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Adult CNS neurons exhibit a reduced capacity for growth compared to developing neurons, due in part to downregulation of growth-associated genes as development is completed. We tested the hypothesis that SnoN, an embryonically regulated transcription factor that specifies growth of the axonal compartment, can enhance growth in injured adult neurons. In vitro, SnoN overexpression in dissociated adult DRG neuronal cultures significantly enhanced neurite outgrowth. Moreover, TGF-β1, a negative regulator of SnoN, inhibited neurite outgrowth, and SnoN over-expression overcame this inhibition. We then examined whether SnoN influenced axonal regeneration in vivo: indeed, expression of a mutant form of SnoN resistant to degradation significantly enhanced axonal regeneration following cervical spinal cord injury, despite peri-lesional upregulation of TGF-β1. Thus, a developmental mechanism that specifies extension of the axonal compartment also promotes axonal regeneration after adult CNS injury.

Transforming growth factor-beta (TGFβ) is a secreted polypeptide that plays essential roles in cellular development and homeostasis. Although mechanisms of TGFβ-induced responses have been characterized, our understanding of TGFβ signaling remains incomplete. Here, we uncover a novel function for the protein kinase NDR1 (nuclear Dbf2-related 1) in TGFβ responses. Using an immunopurification approach, we find that NDR1 associates with SnoN, a key component of TGFβ signaling. Knockdown of NDR1 by RNA interference promotes the ability of TGFβ to induce transcription and cell cycle arrest in NMuMG mammary epithelial cells. Conversely, expression of NDR1 represses TGFβ-induced transcription and inhibits the ability of TGFβ to induce cell cycle arrest in NMuMG cells. Mechanistically, we find that NDR1 acts in a kinase-dependent manner to suppress the ability of TGFβ to induce the phosphorylation and consequent nuclear accumulation of Smad2, which is critical for TGFβ-induced transcription and responses. Strikingly, we also find that TGFβ reciprocally regulates NDR1, whereby TGFβ triggers the degradation of NDR1 protein. Collectively, our findings define a novel and intimate link between the protein kinase NDR1 and TGFβ signaling. NDR1 suppresses TGFβ-induced transcription and cell cycle arrest, and counteracting NDR1's negative regulation, TGFβ signaling induces the downregulation of NDR1 protein. These findings advance our understanding of TGFβ signaling, with important implications in development and tumorigenesis.

The elaboration of dendrites in neurons requires secretory trafficking through the Golgi apparatus, but the mechanisms that govern Golgi function in neuronal morphogenesis in the brain have remained largely unexplored. Here, we report that the E3 ubiquitin ligase Cul7(Fbxw8) localizes to the Golgi complex in mammalian brain neurons. Inhibition of Cul7(Fbxw8) by independent approaches including Fbxw8 knockdown reveals that Cul7(Fbxw8) is selectively required for the growth and elaboration of dendrites but not axons in primary neurons and in the developing rat cerebellum in vivo. Inhibition of Cul7(Fbxw8) also dramatically impairs the morphology of the Golgi complex, leading to deficient secretory trafficking in neurons. Using an immunoprecipitation/mass spectrometry screening approach, we also uncover the cytoskeletal adaptor protein OBSL1 as a critical regulator of Cul7(Fbxw8) in Golgi morphogenesis and dendrite elaboration. OBSL1 forms a physical complex with the scaffold protein Cul7 and thereby localizes Cul7 at the Golgi apparatus. Accordingly, OBSL1 is required for the morphogenesis of the Golgi apparatus and the elaboration of dendrites. Finally, we identify the Golgi protein Grasp65 as a novel and physiologically relevant substrate of Cul7(Fbxw8) in the control of Golgi and dendrite morphogenesis in neurons. Collectively, these findings define a novel OBSL1-regulated Cul7(Fbxw8) ubiquitin signaling mechanism that orchestrates the morphogenesis of the Golgi apparatus and patterning of dendrites, with fundamental implications for our understanding of brain development.

Objective. To compare the infectious complication rates from cesarean delivery of human immunodeficiency virus (HIV)-infected women and HIV-negative women. Materials and Methods. A retrospective analysis was performed on data derived from HIV-infected women and HIV-negative women, who underwent cesarean delivery at two teaching hospitals. Main outcome measures were infectious postoperative morbidity. Descriptive, comparison analysis, and multiple logistic regression analysis were performed. Results. One hundred and nineteen HIV-infected women and 264 HIV-negative women delivered by cesarean section and were compared. The HIV-negative women were more likely than the HIV-infected women to deliver by emergent cesarean section (78.0% versus 51.3%, resp., 𝑃.05). In a multivariate stepwise logistic analysis, emergent cesarean delivery and chorioamnionitis but not HIV infection were associated with increased rate of post-operative endometritis (odds ratio (OR) 4.10, 95% confidence interval (95% CI) 1.41–11.91, 𝑃

Priapism is a rare condition characterized by prolonged and often painful penile erection unrelated to sexual stimulation. Ischemic priapism, the most common subtype, requires immediate attention to prevent irreversible damage to erectile tissue. This narrative review explores the initial management strategies for ischemic priapism. Intracavernosal phenylephrine injection and aspiration with or without irrigation are recommended as first-line treatments, with alternative options available depending on clinical settings and patient factors. While guidelines offer clear recommendations for priapism lasting more than 4 h, management of shorter-duration cases remains challenging due to limited evidence., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Our article outlines a case study assessing the use of low-intensity shock wave therapy (LiSWT) for managing Hard Flaccid Syndrome (HFS). Given the absence of standardized treatments for HFS, LiSWT could serve as an additional tool in the treatment arsenal. The case involved a 36-year-old male presenting HFS, low libido, chronic pain, and erectile dysfunction. Treatment comprised phosphodiesterase type 5 inhibitor (PDE5-I), physical therapy, and LiSWT. Following six sessions, the patient experienced regression of bothersome symptoms and improved erections. A 2-year follow-up revealed sustained symptom relief. LiSWT presents a non-invasive means of inducing mechanical stress and microtrauma in targeted tissues, fostering neovascularization and potentially enhancing blood supply. The integration of LiSWT with PDE5-I and physical therapy suggests a potential avenue for effective HFS management. Nevertheless, further systematic research is essential to validate the therapy's benefits and assess, if any, potential drawbacks., (© 2024. The Author(s).)

