Miracle-dz/UniFAR-FTUs huggingface dataset:
Bimodal serotonin synthesis in the diurnal rodent, Arvicanthis ansorgei

In mammals, behavioral activity is regulated both by the circadian system, orchestrated by the suprachiasmatic nucleus (SCN), and by arousal structures, including the serotonergic system. While the SCN is active at the same astronomical time in diurnal and nocturnal species, little data are available concerning the serotonergic (5HT) system in diurnal mammals. In this study, we investigated the functioning of the 5HT system, which is involved both in regulating the sleep/wake cycle and in synchronizing the SCN, in a diurnal rodent, Arvicanthis ansorgei. Using in situ hybridization, we characterized the anatomical extension of the raphe nuclei and we investigated 24 h mRNA levels of the serotonin rate‐limiting enzyme, tryptophan hydroxylase 2 (tph2). Under both 12 h:12 h light/dark (LD) and constant darkness (DD) conditions, tph2 mRNA expression varies significantly over 24 h, displaying a bimodal profile with higher values around the (projected) light transitions. Furthermore, we considered several SCN outputs, namely melatonin, corticosterone, and locomotor activity. In both LD and DD, melatonin profiles display peak levels during the biological night. Corticosterone plasma levels show a bimodal rhythmic profile in both conditions, with higher levels preceding the two peaks of Arvicanthis locomotor activity, occurring at dawn and dusk. These data demonstrate that serotonin synthesis in Arvicanthis is rhythmic and reflects its bimodal behavioral phenotype, but differs from what has been previously described in nocturnal species.
Bone morphogenetic protein 10 alleviates doxorubicin-induced cardiac injury via signal transducer and activator of transcription 3 signaling pathway

ABSTRACT Doxorubicin (DOX) has limited antitumor applications owing to its association with life-threatening cardiac injury. Oxidative damage and cardiac apoptosis are crucial in DOX-induced cardiac injury. Bone morphogenetic protein 10 (BMP10) is predominantly distributed in the heart and acts as a cardioprotective factor that preserves cardiac function. However, the role of BMP10 in DOX-induced cardiac injury has not yet been explored. The current study aimed to examine the function and mechanism of action of BMP10 in DOX-induced cardiac injury. An adeno-associated viral system was used for the overexpression or silencing of cardiac-specific BMP10, and subsequently, a single dose of DOX was intraperitoneally injected to induce cardiac injury. Results showed that DOX exposure decreased BMP10 expression in the heart. Cardiac-specific overexpression of BMP10 alleviated the oxidative stress and apoptosis and improved cardiac function. Conversely, cardiac-specific silencing of BMP10 aggravated the redox disorder and apoptosis and worsened the cardiac dysfunction caused by DOX. Exogenous BMP10 supplementation amelioratesd the DOX-induced cardiac contractile dysfunction. Mechanistically, we found that phosphorylation of signal transducer and activator of transcription 3 (STAT3) is reduced in DOX-induced cardiotoxicity, and, BMP10 activated impaired STAT3 via a non-canonical pathway. BMP10 lost its cardioprotective function in cardiomyocyte-specific STAT3 knockout (STAT3-cKO) mice. Based on our findings, we suggested that BMP10 is a potential therapeutic agent against DOX-induced cardiac injury and that the cardioprotective effects of BMP10 are dependent on the activation of STAT3. GraphicalAbstract
Roles of leptin in initiation of acquired growth hormone resistance and control of metabolism in rainbow trout.

Catabolic conditions often induce concomitant changes in plasma leptin (Lep), growth hormone (GH) and insulin growth factor I (IGF-I) levels in teleost fish, but it is unclear whether these parts of the endocrine system are responding independently or functionally linked. In this study, fasted rainbow trout was used to study the effects of Lep on the GH-IGF-I system and metabolism. Fish were implanted intraperitoneally with recombinant rainbow trout Lep pellets and remained unfed. After 4 days, plasma GH levels were elevated in the Lep-treated fish in a dose-dependent manner; the expression of hepatic igf1 and plasma IGF-I levels were suppressed accordingly. In vitro Lep treatment reversed ovine GH (oGH)-stimulated expression of igf1 and igf2 in hepatocytes isolated from fasted fish, similar to the inhibitory effects of the MEK1/2 inhibitor U0126 treatment. However, Lep treatment alone had no effect on the expression of igfs or oGH-stimulated ghr2a expression in the hepatocytes. These results demonstrate an additive effect of Lep on suppression of IGF-I under catabolic conditions, indicating that Lep is likely involved in initiation of acquired GH resistance. Although the Lep-implant treatment had no effect on standard metabolic rate, it significantly suppressed gene expression of hepatic hydroxyacyl-CoA dehydrogenase, phosphoenolpyruvate carboxykinase and glucose 6-phosphatase, which are key enzymes in lipid utilization and gluconeogenesis, in different patterns. Overall, this study indicates that the Lep increase in fasting salmonids is an important regulatory component for physiological adaptation during periods of food deprivation, involved in suppressing growth and hepatic metabolism to spare energy expenditure.
Altered Response Pattern following AZD5582 Treatment of SIV-Infected, ART-Suppressed Rhesus Macaque Infants

