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The locus coeruleus (LC) has a long-established role in the attentional and arousal response to threat, and in the emergence of pathological anxiety in pre-clinical models. However, human evidence of links between LC function and pathological anxiety has been restricted by limitations in discerning LC with current neuroimaging techniques. We combined ultra-high field 7-Tesla and 0.4 × 0.4 × 0.5 mm quantitative MR imaging with a computational LC localization and segmentation algorithm to delineate the LC in 29 human subjects including subjects with and without an anxiety or stress-related disorder. Our automated, data-driven LC segmentation algorithm provided LC delineations that corresponded well with postmortem anatomic definitions of the LC. There was variation of LC size in healthy subjects (125.7 +/- 59.3 mm3), which recapitulates histological reports. Patients with an anxiety or stress-related disorder had larger LC compared to controls (Cohen's d = 1.08, p = 0.024). Larger LC was additionally associated with poorer attentional and inhibitory control and higher anxious arousal (FDR-corrected p's

On March 25th 2019, the Belle II detector recorded the first collisions delivered by the SuperKEKB accelerator. This marked the beginning of the physics run with vertex detector. The vertex detector was aligned initially with cosmic ray tracks without magnetic field simultaneously with the drift chamber. The alignment method is based on Millepede II and the General Broken Lines track model and includes also the muon system or primary vertex position alignment. To control weak modes, we employ sensitive validation tools and various track samples can be used as alignment input, from straight cosmic tracks to mass-constrained decays. With increasing luminosity and experience, the alignment is approaching the target performance, crucial for the first physics analyses in the era of Super-BFactories. We will present the software framework for the detector calibration and alignment, the results from the first physics run and the prospects in view of the experience with the first data.

The Belle II experiment features a substantial upgrade of the Belle detector and will operate at the SuperKEKB energy-asymmetric e+e− collider at KEK in Tsukuba, Japan. The accelerator completed its first phase of commissioning in 2016, and the Belle II detector saw its first electron-positron collisions in April 2018. Belle II features a newly designed silicon vertex detector based on double-sided strip layers and DEPFET pixel layers. A subset of the vertex detector was operated in 2018 to determine background conditions (Phase 2 operation). The collaboration completed full detector installation in January 2019, and the experiment started full data taking. This paper will report on the final arrangement of the silicon vertex detector part of Belle II with a focus on online monitoring of detector conditions and data quality, on the design and use of diagnostic and reference plots, and on integration with the software framework of Belle II. Data quality monitoring plots will be discussed with a focus on simulation and acquired cosmic and collision data.

Abstract Under certain experimental conditions, neurotrophic factors may reduce epileptogenesis. We have previously reported that local, intrahippocampal supplementation of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) increases neurogenesis, reduces neuronal loss, and reduces the occurrence of spontaneous seizures in a model of damage-associated epilepsy. Here, we asked if these possibly anti-epileptogenic effects might involve anti-inflammatory mechanisms. Thus, we used a Herpes-based vector to supplement FGF-2 and BDNF in rat hippocampus after pilocarpine-induced status epilepticus that established an epileptogenic lesion. This model causes intense neuroinflammation, especially in the phase that precedes the occurrence of spontaneous seizures. The supplementation of FGF-2 and BDNF attenuated various parameters of inflammation, including astrocytosis, microcytosis and IL-1β expression. The effect appeared to be most prominent on IL-1β, whose expression was almost completely prevented. Further studies will be needed to elucidate the molecular mechanism(s) for these effects, and for that on IL-1β in particular. Nonetheless, the concept that neurotrophic factors affect neuroinflammation in vivo may be highly relevant for the understanding of the epileptogenic process.