Hard-flaccid syndrome (HFS) is a poorly understood condition of male sexual dysfunction (MSD) that has more recently become a new topic of discussion in online forums and sexual medicine conferences. There has been limited research looking into HFS and consequently there are no evidence-based guidelines for its work-up and management. In order to identify the current level of understanding of HFS in the sexual medicine community, a survey was distributed at a national urologic conference focusing on pertinent management strategies employed by practitioners, and their own thoughts on HFS. This showed that nearly one-third of those surveyed had never seen HFS in their practice. Of those that had, diagnosis was mainly made via clinical history as well as patient self-diagnosis. Additionally, only about half of the respondents who had seen HFS were confident in its legitimacy as a real medical syndrome. This analysis is one of the first of its kind, and highlights the ongoing lack of familiarity of HFS among the sexual medicine community. There were limitations, most notably its survey format as well as low sample size, however, it importantly emphasizes the critical need for continued education and research into HFS to improve diagnostic accuracy, enhance patient care, and develop effective treatment strategies., (© 2024. The Author(s).)

Purpose: RNYK is a selective agonist of the neurotrophic tyrosine kinase receptor type 2 (NTRK2) which has been screened from a phage-displayed peptide library. Its sequence is SGVYKVAYDWQH, similar to a native NTRK2 ligand, that is, brain-derived neurotrophic factor (BDNF). The current study was performed to recognize and confirm critical residues for RNYK activity in a glaucoma-on-a-chip model., Methods: We designed a modified RNYK (mRNYK) peptide based on hotspots of the RNYK sequence identified by alanine scanning. The critical residues consisted of tyrosine, valine, aspartic acid, and tryptophan (YVDW); however, lysine and glutamine were also maintained in the final sequence (YKVDWQ) for forming amide bonds and peptide dimerization. The affinity of mRNYK binding was confirmed by testing against NTRK2 receptors on the surface of ATRA-treated SH-SY5Y cells. The neuroprotective effect of mRNYK was also evaluated in cell culture after elevated pressure insult in a glaucoma-on-a-chip model., Results: The primary amine on the lysine side-chain from one sequence (YKVDWQ) reacted with a γ-carboxamide group of glutamine from the other sequence, forming dimeric mRNYK. In silico , molecular dynamic simulations of the mRNYK-NTRK2 complex showed more stable and stronger interactions as compared to the RNYK-NTRK2 complex. In vitro , mRNYK demonstrated a neuroprotective effect on SH-SY5Y cells under normal and elevated pressure comparable to RNYK. The 50% effective concentration (logEC50) for mRNYK was 0.7009, which was better than RNYK with a logEC50 of 0.8318., Conclusion: The modified peptide studied herein showed improved stability over the original peptide (RNYK) and demonstrated potential for use as a BDNF agonist with neuroprotective properties for treatment of neurodegenerative disorders such as glaucoma., Competing Interests: None., (Copyright © 2024 Nafian et al.)

This article presents a solid-phase extraction method combined with a spectrofluorometric method for the extraction/pre-concentration and determination of metoprolol (MET) in exhaled breath condensate. The extraction sorbent is an agarose aerogel nanocomposite grafted with graphene oxide (GO) Fe 3 O 4 . The size and morphology of the nanosorbent were characterized via X-ray crystallography, scanning electron microscopy, Fourier-transform infrared spectrometry, and Brunauer-Emmett-Teller analysis. Factors affecting the extraction/determination of MET were optimized using the one-at-a-time method. Under optimized experimental conditions, the calibration graph was linear in the range of 0.005 to 2.0 μg mL -1 with a detection limit of 0.001 μg mL -1 . The method was successfully applied for the determination of MET in biological samples taken from patients receiving MET., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Vision Transformer (ViT) models have demonstrated a breakthrough in a wide range of computer vision tasks. However, compared to the Convolutional Neural Network (CNN) models, it has been observed that the ViT models struggle to capture high-frequency components of images, which can limit their ability to detect local textures and edge information. As abnormalities in human tissue, such as tumors and lesions, may greatly vary in structure, texture, and shape, high-frequency information such as texture is crucial for effective semantic segmentation tasks. To address this limitation in ViT models, we propose a new technique, Laplacian-Former, that enhances the self-attention map by adaptively re-calibrating the frequency information in a Laplacian pyramid. More specifically, our proposed method utilizes a dual attention mechanism via efficient attention and frequency attention while the efficient attention mechanism reduces the complexity of self-attention to linear while producing the same output, selectively intensifying the contribution of shape and texture features. Furthermore, we introduce a novel efficient enhancement multi-scale bridge that effectively transfers spatial information from the encoder to the decoder while preserving the fundamental features. We demonstrate the efficacy of Laplacian-former on multi-organ and skin lesion segmentation tasks with +1.87% and +0.76% dice scores compared to SOTA approaches, respectively. Our implementation is publically available at GitHub.