While antiretroviral therapy (ART) has improved HIV-1 disease outcome and reduced transmission, interruption of ART results in rapid viral rebound due to the persistent latent reservoir. Interventions to reduce the viral reservoir are of critical importance, especially for children who must adhere to lifelong ART to prevent disease progression. ABSTRACT The “shock and kill” strategy for HIV-1 cure incorporates latency-reversing agents (LRA) in combination with interventions that aid the host immune system in clearing virally reactivated cells. LRAs have not yet been investigated in pediatric clinical or preclinical studies. Here, we evaluated an inhibitor of apoptosis protein (IAP) inhibitor (IAPi), AZD5582, that activates the noncanonical NF-κB (ncNF-κB) signaling pathway to reverse latency. Ten weekly doses of AZD5582 were intravenously administered at 0.1 mg/kg to rhesus macaque (RM) infants orally infected with SIVmac251 at 4 weeks of age and treated with a triple ART regimen for over 1 year. During AZD5582 treatment, on-ART viremia above the limit of detection (LOD, 60 copies/mL) was observed in 5/8 infant RMs starting at 3 days post-dose 4 and peaking at 771 copies/mL. Of the 135 measurements during AZD5582 treatment in these 5 RM infants, only 8 were above the LOD (6%), lower than the 46% we have previously reported in adult RMs. Pharmacokinetic analysis of plasma AZD5582 levels revealed a lower Cmax in treated infants compared to adults (294 ng/mL versus 802 ng/mL). RNA-Sequencing of CD4+ T cells comparing pre- and post-AZD5582 dosing showed many genes that were similarly upregulated in infants and adults, but the expression of key ncNF-κB genes, including NFKB2 and RELB, was significantly higher in adult RMs. Our results suggest that dosing modifications for this latency reversal approach may be necessary to maximize virus reactivation in the pediatric setting for successful “shock and kill” strategies. IMPORTANCE While antiretroviral therapy (ART) has improved HIV-1 disease outcome and reduced transmission, interruption of ART results in rapid viral rebound due to the persistent latent reservoir. Interventions to reduce the viral reservoir are of critical importance, especially for children who must adhere to lifelong ART to prevent disease progression. Here, we used our previously established pediatric nonhuman primate model of oral SIV infection to evaluate AZD5582, identified as a potent latency-reversing agent in adult macaques, in the controlled setting of daily ART. We demonstrated the safety of the IAPi AZD5582 and evaluate the pharmacokinetics and pharmacodynamics of repeated dosing. The response to AZD5582 in macaque infants differed from what we previously showed in adult macaques with weaker latency reversal in infants, likely due to altered pharmacokinetics and less inducibility of infant CD4+ T cells. These data supported the contention that HIV-1 cure strategies for children are best evaluated using pediatric model systems.
Anti-HIV Drugs Cause Mitochondrial Dysfunction in Monocyte-Derived Macrophages