Pharmacogenomics has transformed the way we approach the treatment of the most common diseases worldwide, especially cardiovascular. In this article, we highlight the main categories of drugs involved in major cardiovascular diseases (CVD), related genetic variability and their effects on metabolism in each case of contrastive operability. This not only explains disparities in treatment outcomes but also unfolds customised management based on genomic studies to improve efficiency and limit side effects. Genetic variations have been identified that impact the efficacy, safety, and adverse effects of drugs commonly used in the treatment of CVDs, such as Angiotensin converting Enzyme Inhibitor (ACEI), Angiotensin Receptor Blocker (ARBs), calcium channel blockers, antiplatelet agents, diuretics, statins, beta-blockers, and anticoagulants. It discusses the impact of genetic polymorphisms on drug metabolism, efficacy, and adverse reactions, highlighting the importance of genetic testing in optimizing treatment outcomes. Pharmacogenomics holds immense potential for revolutionizing the management of CVDs by enabling personalized medicine approaches tailored to individual genetic profiles. However, challenges such as clinical implementation, cost-effectiveness, and ethical considerations need to be addressed to completely incorporate pharmacogenomic testing into standard clinical practice. Continued research and clinical diligence are required for the utilization of pharmacogenomics to improve therapeutic outcomes and reduce the burden of CVD globally., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Penetrating cardiac trauma is an entity with high pre and intrahospital mortality due to complications such as cardiac tamponade and massive hemothorax. A ventricular septal defect (VSD) occurs in 1-5% of cases and can present early or late. The management strategy for VSD resulting from penetrating cardiac trauma is uncertain., Case Presentation: A 19-year-old man was admitted in cardiorespiratory arrest after a precordial stab wound. Cardiopulmonary resuscitation was initiated achieving return of spontaneous circulation. eFAST evaluation revealed cardiac tamponade, he was taken to emergency left thoracotomy finding a perforation of the free wall of the left ventricle and a tear of the upper lobe of the left lung that were sutured. The patient was discharged and six days later was readmitted with fever and dyspnea. During treatment for a surgical site infection a new-onset pansystolic murmur was found: A transthoracic echocardiogram revealed a 13-mm VSD with left-to-right shunt. A multidisciplinary team recommended percutaneous closure of the defect which was successfully performed without complications., Conclusions: Traumatic VSD is a rare complication of penetrating cardiac trauma. A thorough clinical and echocardiographic evaluation is essential for its diagnosis and characterization. Symptomatic septal defects, those 10 mm or larger, with Qp: Qs greater than 1.5, or causing complications such as pulmonary hypertension or valvular involvement, are usually closed to prevent progression of heart failure. Management of traumatic VSD has traditionally been surgical. However, a percutaneous intervention is a viable alternative in selected stable patients. Unlike ischemic VSD, early intervention after patient stabilization generally yields favorable outcomes., Competing Interests: Declarations. Ethics approval and consent to participate: This case report was reviewed and approved by the Institutional Review Board (IRB) of Fundación Valle del Lili, Cali, Colombia. The patient provided informed consent for the use and publication of their medical information, and all identifying details have been anonymized to ensure confidentiality. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Excess weight (overweight and obesity) is the major modifiable risk factor for type 2 diabetes mellitus (T2DM) and other non-communicable diseases. However, excess weight may not be as predictive of diabetes risk as once thought. While excess weight and other obesity-related non-communicable diseases are of growing concern in low-middle income countries in Latin America, there is limited research on risk factors associated with T2DM in adolescents. This study investigated prevalence of overweight, obesity, prediabetes, diabetes and metabolic syndrome in adolescents in Ecuador., Methods: A cross-sectional study was conducted with 433 adolescents from two schools in a small urban center in southern Ecuador and two schools in a large urban center in Quito. Risk factors were measured, including: height, weight, BMI, waist-to-hip ratio, fasting glucose, lipid panel, and HbA1c. Multivariate analysis of variance (MANOVA) was separately applied to risk factors and demographic factors as a set of dependent variables with sex, location and their interaction included as predictors. An independent t test was run on the data at 95% confidence intervals for the mean difference. The values for the triglycerides, LDL and VLDL were positively skewed. A Mann-Whitney U test was run on these data., Results: Using IOTF standards, 9.8% were overweight and 1.9% were obese. Only 1.6% of the sample met the criteria for prediabetes by fasting glucose but 12.4% of the sample met the criteria for prediabetes by HbA1c. None of the participants met criteria for diabetes. There were 2.3% of the participants that met the IDF criteria for metabolic syndrome. Adolescents from the larger urban center had higher rates of prediabetes, higher mean HbA1c, blood pressure, lipid values, and lower HDL levels., Conclusions: Use of HbA1c identified more adolescents with prediabetes than FBG. The HbA1c measure is an attractive screening tool for prediabetes in developing countries. Although rates of obesity in Ecuadorian adolescents are low there is significant evidence to suggest that prediabetes is permeating the smaller urban centers. Traditional screening tools may underestimate this risk.