In the present study, we aimed to synthesize (Ag) 1-x (GNPs) x nanocomposites in variable ratios (25% GNPs-Ag, 50% GNPs-Ag, and 75% GNPs-Ag) via an ex situ approach to investigate the incremental effects of GNPs (graphene nanoparticles) on AgNPs (silver nanoparticles). The prepared nanocomposites were successfully characterized using different microscopic and spectroscopic techniques, including X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, ultraviolet spectroscopy, and Raman spectroscopic analysis. For the evaluation of morphological aspects, shape, and percentage elemental composition, SEM and EDX analyses were employed. The bioactivities of the synthesized nanocomposites were briefly investigated. The antifungal activity of (Ag) 1-x (GNPs) x nanocomposites was reported to be 25% for AgNPs and 66.25% using 50% GNPs-Ag against Alternaria alternata . The synthesized nanocomposites were further evaluated for cytotoxic potential against U87 cancer cell lines with improved results (for pure AgNPs IC 50 : ~150 µg/mL, for 50% GNPs-Ag IC 50 : ~12.5 µg/mL). The photocatalytic properties of the nanocomposites were determined against the toxic dye Congo red, and the percentage degradation was recorded as 38.35% for AgNPs and 98.7% for 50% GNPs-Ag. Hence, from the results, it is concluded that silver nanoparticles with carbon derivatives (graphene) have strong anticancer and antifungal properties. Dye degradation strongly confirmed the photocatalytic potential of Ag-graphene nanocomposites in the removal of toxicity present in organic water pollutants.

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, there have been various approaches for SARS-CoV-2 detection, each having its pros and cons. The current gold-standard method for SARS-CoV-2 detection, which offers acceptable specificity and sensitivity, is the quantitative reverse transcription-PCR (qRT-PCR). However, this method requires considerable cost and time to transport samples to specialized laboratories and extract, amplify, and detect the viral genome. On the other hand, antigen and antibody testing approaches that bring rapidity and affordability into play have lower sensitivity and specificity during the early stages of COVID-19. Moreover, the immune response is variable depending on the individual. Methods based on clustered regularly interspaced short palindromic repeats (CRISPR) can be used as an alternative approach to controlling the spread of disease by a high-sensitive, specific, and low-cost molecular diagnostic system. CRISPR-based detection systems (CRISPR-Dx) target the desired sequences by specific CRISPR-RNA (crRNA)-pairing on a pre-amplified sample and a subsequent collateral cleavage. In the present article, we have reviewed different CRISPR-Dx methods and presented their benefits and drawbacks for point-of-care testing (POCT) of suspected SARS-CoV-2 infections at home or in small clinics., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bis-acyl-thiourea derivatives, namely N,N' -(((4-nitro-1,2-phenylene)bis(azanediyl)) bis(carbonothioyl))bis(2,4-dichlorobenzamide) (UP-1), N,N' -(((4-nitro-1,2-phenylene) bis(azanediyl))bis(carbonothioyl))diheptanamide (UP-2), and N,N' -(((4-nitro-1,2-phenylene)bis(azanediyl))bis(carbonothioyl))dibutannamide (UP-3), were synthesized in two steps. The structural characterization of the derivatives was carried out by FTIR, 1 H-NMR, and 13 C-NMR, and then their DNA binding, anti-urease, and anticancer activities were explored. Both theoretical and experimental results, as obtained by density functional theory, molecular docking, UV-visible spectroscopy, fluorescence (Flu-)spectroscopy, cyclic voltammetry (CV), and viscometry, pointed towards compounds' interactions with DNA. However, the values of binding constant ( K b ), binding site size (n), and negative Gibbs free energy change (ΔG) (as evaluated by docking, UV-vis, Flu-, and CV) indicated that all the derivatives exhibited binding interactions with the DNA in the order UP-3 > UP-2 > UP-1. The experimental findings from spectral and electrochemical analysis complemented each other and supported the theoretical analysis. The lower diffusion coefficient (D o ) values, as obtained from CV responses of each compound after DNA addition at various scan rates, further confirmed the formation of a bulky compound-DNA complex that caused slow diffusion. The mixed binding mode of interaction as seen in docking was further verified by changes in DNA viscosity with varying compound concentrations. All compounds showed strong anti-urease activity, whereas UP-1 was found to have comparatively better inhibitory efficiency, with an IC 50 value of 1.55 ± 0.0288 µM. The dose-dependent cytotoxicity of the synthesized derivatives against glioblastoma MG-U87 cells (a human brain cancer cell line) followed by HEK-293 cells (a normal human embryonic kidney cell line) indicated that UP-1 and UP-3 have greater cytotoxicity against both cancerous and healthy cell lines at 400 µM. However, dose-dependent responses of UP-2 showed cytotoxicity against cancerous cells, while it showed no cytotoxicity on the healthy cell line at a low concentration range of 40-120 µM.

Multiple Myeloma (MM) is an emerging ailment of global concern. Its diagnosis at the early stages is critical for recovery. Therefore, efforts are underway to produce digital pathology tools with human-level intelligence that are efficient, scalable, accessible, and cost-effective. Following the trend, a medical imaging challenge on "Segmentation of Multiple Myeloma Plasma Cells in Microscopic Images (SegPC-2021)" was organized at the IEEE International Symposium on Biomedical Imaging (ISBI), 2021, France. The challenge addressed the problem of cell segmentation in microscopic images captured from the slides prepared from the bone marrow aspirate of patients diagnosed with Multiple Myeloma. The challenge released a total of 775 images with 690 and 85 images of sizes 2040×1536 and 1920×2560 pixels, respectively, captured from two different (microscope and camera) setups. The participants had to segment the plasma cells with a separate label on each cell's nucleus and cytoplasm. This problem comprises many challenges, including a reduced color contrast between the cytoplasm and the background, and the clustering of cells with a feeble boundary separation of individual cells. To our knowledge, the SegPC-2021 challenge dataset is the largest publicly available annotated data on plasma cell segmentation in MM so far. The challenge targets a semi-automated tool to ensure the supervision of medical experts. It was conducted for a span of five months, from November 2020 to April 2021. Initially, the data was shared with 696 people from 52 teams, of which 41 teams submitted the results of their models on the evaluation portal in the validation phase. Similarly, 20 teams qualified for the last round, of which 16 teams submitted the results in the final test phase. All the top-5 teams employed DL-based approaches, and the best mIoU obtained on the final test set of 277 microscopic images was 0.9389. All these five models have been analyzed and discussed in detail. This challenge task is a step towards the target of creating an automated MM diagnostic tool., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This work aims to examine the interaction between apo A2 (Apo A-II) -265T > C SNP and dietary total antioxidant capacity (DTAC) on inflammation and oxidative stress in patients with type 2 diabetes mellitus. The present cross-sectional study included 180 patients (35-65 years) with identified Apo A-II genotype. Dietary intakes were assessed by a FFQ. DTAC was computed using the international databases. IL-18 (IL18), high-sensitivity C-reactive protein (hs-CRP), pentraxin (PTX3), serum total antioxidant capacity (TAC), superoxide dismutase (SOD) activity and 8-isoprostaneF2 α (PGF2 α ) markers were obtained according to standard protocols. General linear model was used to evaluate the interaction. The interaction of gene and DTAC ( P FRAP = 0·039 and P ORAC = 0·042) on PGF2 α level was significant after adjusting for confounders. A significant interaction was observed on IL18 level ( P ORAC = 0·018 and P FRAP = 0·048) and SOD ( P TEAC = 0·037) in obese patients. Among patients whose DTAC was higher than the median intake, the levels of hs-CRP and PGF2α were significantly higher only in individuals with CC genotype. Serum TAC ( P FRAP = 0·030, P ORAC = 0·049) and SOD were significantly lower in the CC genotype. There was a favourable relationship between the high-DTAC and SOD (obese: P TEAC = 0·034, non-obese: P FRAP = 0·001, P TRAP < 0·0001, P TEAC = 0·003 and P ORAC = 0·001) and PGF2 α (non-obese: P ORAC = 0·024) in T-allele carriers. The rs5082 SNP interacts with DTAC to influence several cardiometabolic risk factors. Also, we found dietary recommendations for antioxidant-rich foods intake might be useful in the prevention of diabetes complications in the T carrier more effectively than the CC genotype. Future large studies are required to confirm these results.