Combination antiretroviral therapy (cART) dramatically changed the face of the HIV/AIDS pandemic, making it one of the most prominent medical breakthroughs of the past 3 decades. However, as the life span of persons living with HIV (PLWH) continues to approach that of the general population, the same cannot be said regarding their quality of life. ABSTRACT Combination antiretroviral therapy (cART) dramatically changed the face of the HIV/AIDS pandemic, making it one of the most prominent medical breakthroughs of the past 3 decades. However, as the life span of persons living with HIV (PLWH) continues to approach that of the general population, the same cannot be said regarding their quality of life. PLWH are affected by comorbid conditions such as high blood pressure, diabetes, and neurocognitive impairment at a higher rate and increased severity than their age-matched counterparts. PLWH also have higher levels of inflammation, the drivers of which are not entirely clear. As cART treatment is lifelong, we assessed here the effects of cART, independent of HIV, on primary human monocyte-derived macrophages (MDMs). MDMs were unskewed or skewed to an alternative phenotype and treated with Atripla or Triumeq, two first-line cART treatments. We report that Triumeq skewed alternative MDMs toward an inflammatory nonsenescent phenotype. Both Atripla and Triumeq caused mitochondrial dysfunction, specifically efavirenz and abacavir. Additionally, transcriptome sequencing (RNA-seq) demonstrated that both Atripla and Triumeq caused differential regulation of genes involved in immune regulation and cell cycle and DNA repair. Collectively, our data demonstrate that cART, independent of HIV, alters the MDM phenotype. This suggests that cART may contribute to cell dysregulation in PLWH that subsequently results in increased susceptibility to comorbidities.
The current state of oxy-fuel technology: demonstrations and technical barriers

As one of the three major carbon capture technologies associated with carbon capture and storage (CCS), oxy-fuel technology is currently undergoing rapid development with a number of international demonstration projects of scale 10-30 MWe having commenced and units with a scale of 250-300 MWe emerging in the progression towards commercialisation. Industrial scale testing of coal combustion and burners is also being conducted by technology vendors.
Usage Intensity of a Relapse Prevention Program and Its Relation to Symptom Severity in Remitted Patients With Anxiety and Depression: Pre-Post Study

Background Given that relapse is common in patients in remission from anxiety and depressive disorders, relapse prevention is needed in the maintenance phase. Although existing psychological relapse prevention interventions have proven to be effective, they are not explicitly based on patients’ preferences. Hence, we developed a blended relapse prevention program based on patients’ preferences, which was delivered in primary care practices by mental health professionals (MHPs). This program comprises contact with MHPs, completion of core and optional online modules (including a relapse prevention plan), and keeping a mood and anxiety diary in which patients can monitor their symptoms. Objective The aims of this study were to provide insight into (1) usage intensity of the program (over time), (2) the course of symptoms during the 9 months of the study, and (3) the association between usage intensity and the course of symptoms. Methods The Guided E-healTh for RElapse prevention in Anxiety and Depression (GET READY) program was guided by 54 MHPs working in primary care practices. Patients in remission from anxiety and depressive disorders were included. Demographic and clinical characteristics, including anxiety and depressive symptoms, were collected via questionnaires at baseline and after 3, 6, and 9 months. Log data were collected to assess the usage intensity of the program. Results A total of 113 patients participated in the study. Twenty-seven patients (23.9%) met the criteria for the minimal usage intensity measure. The core modules were used by ≥70% of the patients, while the optional modules were used by <40% of the patients. Usage decreased quickly over time. Anxiety and depressive symptoms remained stable across the total sample; a minority of 15% (12/79) of patients experienced a relapse in their anxiety symptoms, while 10% (8/79) experienced a relapse in their depressive symptoms. Generalized estimating equations analysis indicated a significant association between more frequent face-to-face contact with the MHPs and an increase in both anxiety symptoms (β=.84, 95% CI .39-1.29) and depressive symptoms (β=1.12, 95% CI 0.45-1.79). Diary entries and the number of completed modules were not significantly associated with the course of symptoms. Conclusions Although the core modules of the GET READY program were used by most of the patients and all patients saw an MHP at least once, usage decreased quickly over time. Most patients remained stable while participating in the study. The significant association between the frequency of contact and the course of symptoms most likely indicates that those who received more support had more symptoms, and thus, it is questionable whether the support offered by the program was sufficient to prevent these patients from relapsing. International Registered Report Identifier (IRRID) RR2-10.1186/s12888-019-2034-6
The mismatched nucleotides encoded in vaccinia virus flip-and-flop hairpin telomeres serve an essential role in virion maturation