In the past, toxinological research on reptiles has focused principally on clinically important species. As a result, our understanding of the evolution of the reptile venom system is limited. Here, for the first time, we describe the structural and molecular evolutionary features of the mandibular toxin-secreting gland of Abronia graminea, a representative of one of the poorly known and entirely arboreal lineages of anguimorph lizards. We show that the mandibular gland is robust and serous, characters consistent with those expected of a toxin-secreting gland in active use. A wide array of transcripts were recovered that were homologous to those encoded by the indisputably venomous helodermatid lizards. We show that some of these toxin transcripts are evolving under active selection and show evidence of rapid diversification. Helokinestatin peptides in particular are revealed to have accumulated residues that have undergone episodic diversifying selections. Conversely, the natriuretic peptides have evolved under tremendous evolutionary constraints despite being encoded in tandem with helokinestatins by the same gene precursor. Of particular note is the sequencing for the first time of kunitz peptides from a lizard toxin-secreting gland. Not only are kunitz peptides shown to be an ancestral toxicoferan toxin, the ancestral state of this peptide is revealed to be a dual domain encoding precursor. This research provides insight into the evolutionary history of the ancient toxicoferan reptile venom system. In addition, it shows that even 'clinically irrelevant' species can be a rich source of novel venom components, worthy of investigation for drug design and biomedical research.

Background: Expression of the early growth response gene-1 (EGR-1) is elevated in prostate cancer and correlates with tumor progression. This study provides insight into the mechanism(s) that regulate EGR-1 expression and activity in malignant and benign prostate cells., Methods: Western blotting and in vitro pulse labeling were used to examine EGR-1 protein levels and half-life in malignant (PC-3) and benign (BPH-1) prostate cell lines. EGR-1 functional ability was assessed by transient transfections with an EGR-1 promoter driven luciferase plasmid and electromobility shift assays (EMSAs) to assess DNA binding of the EGR-1 protein. Protein levels of casein kinase II (CKII) were evaluated by Western blotting., Results: PC-3 cells maintain high steady-state levels of EGR-1 protein, in part due to a longer half-life of EGR-1 protein. BPH-1 cells responded to mitogenic stimuli with increased EGR-1 protein levels, and enhanced transcriptional activity. In contrast, PC-3 cells showed no response to stimuli. DNA binding of EGR-1 was higher in BPH-1 cells than in PC-3 cells. This appears to be related to the heavily phosphorylated state of EGR-1 in PC-3 cells which is correlated with increased levels of CKII found in these cells., Conclusions: PC-3 cells maintain a long lasting, heavily phosphorylated pool of EGR-1, which binds poorly to DNA and responds poorly to mitogenic stimulus. BPH-1 cells, in contrast, maintain a more responsive, less phosphorylated EGR-1 pool. These findings suggest that EGR-1 expression and activity is differentially regulated in PC-3 and BPH-1 cell lines., ((c) 2004 Wiley-Liss, Inc.)

Prostate cancer is the most prevalent malignancy and the second leading cause of cancer mortality in men. Early growth response gene-1 (EGR-1) plays a crucial role in the development and progression of prostate cancer. The presented data show that EGR-1 differs in cellular localization in benign cells compared with malignant prostate cells and that this localization is critical for the transcriptional activation of EGR-1-dependent genes. Immunohistochemistry of human prostate cancer specimens demonstrated higher levels of EGR-1 in malignant cells located predominantly in the cytoplasm, whereas benign cells contained lower levels of EGR-1 located predominantly in the nucleus. Benign prostate cells responded to mitogens in vitro, with increased levels of EGR-1, rapid nuclear translocation, and enhanced transcriptional activity, whereas malignant prostate cells did not exhibit the same responses, and the protein remained in the cytoplasm. The central aspect of this difference is the association of EGR-1 with microtubules, which is exclusive to the benign cells of the prostate and is requisite for the nuclear translocation and transcriptional activity of EGR-1. Our in vitro data demonstrate that the differences in EGR-1 between benign and malignant prostate cells extend beyond cellular levels, which was confirmed by immunohistochemistry in human tissues. Thus, we add the novel concept that microtubules regulate EGR-1 localization in benign prostate cells but not in malignant prostate cells.

Several studies have documented that androgens have the ability to autoregulate their own receptor levels; however, the mechanism of such autoregulation remains poorly understood. Along these lines, our laboratory has shown that testosterone increased androgen receptor (AR) protein levels and binding in the castrated rat ventral prostate within 1 h. Ongoing protein synthesis was required for the testosterone effect, as the protein synthesis inhibitor cycloheximide blocked this effect. Testosterone and/or actinomycin D, an mRNA synthesis inhibitor, did not affect the steady-state AR mRNA levels. Therefore, we suggest that the early events induced by testosterone are posttranscriptional and that protein synthesis is required for the maintenance of AR protein and AR mRNA levels. In addition, we hypothesize that the testosterone posttranscriptional effect is primarily through the sequestering of AR mRNA in the prostate polyribosomes. To test this hypothesis, total RNA was isolated from prostate polyribosomes of controls and testosterone-treated rats and AR mRNA levels were quantitated by competitive reverse transcription-polymerase chain reaction. Polyribosomes profiles on linear sucrose gradients showed no difference in the sedimentation characteristics of ribosomal particles from the vehicle-treated control or testosterone-treated animals. Furthermore, because both polyribosomal preparations can direct protein synthesis to the same extent in a cell-free system, testosterone does not increase the efficiency of translation. However, competitive reverse transcription-polymerase chain reaction revealed that testosterone increases AR mRNA associated with polyribosomes by threefold after 1 h of treatment compared with control. These data suggest a rapid testosterone-mediated posttranscriptional mechanism, in which testosterone regulates the stability of the AR mRNA by sequestering it in polyribosomes, and consequently increasing its translation.