Diabetic macular edema (DME) is the most common cause of visual impairment among patients with diabetes mellitus. Anti-vascular endothelial growth factors (Anti-VEGFs) are considered the first line in its management. The aim of this research has been to develop a deep learning (DL) model for predicting response to intravitreal anti-VEGF injections among DME patients. The research included treatment naive DME patients who were treated with anti-VEGF. Patient's pre-treatment and post-treatment clinical and macular optical coherence tomography (OCT) were assessed by retina specialists, who annotated pre-treatment images for five prognostic features. Patients were also classified based on their response to treatment in their post-treatment OCT into either good responder, defined as a reduction of thickness by >25% or 50 µm by 3 months, or poor responder. A novel modified U-net DL model for image segmentation, and another DL EfficientNet-B3 model for response classification were developed and implemented for predicting response to anti-VEGF injections among patients with DME. Finally, the classification DL model was compared with different levels of ophthalmology residents and specialists regarding response classification accuracy. The segmentation deep learning model resulted in segmentation accuracy of 95.9%, with a specificity of 98.9%, and a sensitivity of 87.9%. The classification accuracy of classifying patients' images into good and poor responders reached 75%. Upon comparing the model's performance with practicing ophthalmology residents, ophthalmologists and retina specialists, the model's accuracy is comparable to ophthalmologist's accuracy. The developed DL models can segment and predict response to anti-VEGF treatment among DME patients with comparable accuracy to general ophthalmologists. Further training on a larger dataset is nonetheless needed to yield more accurate response predictions.

Purpose: To evaluate the efficacy of symmetric bilateral medial rectus recession in large-angle esotropic Duane retraction syndrome (DRS) with moderate to severe globe retraction., Methods: In a retrospective study, medical reports of 30 patients with esotropia of equal or more than 20 prism diopters (pd) and moderate to serve globe retraction due to unilateral DRS who underwent symmetric bilateral medial rectus recession were reviewed. Age, gender, laterality, amblyopia, length of follow-up, pre- and postoperative measurements of primary position deviation, ocular ductions and severity of globe retraction and abnormal head posture were evaluated. A successful result was defined as decreasing esotropia to equal or less than 8 pd or equal or less than 8 pd of consecutive exotropia., Results: The mean age of patients at surgery was 13.7 ± 8.5 years old (range: 3-38). The mean preoperative esotropia measured 28.9 ± 9.1 pd in distance and 25.7 ± 7.2 pd in near, which decreased to 4.9 ± 6.1 pd in distance and 3.9 ± 8.8 pd in near postoperatively. The mean bilateral medial rectus recession was 4.9 ± 0.9 mm (range: 3-6 mm). The mean abnormal head posture improved from 19.1 ± 6.9 degrees (range: 10-30 degrees) to 3.3 ± 4.7 degrees (range: 0-15 degrees) postoperatively. At the last follow-up visit, 23 patients (76.7%) had a successful outcome., Conclusions: In the large-angle esotropic DRS patients with moderate to severe globe retraction, symmetric bilateral medial rectus recession, can be conducted to successfully resolve primary position deviation and abnormal head posture.

The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large-scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans-agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5-HT) 1A receptor agonists; (5) fentanyl-binding cyclodextrin scaffolds; (6) detoxifying biomimetic "nanosponge" decoy receptors; and (7) antibody-based strategies. These approaches could also be applied to treat opioid use disorder., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

The present study aimed to investigate the interaction of Apo A-II polymorphism and dietary total antioxidant capacity (DTAC) with lipid profile and anthropometric markers in patients with type 2 diabetes (T2DM) that are at risk for atherosclerosis. This cross-sectional study was conducted on 778 patients with T2DM (35-65 years). Dietary intakes were assessed by a 147-item food frequency questionnaire. DTAC was computed using international databases. Participants were categorised into two groups based on rs5082 genotypes. The gene-diet interaction was analysed by an ANCOVA multivariate interaction model. Total cholesterol, TC; triacylglycerol, TG; high- and low-density lipoprotein, HDL and LDL; TC-HDL ratio; waist circumference, WC and body mass index, BMI were obtained according to standard protocols. Overall, the frequency of CC homozygous was 12⋅1 % among study participants. We found that a significant interaction between rs5082 variants and DTAC on mean WC ( P TEAC = 0⋅044), TC concentration ( P FRAP = 0⋅049 and P TEAC = 0⋅031) and TC/HDL ( P FRAP = 0⋅031 and P TRAP = 0⋅040). Among patients whose DTAC was higher than the median intake, the mean of weight, WC and TC/HDL were significantly higher only in individuals with CC genotype. Also, the high DTAC was associated with a lower TC concentration only in T-allele carriers ( P FRAP = 0⋅042). We found that adherence to a diet with high total antioxidant capacity can improve the complications of diabetes and atherosclerosis in the T carrier genotype more effectively than the CC genotype. These results could indicate the anti-atherogenic properties of Apo A-II. However, further studies are needed to shed light on this issue., (© The Author(s) 2021.)