Poxvirus genomes consist of a linear duplex DNA that ends in short inverted and complementary hairpin structures. These elements also encode loops and mismatches that likely serve a role in genome packaging and perhaps replication. We constructed mutant vaccinia viruses (VACV) where the native hairpins were replaced by altered forms and tested effects on replication, assembly, and virulence. Our studies showed that structure, not sequence, likely determines function as one can replace an Orthopoxvirus (VACV) hairpin with one copied from a Leporipoxvirus with no effect on growth. Some loops can be deleted from VACV hairpins with little effect, but VACV bearing too few mismatches grew poorly and we couldn’t recover viruses lacking all mismatches. Further studies were conducted using a mutant bearing only one of six mismatches found in wild-type hairpins (SΔ1Δ3–6). This virus grew to ~20-fold lower titers, but neither DNA synthesis nor telomere resolution was affected. However, the mutant exhibited a particle-to-PFU ratio 10-20-fold higher than wild-type viruses and p4b/4b core protein processing was compromised, indicating an assembly defect. Electron microscopy showed that SΔ1Δ3–6 mutant development was blocked at the immature virus (IV) stage, which phenocopies known effects of I1L mutants. Competitive DNA binding assays showed that recombinant I1 protein had less affinity for the SΔ1Δ3–6 hairpin than the wild-type hairpin. The SΔ1Δ3–6 mutant was also attenuated when administered to SCID-NCR mice by tail scarification. Mice inoculated with viruses bearing wild-type hairpins exhibited a median survival of 30–37 days, while mice infected with SΔ1Δ3–6 virus survived >70 days. Persistent infections favor genetic reversion and genome sequencing detected one example where a small duplication near the hairpin tip likely created a new loop. These observations show that mismatches serve a critical role in genome packaging and provide new insights into how VACV “flip and flop” telomeres are arranged.
miR‐200a‐3p promoted cell proliferation and metastasis by downregulating SOX17 in non‐small cell lung cancer cells

Lung cancer has high mortality and incidence rates in which non‐small cell lung cancer (NSCLC) is the primary type of lung cancer that accounts for about 80%–85% of total patients. It has been demonstrated that microRNAs (miRNAs) are critical in the incidence and progression of tumors, while the role and inner mechanism of miR‐200a‐3p, one type of essential miRNAs, in NSCLC have yet to be revealed. Herein, we investigated the in vitro and vivo pro‐/antiproliferative influence of miR‐200a‐3p on NSCLC cells and utilized bioinformatic programs to further predict the SOX17 gene as miR‐200a‐3p's potential target. A double luciferase reporter gene experiment was performed to confirm that miR‐200a‐3p interacts with the SOX17 3ʹ‐UTR region specifically. On the basis of the results of Western blot and quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR), miR‐200a‐3p impacted the posttranscriptional levels of SOX17 rather than influencing its mRNA expression. In the end, we found that overexpressed SOX17 can reverse miR‐200a‐3p's impact on NSCLC cell proliferation and metastasis. Therefore, this study demonstrated that miR‐200a‐3p influences NSCLC cell proliferation and metastasis by modulating the levels of SOX17.
Treatment by PI3K/mTOR Inhibitor BEZ235 Combined with TLR-7/8 Agonist Interfere with Immune Evasion Mechanisms of WEHI-3 Mouse Leukemia Cells.

BACKGROUND Several PI3K/Akt/mTOR pathway inhibitors and TLR agonists induce tumor cell death. However, the mechanisms of these therapeutic approaches in acute myeloid leukemia (AML) cells are still unknown. OBJECTIVES To investigate the effects of BEZ235, as a dual inhibitor of PI3K and mTOR pathways, and TLR7/8 agonist R848 on the expression and regulation of the immune inhibitory molecules in myeloid leukemia cells. METHODS WEHI-3 leukemia cells were incubated with dual PI3K and mTOR inhibitor BEZ235 and TLR7/8 agonist R848 for 48 hrs. Firstly, cell viability was assessed by MTT method. The semi-quantitative relative mRNA expression of Galectin-9 (Gal-9), PD-L1, PVR, and STAT3 was assessed according to HPRT as a housekeeping gene. Finally, the protein expression of phosphorylated STAT3 was evaluated by western blotting analysis. RESULTS WEHI-3 cells showed growth inhibition following treatment with BEZ235 and R848 whose combination exerted more proliferation arrest. The mRNA expression of Gal-9, PD-L1 and PVR immune checkpoint molecules significantly reduced in treated cells with BEZ235 and R848. Combined treatment indicated more reduction compared with the single treatment. Finally, the expression and phosphorylation of STAT3 were down-regulated after a single or dual treatment with BEZ235 and R848. CONCLUSION Our results conclude that treatment with the combination of BEZ235 and R848 interferes with immune evasion mechanisms through STAT3-signaling pathway in WEHI-3 leukemia cells.
Effects of endovascular therapy for mild stroke due to proximal or M2 occlusions: meta-analysis

