "One Health," improving indoor environments should be considered to prevent the development of AD.

Enhanced Intervertebral Disc Repair via Genetically Engineered Mesenchymal Stem Cells with Tetracycline Regulatory System.

The therapeutic potential of Mesenchymal stem cells (MSCs) for the treatment of Intervertebral disc (IVD) degeneration can be enhanced by amplifying specific cytokines and proteins. This study aimed to investigate the therapeutic potential of tetracycline-off system-engineered tonsil-derived mesenchymal stem cells (ToMSC-Tetoff-TGFß1-IGF1-BMP7) for treating intervertebral disc (IVD) degeneration. ToMSCs were isolated from a tonsillectomy patient and genetically modified with four distinct plasmids via CRISPR/Cas9-mediated knock-in gene editing. Transgene expression was confirmed through immunofluorescence, western blots, and an enzyme-linked immunosorbent assay for transforming growth factor beta 1 (TGFß1) protein secretion, and the effect of MSC-TetOff-TGFß1-IGF1-BMP7 on disc injury was assessed in a rat model. The ToMSC-Tetoff-TGFß1-IGF1-BMP7 treatment exhibited superior therapeutic effects compared to ToMSC-TGFß1, and ToMSC-SDF1α implantation groups, stimulating the regeneration of nucleus pulposus (NP) cells crucial for IVD. The treatment showed potential to restore the structural integrity of the extracellular matrix (ECM) by upregulating key molecules such as aggrecan and type II collagen. It also exhibited anti-inflammatory properties and reduced pain-inducing neuropeptides. ToMSC-Tetoff-TGFß1-IGF1-BMP7 holds promise as a novel treatment for IVD degeneration. It appears to promote NP cell regeneration, restore ECM structure, suppress inflammation, and reduce pain. However, more research and clinical trials are required to confirm its therapeutic potential.

Identification of integrative hepatotoxicity induced by lysosomal phospholipase A2 inhibition of cationic amphiphilic drugs via metabolomics.

Drug-induced liver injury (DILI) is a condition caused by drugs that leads to abnormal hepatic function. Hepatotoxicity caused by DILI has been shown to be due to cellular stress, mitochondrial dysfunction, cell necrosis and apoptosis and many types of hepatotoxicity, such as phospholipidosis, steatosis and hepatitis, commonly share intracellular molecular mechanisms. Metabolomics can be useful for mechanism-based toxicity evaluations and has been recently utilized as a scientific technique that can effectively predict the risk factors for chemical substances. To evaluate the key events in hepatotoxicity associated with lysosomal phospholipase A2 (LPLA2) inhibition by cationic amphiphilic drugs (CADs), LPLA2 inhibition assays and phospholipid accumulation assays were performed in HepG2 cells. Additionally, to suggest the integrative molecular mechanisms of hepatotoxicity by CADs, we profiled intracellular metabolites. Cell-based metabolomics was performed using an UPLC-Orbitrap-MS instrument equipped with heated electrospray ionization in positive and negative ion modes. As a result, CADs such as amiodarone, fluoxetine, chlorpromazine and tamoxifen significantly inhibited LPLA2 and accumulated phospholipids. In metabolomics, a total of 17 significant metabolites were identified, and the changed metabolite types were as follows: nucleotide sugars, conjugated bile acids, branched-chain amino acids, polyamine biosynthesis, and long-chain fatty acid and glycerophospholipid metabolism. From these data, it was suggested that the integrative mechanism of DILI could be verified and that a toxicological approach is possible using metabolomics.

Clinical Characteristics of recurrent intraocular lens dislocation after scleral-fixated sutured intraocular lens and long-term outcomes of intraocular lens re-fixation.

PURPOSE: This study aimed to investigate the clinical characteristics of patients with recurrent intraocular lens (IOL) dislocation after scleral-fixated sutured IOL implantation and evaluate the long-term outcomes of scleral re-fixation of IOL. METHODS: The medical records of patients who underwent surgery for IOL dislocation between January 2011 and January 2021 were reviewed. The study included 164 patients (male: 131, female: 33) (176 eyes). Patient demographics, preoperative, intraoperative and postoperative data, and the ocular and systemic conditions associated with IOL re-dislocation were analyzed. RESULTS: The study included 176 consecutive cases of scleral-fixated sutured IOL. Twenty-six eyes (14.8%) showed re-dislocation of IOL after the initial IOL scleral fixation and underwent reoperation (mean 75.5 ± 62.5 months after the first surgery); three (11.5%) of them required a third surgery. Younger adults (aged less than 40 years), and patients who underwent IOL scleral fixation in complicated cataract surgery or aphakic state had a higher risk of re-dislocation. Diabetes mellitus (DM) was the only statistically significantly higher risk factor in the re-dislocated group (p = 0.041). The complication rate with scleral re-fixation was higher than that in the non-re-dislocated group. No statistically significant differences were observed, except for vitreous hemorrhage (p = 0.024). CONCLUSIONS: Caution should be exercised when performing sutured scleral fixation of IOL in younger patients, cases of complicated cataract surgery and aphakia, and patients with DM to prevent IOL re-dislocation. Scleral-fixated sutured IOL in eyes with recurrent IOL dislocation seems to be a safe and effective procedure with a relatively low complication rate.