The findings of trials investigating the effect of cocoa products consumption on vascular stiffness and platelet are controversial. The aim of this study is to summarize the findings on the acute and chronic effects of different forms of cocoa on the risk factors of cardiovascular disease. We searched SCOPUS, Pub Med and Web of Science from inception to Jan 2020. Finally, the random-effect model was used to report the pooled effect sizes. Results are expressed as weighted mean difference (WMD) with 95% confidence intervals (CI).Overall, 41 trials were included, of which only 14 studies met the eligibility criteria for analysis, including 11 long-term RCTs (more than a week was considered as a chronic phase) and 7 short-term RCTs (less than a week was considered as an acute phase). According to the result of 11 long-term RCTs, cocoa products had a negative significant effect on pulse wave velocity; PWV (WMD: -0.33   m/s, P   <   0.0001), Augmentation index; AIx (WMD: -4.50%, P   =   0.001) but had no significant effect on platelet count (WMD: -10.41 10 9 /L, P   =   0.053). Also, according to the results of 7 short-term RCTs, cocoa products had a negative significant effect on PWV (WMD: -0.27   m/s, P   =   0.019), AIx (WMD: -4.47%, P   =   0.003).Current study indicated the beneficial effect of acute and chronic consumption of cocoa-based products ingestion on platelet function and arterial stiffness in healthy adult regardless of age especially in male and for consumption (≤4   weeks) in the chronic intake and (≤120   minutes) in acute intake, but did not affect on platelet count. However, further studies are required to shed light on this issue.

Aims: We developed a glaucoma-on-a-chip model to evaluate the viability of retinal ganglion cells (RGCs) against high pressure and the potential effect of neuroprotection., Methods: A three-layered chip consisting of interconnecting microchannels and culture wells was designed and fabricated from poly-methyl methacrylate sheets. The bottom surface of the wells was modified by air plasma and coated with different membranes to provide a suitable extracellular microenvironment. RGCs were purified from postnatal Wistar rats by magnetic assisted cell sorting up to 70% and characterized by flow cytometry and immunocytochemistry. The cultured RGCs were exposed to normal (15 mmHg) or elevated pressure (33 mmHg) for 6, 12, 24, 36, and 48 hr, with and without adding brain-derived neurotrophic factor (BDNF) or a novel BDNF mimetic (RNYK)., Results: Multiple inlet ports allow culture media and gas into the wells under elevated hydrostatic pressure. PDL/laminin formed the best supporting membrane. RGC survival rates were 85%, 78%, 70%, 67%, and 61% under normal pressure versus 40%, 22%, 18%, 12%, and 10% under high pressure at 6, 12, 24, 36, and 48 hr, respectively. BDNF and RNYK separately reduced RGC death rates about twofold under both normal and elevated pressures., Conclusion: This model recapitulated the effects of elevated pressure over relatively short time periods and demonstrated the neuroprotective effects of BDNF and RNYK., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Neuronal ceroid lipofuscinosis (NCL) is a hereditary lysosomal storage disease with progressive brain neurodegeneration. Mutations in ceroid lipofuscinosis neuronal protein 5 (CLN5) cause CLN5 disease, a severe condition characterized by seizures, visual failure, motor decline, and progressive cognitive deterioration. This study aimed to identify causative gene variants in Pakistani consanguineous families diagnosed with NCL., Methods: After a thorough clinical and neuroradiological characterization, whole exome sequencing (WES) was performed in 3 patients from 2 unrelated families. Segregation analysis was subsequently performed through Sanger sequencing ANALYSIS: WES led to the identification of the 2 novel homozygous variants c.925&#95;926del, (p.Leu309AlafsTer4) and c.477 T > C, (p.Cys159Arg)., Conclusion: In this study, we report two novel CLN5 cases in the Punjab region of Pakistan. Our observations will help clinicians observe and compare common and unique clinical features of NCL patients, further improving our current understanding of NCL., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The aim of the present study was translation, cross cultural adaptation and face validity evaluation of the Persian version of Patient-Reported Outcome Measure for Urethral Stricture Surgery (USS-PROM) Questionnaire., Materials and Methods: This study was assessed: translation, translation quality, reverse translation and comparison of the english version, Content validity, internal consistency and stability. Content validity presents by index of content validity (CVI) and the content validity ratio (CVR). Internal consistency reliability was tested by Cronbach's ?, and test-retest reliability was evaluated by Intraclass Correlation Coefficient (ICC) assessed by Guttman two way mixed absolute agreements., Result: Frothy males with history urethroplasty and mean age of 41.4±9.08 (range of 19 to 52) years old; enrolled.  In the case of mean scores of difficulty from the 16 translated items, 80% had easy translation. In terms of translation quality, 92% were the satisfactorily clear. In terms of similar concept, 92% were satisfactory. The overall quality of the translation was satisfactory at 88%. The translated questionnaire has a good internal consistency (Cronbach's alpha as 0.84). CVI and the CVR, test-retest ICC evaluation were appropriate/acceptable in all questions. The questionnaire ICC was .791(CI 95%, .678-.876). Two main different aspects of the questionnaire consisted of urinary symptoms (question 1-10) and Quality of life (question 11-15) Cronbach's alpha were .800 and .671 respectively., Conclusion: The Persian version of the questionnaire has acceptable cultural adaptation and face Validity. Further studies should be done using this translated tool to determine its applicability in the urethroplasty patients.