Objective To conduct a meta-analysis to evaluate the effect of endovascular therapy (EVT) in mild acute ischemic stroke (AIS) due to proximal versus distal occlusions. Methods We searched PubMed, Embase, the Cochrane Library, and clinicaltrials.gov from January 2000 to September 2021 to identify studies comparing EVT versus best medical management (BMM) in AIS with National Institutes of Health Stroke Scale (NIHSS) scores ≤5 due to proximal internal carotid artery (ICA) or M1 versus distal M2 occlusions. We included studies that reported the number of patients with proximal or distal occlusions separately and reported the number of patients with freedom of disability (modified Rankin Scale (mRS) score 0–1) or functional independence (mRS score 0–2) at 90 days in proximal or M2 occlusions, respectively. OR with 95% CI was used. Results We identified six studies with 653 proximal ICA and M1 occlusion patients and 666 distal M2 occlusion patients. Pooled results showed EVT versus BMM was associated with a higher rate of being disability-free in patients with proximal occlusions (OR 1.58, 95% CI 1.09 to 2.30), but was associated with a lower rate of being disability-free in patients with M2 occlusions (OR 0.70, 95% CI 0.49 to 0.99). Effect of EVT in proximal versus distal occlusions was substantially different (P for interaction=0.002). A similar pattern was seen for functional independence (P for interaction=0.05). Conclusions For patients with mild AIS, observational data suggest that EVT may be beneficial for proximal ICA or M1 but not for distal M2 occlusions. Randomized trials are needed to confirm these findings. PROSPERO registration number CRD42021281034.
Frequency of spontaneous detection of pulmonary arterial thrombi in unenhanced chest computed tomography in patients diagnosed with pulmonary embolism

Pulmonary embolism (PE) is the third most frequent cardiovascular disease, and can be lethal in the acute phase or cause significant late repercussions, such as chronic hypertensive pulmonary embolism. From a clinical point of view, the symptoms of acute PE are extensive, including asymptomatic presentation, dyspnea at rest, chest pain, and episodes of syncope. (1) Given the variability of manifestations of acute presentation, even in face of clinical suspicion, alternative diagnoses can be obtained after angiography by multidetector computed tomography (CT angiography or CTA). CTA is considered the method of choice for the imaging diagnosis of PE, being identified as a safe method for excluding PE in tests with satisfactory technical quality, reaching a negative predictive value of 95%. (1-3) Considering the limitations of the clinical diagnosis of PE and possible contraindications regarding the injection of iodized contrast medium, unenhanced chest CT scans are often performed to assess patients with non-specific acute cardiopulmonary symptoms, making the detection of indirect signs of PE crucial to raise the need for complementary tests that confirm the diagnosis in a timely manner.
Not Just How Much, But How Many: Overall and Domain-Specific Activity Variety and Cognitive Functioning in Adulthood.

OBJECTIVES Active lifestyles are related to higher levels of cognitive functioning. Fewer studies have examined the importance of engaging in different activities (activity variety) for cognitive functioning. Moreover, it is unclear whether activity variety in specific domains (i.e., cognitive, physical, or social) is important for cognitive health. The current study examined whether overall activity variety as well as variety in specific domains relates to cognitive functioning. METHOD In Waves 2 and 3 of the Survey of Midlife Development in the United States (MIDUS), 3,337 adults reported their activity engagement and completed a cognitive battery. For longitudinal analyses, 2,049 participants were classified into four groups based on their rank-ordering of activity variety across nine years (remained high, increased, decreased, or remained low). RESULTS Cross-sectional analyses revealed that overall activity variety was related to higher cognitive functioning over and above activity frequency; physical and social activity variety each contributed significantly and uniquely to this association. Longitudinal analyses revealed that those with consistently low overall activity variety at both waves had lower cognitive functioning at Wave 3 than those with high activity variety at either wave, after adjusting for cognitive functioning at Wave 2. Those with consistently high or increasing social activity variety had higher cognitive functioning at Wave 3 than participants with low activity variety at both waves. DISCUSSION Findings suggest that activity variety, particularly in the social domain, is related to concurrent and future cognitive function across adulthood.