Association of potentially inappropriate medications and need for long-term care among older adults: a matched cohort study.

BACKGROUND: With an increase in the aging population, the number of older adults who require long-term care (LTC) is growing, enhancing drug-related issues. The reduced capacity of LTC users to precisely utilize medical services poses additional challenges owing to restrictions in daily activities. We compared older adults who required LTC with those who did not require LTC to confirm differences in the use of potentially inappropriate medications (PIMs), frequently used PIMs, and associating factors in Korea. METHODS: Using the Korean National Health Insurance Service cohort data, adults aged ≥ 65 years as of 2017 who were LTC beneficiaries (at home and LTC facilities) were selected and matched 1:1 with a control group (LTC non-beneficiaries). PIM was defined based on the 2019 American Society of Geriatrics Beers criteria. PIM use and medical resource utilization according to LTC requirements were compared for one year after the index date. After correcting for other confounding variables, differences in the risk of PIM use on person-based according to LTC eligibility were assessed using multivariate logistic regression. RESULTS: Among the 13,251 older adults requiring LTC in 2017, 9682 were matched with counterparts and included. Among those who received an outpatient prescription including PIM at least once yearly, 83.6 and 87.6% were LTC beneficiaries and LTC non-beneficiaries, respectively (p < 0.001). Using the number of outpatient prescriptions as the baseline, 37.2 and 33.2% were LTC beneficiaries and LTC non-beneficiaries, respectively (p < 0.001). In both groups, elevated PIM use depended on increased medical resource utilization, as shown by increased outpatient visits and medical care institutions visited. Adjusting other influencing factors, the need for LTC did not significantly associated with PIM use (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.84-1.04); the number of drugs consumed (3-4: OR 1.42, 95% CI 1.25-1.61; 5-9: OR 2.24, 95% CI 1.98-2.53; 10 and more: OR 3.72, 95% CI 3.03-4.55; reference group: 2 and less), frequency of visits (7-15: OR 1.95, 95% CI 1.71-2.23; 16-26: OR 3.51, 95% CI 3.02-4.07; 27-42: OR 5.84, 95% CI 4.84-7.05; 43 and more: OR 10.30, 95% CI 8.15-13.01; reference group: 6 and less), and visits to multiple medical care institutions (3-4: OR 1.96, 95% CI 1.76-2.19; 5 and more: OR 3.21, 95% CI 2.76-3.73; reference group: 2 and less) emerged as primary influencing factors. PIMs mainly prescribed included first-generation antihistamines, benzodiazepines, and Z-drugs in both groups; quetiapine ranked second-highest among LTC beneficiaries. CONCLUSIONS: The LTC demand did not significantly associated with PIM utilization. However, the number of drugs consumed, and the pattern of medical resource use were important factors, regardless of LTC requirements. This highlights the need to implement comprehensive drug management focusing on patients receiving polypharmacy and visiting multiple care institutions, regardless of LTC needs.

The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA.

RNA methylations are essential both for RNA structure and function, and are introduced by a number of distinct methyltransferases (MTases). In recent years, N6-methyladenosine (m6A) modification of eukaryotic mRNA has been subject to intense studies, and it has been demonstrated that m6A is a reversible modification that regulates several aspects of mRNA function. However, m6A is also found in other RNAs, such as mammalian 18S and 28S ribosomal RNAs (rRNAs), but the responsible MTases have remained elusive. 28S rRNA carries a single m6A modification, found at position A4220 (alternatively referred to as A4190) within a stem-loop structure, and here we show that the MTase ZCCHC4 is the enzyme responsible for introducing this modification. Accordingly, we found that ZCCHC4 localises to nucleoli, the site of ribosome assembly, and that proteins involved in RNA metabolism are overrepresented in the ZCCHC4 interactome. Interestingly, the absence of m6A4220 perturbs codon-specific translation dynamics and shifts gene expression at the translational level. In summary, we establish ZCCHC4 as the enzyme responsible for m6A modification of human 28S rRNA, and demonstrate its functional significance in mRNA translation.