Several studies have been conducted on the effects of peanut consumption on cardiovascular diseases (CVD) risk factors. However, the findings are conflicting and appear inconsistent. The aim of this review is to summarize the findings on the effect of peanut consumption on the risk factors of CVDs. We used relevant keywords and searched through PubMed, Scopus and Web of Science for articles published studies up to November 2018. Randomized controlled trials (RCTs) were included in this meta-analysis. Random or fixed-effects meta-analysis method depending on the results of heterogeneity tests was used to estimate the effect size. Between-study heterogeneity was assessed by Q test and I 2 index. Subgroup analysis was conducted to find any excess relationship. Publication bias was checked by Egger's test and funnel plot. Quality of studies was assessed by the Cochrane criteria. According to the results of 13 RCTs, peanuts has no significant effect on weight (WMD: -0.11 kg, P = 0.773), waist circumference (WMD: -1.41 cm, P = 0.139), body mass index (WMD: -0.14 kg/m 2 , P = 0.428), systolic and diastolic blood pressure (WMD: -0.09 mmHg, P = 0.939 and WMD: 0.60 mmHg, P = 0.652, respectively), low-density lipoprotein cholesterol (WMD: -3.31 mg/dl, P = 0.472), triglyceride (WMD: -7.59 mg/dl, P = 0.180), total cholesterol (WMD: 3.15 mg/dl, P = 0.171), fasting blood sugar (WMD: 0.57 mg/dl, P = 0.604) and serum insulin (WMD: -0.40, P = 0.582). Also, this meta-analysis showed that peanut had a positive significant effect on high-density lipoprotein cholesterol (HDL) (WMD: 2.72 mg/dl, P = 0.001). Peanuts consumption has a positive significant effect on HDL especially at the type of peanut oil, high-oleic peanut and peanut sprout and in healthy subjects and for consumption more than 12 weeks, while has no significant effect on other CVD risk factors.

Congenital stricture, specifically with manifestation in adulthood is extremely a rare cause of urethral stricture and is not associated with known etiologies. It was first described by Cobb et al., and to our knowledge only 5 families were reported in English literatures to have familial urethral stricture.We report two families with urethral stricture including five male patients referred to our tertiary reconstructive urology department during 1994 to 2017. The age and severity of symptoms at presentation are variable; as are the surgical interventions required. There are no phylogenetic, familiar or racial relationship between the two families described.

Introduction: The retrograde approach is a modification that makes the percutaneous cystolitholapaxy (PCCL) a more trendy method, especially in operating rooms with limited facilities. The transurethral approach for bladder calculi lithotripsy by a laser has become popular among urologists. In this study, we investigate the feasibility and safety of retrograde assisted access for PCCL in comparison with transurethral cystolithotripsy by the holmium-YAG laser (Ho: YAG). Methods: According to the type of intervention, the patients were stratified to two matched groups. In the retrograde-assisted percutaneous cystolitholapaxy (RPCCL) group, a Benique was conducted through the urethra into the bladder; palpating the suprapubic region, an about 1.5 cm incision was done over the tip, then an Amplatz sheath was placed over it, treading into the bladder; further cystolitholapaxy was done by a routine order. In transurethral Ho: YAG laser lithotripsy (TULL) via 200 µm fiber vaporize the stone. Results: A total of 124 male patients with the mean age of 50.33±9.64 years and the average stone burden of 3.35±1.07 cm were included in the study. The most common cause of vesical calculi was spinal cord injury. Statistically significant differences were found in terms of the mean operation time in favor of the RPCCL group (P≤0.05) and the mean hospital stay in favor of the TULL group (P≤0.05). The stone-free rate (SFR) was 100% in both methods after a onemonth follow-up. None of the interventions changed to open surgery. There were not any major complications in both methods. Conclusion: RPCCL is a safe and effective method in bladder stone treatment and is applicable in medical centres without Ho: YAG equipment., (Copyright © 2019 J Lasers Med Sci.)

Introduction: We have recently shown that intracerebral delivery of an anti-VEGF monoclonal antibody bevacizumab using an intra-arterial (IA) infusion is more effective than intravenous administration. While antibodies are quickly emerging as therapeutics, their disadvantages such as large size, production logistics and immunogenicity motivate search for alternatives. Thus we have studied brain uptake of nanobodies and polyamidoamine (PAMAM) dendrimers., Methods: Nanobodies were conjugated with deferoxamine (DFO) to generate NB(DFO) 2 . Generation-4 PAMAM dendrimers were conjugated with DFO, and subsequently primary amines were capped with butane-1,2-diol functionalities to generate G4(DFO) 3 (Bdiol) 110 . Resulting conjugates were radiolabeled with zirconium-89. Brain uptake of 89 ZrNB(DFO) 2 and 89 ZrG4(DFO) 3 (Bdiol) 110 upon carotid artery vs tail vein infusions with intact BBB or osmotic blood-brain barrier opening (OBBBO) with mannitol in mice was monitored by dynamic positron emission tomography (PET) over 30 min to assess brain uptake and clearance, followed by whole-body PET-CT (computed tomography) imaging at 1 h and 24 h post-infusion (pi). Imaging results were subsequently validated by ex-vivo biodistribution., Results: Intravenous administration of 89 ZrNB(DFO) 2 and 89 ZrG4(DFO) 3 (Bdiol) 110 resulted in their negligible brain accumulation regardless of BBB status and timing of OBBBO. Intra-arterial (IA) administration of 89 ZrNB(DFO) 2 dramatically increased its brain uptake, which was further potentiated with prior OBBBO. Half of the initial brain uptake was retained after 24 h. In contrast, IA infusion of 89 ZrG4(DFO) 3 (Bdiol) 110 resulted in poor initial accumulation in the brain, with complete clearance within 1 h of administration. Ex-vivo biodistribution results reflected those on PET-CT., Conclusions: IA delivery of nanobodies might be an attractive therapeutic platform for CNS disorders where prolonged intracranial retention is necessary.