Recent work from our laboratory has focused on elucidating the mechanism of androgen regulation of the androgen receptor (AR). We have demonstrated that testosterone increases AR protein and binding within 1 h in the ventral prostate of adult rats castrated for 24 h. Cycloheximide administered with testosterone reduces AR and AR mRNA levels. AP-1/c-fos transcription factor has been shown to function as a negative in many systems. c-fos mRNA levels were decreased 1 h after testosterone treatment in the ventral prostate, whereas they were increased in cycloheximide alone or cycloheximide-testosterone treated groups as compared to vehicle control. c-fos protein was also increased in the testosterone-cycloheximide treated group as compared to testosterone alone or cycloheximide alone groups at 1 h. By 3 h, the tissue recovers from the inhibitory effect of cycloheximide as evidenced by restoration of AR and an increase in AR mRNA levels. At this time c-fos protein levels were reduced after treatment with cycloheximide and testosterone and c-fos mRNA levels were comparable to the controls. These results suggest that elevation of c-fos expression is associated with a decrease in AR and mRNA and provide correlative data supporting negative repression by c-fos on androgen receptors levels. Between the age of 25-85 days, serum testosterone levels reached adult levels by the age of 55 days. Steady-state AR mRNA levels increased significantly by the age of 85 days while c-fos mRNA levels remained at low baseline levels at all ages. Thus, in addition to the circulating levels of serum testosterone, other age related factors are also involved in the regulation of AR mRNA levels. Furthermore, androgens appear to maintain androgen receptor levels and androgen sensitivity by continuous suppression of the repressor, c-fos.

In order to investigate the role of protein synthesis in the testosterone regulation of androgen receptor (AR) levels, in vivo studies were undertaken using the ventral prostate gland from adult male rats castrated 24 h previously. Our results showed that testosterone (400 microg/100 g body weight) increased nuclear AR binding 1 h after administration, whereas the protein synthesis inhibitor cycloheximide (400 microg/100 g body weight) by itself did not alter AR binding. However, concomitant administration of testosterone and cycloheximide blocked the testosterone-induced nuclear AR accumulation after 1 h. To determine if changes in AR binding reflected changes in AR protein levels, immunocytochemical studies were conducted on individually dissected ventral prostatic ducts. Castration 24 h previously induced a decrease in nuclear AR immunostaining when compared to intact animals. Testosterone treatment restored the nuclear staining, particularly at the distal tips of the prostatic ducts. Cycloheximide alone did not change AR immunostaining when compared to castrated vehicle-treated rats, yet it significantly decreased the nuclear AR staining induced by testosterone. Our results suggest that AR is being newly synthesized during testosterone treatment. To determine if the effect of testosterone in the regulation of the AR protein was ultimately due to changes at the messenger RNA (mRNA) levels, steady-state AR mRNA levels were measured. Northern blot analysis of poly A+ mRNA preparations revealed that androgen withdrawal for 24 h increased AR mRNA and that testosterone treatment for 1 h did not alter these increased AR mRNA levels. The inhibition of protein synthesis by cycloheximide did not change AR mRNA, but, when cycloheximide was administered in conjunction with testosterone, AR mRNA levels were significantly decreased. In an attempt to relate these responses to changes in transcriptional activity, the transcription inhibitor actinomycin D was administered in vivo. Whereas simultaneous administration of testosterone and cycloheximide modified AR mRNA and AR protein levels, concomitant administration of testosterone with actinomycin D did not alter these levels. It is therefore unlikely that testosterone modifies the transcription of AR mRNA within 1 h after its administration. Collectively, these results suggest that protein synthesis is involved in the mechanism of testosterone-promoted AR regulation. This protein synthesis-dependent mechanism may be involved in the regulation of the stability and/or the translation of AR mRNA in the prostate.