An Octopus-Derived Peptide with Antidiuretic Activity in Rats.

Discovering new drug candidates with high efficacy and few side effects is a major challenge in new drug development. The two evolutionarily related peptides oxytocin (OXT) and arginine vasopressin (AVP) are known to be associated with a variety of physiological and psychological processes via the association of OXT with three types of AVP receptors. Over decades, many synthetic analogs of these peptides have been designed and tested for therapeutic applications; however, only a few studies of their natural analogs have been performed. In this study, we investigated the bioactivity and usefulness of two natural OXT/AVP analogs that originate from the marine invertebrate Octopus vulgaris, named octopressin (OTP) and cephalotocin (CPT). By measuring the intracellular Ca2+ or cyclic AMP increase in each OXT/AVP receptor subtype-overexpressing cell, we found that CPT, but not OTP, acts as a selective agonist of human AVP type 1b and 2 receptors. This behavior is reminiscent of desmopressin, the most widely prescribed antidiuretic drug in the world. Similar to the case for desmopressin, a single intravenous tail injection of CPT into Sprague-Dawley rats reduced urine output and increased urinary osmolality. In conclusion, we suggest that CPT has a significant antidiuretic effect and that CPT might be beneficial for treating urological conditions such as nocturia, enuresis, and diabetes insipidus.

AIDM-Strat: Augmented Illegal Dumping Monitoring Strategy through Deep Neural Network-Based Spatial Separation Attention of Garbage.

Economic and social progress in the Republic of Korea resulted in an increased standard of living, which subsequently produced more waste. The Korean government implemented a volume-based trash disposal system that may modify waste disposal characteristics to handle vast volumes of waste efficiently. However, the inconvenience of having to purchase standard garbage bags on one's own led to passive participation by citizens and instances of illegally dumping waste in non-standard plastic bags. As a result, there is a need for the development of automatic detection and reporting of illegal acts of garbage dumping. To achieve this, we suggest a system for tracking unlawful rubbish disposal that is based on deep neural networks. The proposed monitoring approach obtains the articulation points (joints) of a dumper through OpenPose and identifies the type of garbage bag through the object detection model, You Only Look Once (YOLO), to determine the distance of the dumper's wrist to the garbage bag and decide whether it is illegal dumping. Additionally, we introduced a method of tracking the IDs issued to the waste bags using the multi-object tracking (MOT) model to reduce the false detection of illegal dumping. To evaluate the efficacy of the proposed illegal dumping monitoring system, we compared it with the other systems based on behavior recognition. As a result, it was validated that the suggested approach had a higher degree of accuracy and a lower percentage of false alarms, making it useful for a variety of upcoming applications.

In Situ Electrical Monitoring of Methylated DNA Based on Its Conformational Change to G-Quadruplex Using a Solution-Gated Field-Effect Transistor.

Methylated DNA is not only a diagnostic but also a prognostic biomarker for early-stage cancer. However, sodium bisulfite sequencing as a "gold standard" method for detection of methylation markers has some drawbacks such as its time-consuming and labor-intensive procedures. Therefore, simple and reliable methods are required to analyze DNA sequences with or without methylated residues. Herein, we propose a simple and direct method for detecting DNA methylation through its conformation transition to G-quadruplex using a solution-gated field-effect transistor (SG-FET) without using labeled materials. The BCL-2 gene, which is involved in the development of various human tumors, contains G-rich segments and undergoes a conformational change to G-quadruplex depending on the K+ concentration. Stacked G-quadruplex strands move close to the SG-FET sensor surface, resulting in large electrical signals based on intrinsic molecular charges. In addition, a dense hydrophilic polymer brush is grafted using surface-initiated atom transfer radical polymerization onto the SG-FET sensor surface to reduce electrical noise based on nonspecific adsorption of interfering species. In particular, control of the polymer brush thickness induces electrical signals based on DNA molecular charges in the diffusion layer, according to the Debye length limit. A platform based on the SG-FET sensor with a well-defined polymer brush is suitable for in situ monitoring of methylated DNA and realizes a point-of-care device with a high signal-to-noise ratio and without the requirement for additional processes such as bisulfite conversion and polymerase chain reaction.