The prostate-specific membrane antigen (PSMA) is a validated target for detection and management of prostate cancer (PC). It has also been utilized for targeted drug delivery through antibody-drug conjugates and polymeric micelles. Polyamidoamine (PAMAM) dendrimers are emerging as a versatile platform in a number of biomedical applications due to their unique physicochemical properties, including small size, large number of reactive terminal groups, bulky interior void volume, and biocompatibility. Here, we report the synthesis of generation 4 PSMA-targeted PAMAM dendrimers [G4(MP-KEU)] and evaluation of their targeting properties in vitro and in vivo using an experimental model of PC. A facile, one-pot synthesis gave nearly neutral nanoparticles with a narrow size distribution of 5 nm in diameter and a molecular weight of 27.3 kDa. They exhibited in vitro target specificity with a dissociation constant ( K d ) of 0.32 ± 0.23 μm and preferential accumulation in PSMA + PC3 PIP tumors versus isogenic PSMA - PC3 flu tumors. Positron emission tomography-computed tomography imaging and ex vivo biodistribution studies of dendrimers radiolabeled with 64 Cu, [ 64 Cu]G4(MP-KEU), demonstrated high accumulation in PSMA + PC3 PIP tumors at 24 h post-injection (45.83 ± 20.09% injected dose per gram of tissue, %ID/g), demonstrating a PSMA + PC3 PIP/PSMA - PC3 flu ratio of 7.65 ± 3.35. Specific accumulation of G4(MP-KEU) and [ 64 Cu]G4(MP-KEU) in PSMA + PC3 PIP tumors was inhibited by the known small-molecule PSMA inhibitor, ZJ-43. On the contrary, G4(Ctrl), control dendrimers without PSMA-targeting moieties, showed comparable low accumulation of ∼1%ID/g in tumors irrespective of PSMA expression, further confirming PSMA + tumor-specific uptake of G4(MP-KEU). These results suggest that G4(MP-KEU) may represent a suitable scaffold by which to target PSMA-expressing tissues with imaging and therapeutic agents.

Magnetic nanoparticle (MNP)-induced hyperthermia is currently being evaluated for localized prostate cancer. We evaluated the feasibility of tumor-selective delivery of prostate-specific membrane antigen (PSMA)-targeted MNPs in a murine model with high-resolution magnetic resonance imaging (MRI) after intravenous administration of MNPs at a concentration necessary for hyperthermia. A PSMA-targeted MNP was synthesized and evaluated using T 2 -weighted MRI, after intravenous administration of 50 mg/kg of the MNP. Significant contrast enhancement ( P < 0.0002, n = 5) was observed in PSMA(+) tumors compared to PSMA(-) tumors 24 h and 48 h after contrast agent administration. Mice were also imaged with near-infrared fluorescence imaging, to validate the MRI results. Two-photon microscopy revealed higher vascular density at the tumor periphery, which resulted in higher  peripheral accumulation of PSMA-targeted MNPs. These results suggest that the delivery of PSMA-targeted MNPs to PSMA(+) tumors is both actively targeted and passively mediated.

Brain-derived neurotrophic factor (BDNF) is a well-known neuroprotectant and a potent therapeutic candidate for neurodegenerative diseases. However, there are several clinical concerns about its therapeutic applications. In the current study, we designed and developed BDNF-mimicking small peptides as an alternative to circumvent these problems. A phage-displayed peptide library was screened using BDNF receptor (neurotrophic tyrosine kinase receptor type2 [NTRK2]) and evaluated by ELISA. The peptide sequences showed similarity to loop2 of BDNF, they were recognized as discontinuous epitopes though. Interestingly, in silico molecular docking showed strong interactions between the peptide three-dimensional models and the surface residues of the NTRK2 protein at the IgC2 domain. A consensus peptide sequence was then synthesized to generate a mimetic construct (named as RNYK). The affinity binding and function of this construct was confirmed by testing against the native structure of NTRK2 in SH-SY5Y cells in vitro using flow-cytometry and MTT assays, respectively. RNYK at 5 ng/mL prevented neuronal degeneration of all- trans-retinoic acid-treated SH-SY5Y with equal efficacy to or even better than BDNF at 50 ng/mL., (© 2018 Wiley Periodicals, Inc.)

Telomeric sequences are generally located at the ends of chromosomes; however, they can also be found in non-terminal chromosomal regions when they are known as interstitial telomeric sequences (ITSs). Distribution of ITSs across closely related and divergent species elucidates karyotype evolution and speciation as ITSs provide evolutionary evidence for chromosome fusion. In this study, we performed physical mapping of telomeric repeats by fluorescence in situ hybridisation (FISH) in seven Australian dragon lizards thought to represent derived karyotypes of squamate reptiles and a gecko lizard with considerably different karyotypic feature. Telomeric repeats were present at both ends of all chromosomes in all species, while varying numbers of ITSs were also found on microchromosomes and in pericentromeric or centromeric regions on macrochromosomes in five lizard species examined. This suggests that chromosomal rearrangements from ancestral squamate reptiles to Iguania occurred mainly by fusion between ancestral types of acrocentric chromosomes and/or between microchromosomes, leading to appearance of bi-armed macrochromosomes, and in the reduction of microchromosome numbers. These results support the previously proposed hypothesis of karyotype evolution in squamate reptiles. In addition, we observed the presence of telomeric sequences in the similar regions to heterochromatin of the W microchromosome in Pogona barbata and Doporiphora nobbi, while sex chromosomes for the two species contained part of the nucleolar organiser regions (NORs). This likely implies that these ITSs are a part of the satellite DNA and not relics of chromosome fusions. Amplification of telomeric repeats may have involved heterochromatinisation of sex-specific W chromosomes and play a role in the organisation of the nucleolus., Competing Interests: The authors have declared that no competing interests exist.

Limited postmortem evidence suggests a diminished availability of the α7 nicotinic acetylcholine receptor (α7-nAChR) in hippocampus in psychosis. Methods: In this cross-sectional PET study, we used 18 F-ASEM, a radiotracer targeting the α7-nAChR, with positron emission tomography to compare the binding of 18 F-ASEM in hippocampus between individuals with recent-onset psychosis and healthy controls. Results: Individuals with recent-onset psychosis [non-affective psychosis (NP) or affective psychosis], and particularly those with NP, showed lower hippocampal binding of 18 F-ASEM than healthy controls. Among patients, lower binding was associated with lower performance in two cognitive domains after controlling for age. Conclusion: Low availability of the α7-nAChR in hippocampus may be linked to recent-onset of psychosis. Further study is needed to assess its clinical relationship to neuropsychiatric symptoms., (Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Scorpion venom is the most expensive and deadly venom with exciting medical prospects and having a potential as a source of drug candidates. A number of scorpion venom peptides have shown promising site specificity and are involved in the regulation of biological mechanisms. Due to the structural and functional specificity, the scorpion peptides are widely used for the development of specific drugs especially for the cardiovascular and other immune diseases. In this review, we summarize scorpion venom's biological activities such as antimicrobial, antiviral, anti-cancerous and in immune diseases. Evolutionary perspective of peptides derived from different scorpion venoms are also described in this review. The most significant venom peptides are; Ctriporin, Chlorotoxins (cltx), Neopladine I and II, Meucin 24, Meucin 25 and Hp 1090. The most recognized scorpion species with pharmaceutical activities are; Pandinus imperator, Chaerilustricostatus, Buthus martensii, Mesobuthus eupeus, Leiurus quinnquestriatus, Tityus discrepans and Heterometrus bengalensis., Conclusion: The role of peptides in cardiovascular events and in treating osteoporosis signifies their importance. The role of peptides against pathogens, skin infections, pain-relieving effects, anti-malarial and anti-viral effects are discussed in detail. We further, summarized the classification of scorpion peptides among different toxins, their evolutionary process and the pattern of scorpion venom resource analysis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Squamates (lizards and snakes) are a speciose lineage of reptiles displaying considerable karyotypic diversity, particularly among lizards. Understanding the evolution of this diversity requires comparison of genome organisation between species. Although the genomes of several squamate species have now been sequenced, only the green anole lizard has any sequence anchored to chromosomes. There is only limited gene mapping data available for five other squamates. This makes it difficult to reconstruct the events that have led to extant squamate karyotypic diversity. The purpose of this study was to anchor the recently sequenced central bearded dragon (Pogona vitticeps) genome to chromosomes to trace the evolution of squamate chromosomes. Assigning sequence to sex chromosomes was of particular interest for identifying candidate sex determining genes., Results: By using two different approaches to map conserved blocks of genes, we were able to anchor approximately 42 % of the dragon genome sequence to chromosomes. We constructed detailed comparative maps between dragon, anole and chicken genomes, and where possible, made broader comparisons across Squamata using cytogenetic mapping information for five other species. We show that squamate macrochromosomes are relatively well conserved between species, supporting findings from previous molecular cytogenetic studies. Macrochromosome diversity between members of the Toxicofera clade has been generated by intrachromosomal, and a small number of interchromosomal, rearrangements. We reconstructed the ancestral squamate macrochromosomes by drawing upon comparative cytogenetic mapping data from seven squamate species and propose the events leading to the arrangements observed in representative species. In addition, we assigned over 8 Mbp of sequence containing 219 genes to the Z chromosome, providing a list of genes to begin testing as candidate sex determining genes., Conclusions: Anchoring of the dragon genome has provided substantial insight into the evolution of squamate genomes, enabling us to reconstruct ancestral macrochromosome arrangements at key positions in the squamate phylogeny, demonstrating that fusions between macrochromosomes or fusions of macrochromosomes and microchromosomes, have played an important role during the evolution of squamate genomes. Assigning sequence to the sex chromosomes has identified NR5A1 as a promising candidate sex determining gene in the dragon.

Unlabelled: The atypical chemokine receptor ACKR3 (formerly CXCR7), overexpressed in various cancers compared with normal tissues, plays a pivotal role in adhesion, angiogenesis, tumorigenesis, metastasis, and tumor cell survival. ACKR3 modulates the tumor microenvironment and regulates tumor growth. The therapeutic potential of ACKR3 has also been demonstrated in various murine models of human cancer. Literature findings underscore the importance of ACKR3 in disease progression and suggest it as an important diagnostic marker for noninvasive imaging of ACKR3-overexpressing malignancies. There are currently no reports on direct receptor-specific detection of ACKR3 expression. Here we report the evaluation of a radiolabeled ACKR3-targeted monoclonal antibody (ACKR3-mAb) for the noninvasive in vivo nuclear imaging of ACKR3 expression in human breast, lung, and esophageal squamous cell carcinoma cancer xenografts., Methods: ACKR3 expression data were extracted from Cancer Cell Line Encyclopedia, The Cancer Genome Atlas, and the Clinical Lung Cancer Genome Project. (89)Zr-ACKR3-mAb was evaluated in vitro and subsequently in vivo by PET and ex vivo biodistribution studies in mice xenografted with breast (MDA-MB-231-ACKR3 [231-ACKR3], MDA-MB-231 [231], MCF7), lung (HCC95), or esophageal (KYSE520) cancer cells. In addition, ACKR3-mAb was radiolabeled with (125)I and evaluated by SPECT imaging and ex vivo biodistribution studies., Results: ACKR3 transcript levels were highest in lung squamous cell carcinoma among the 21 cancer type data extracted from The Cancer Genome Atlas. Also, Clinical Lung Cancer Genome Project data showed that lung squamous cell carcinoma had the highest CXCR7 transcript levels compared with other lung cancer subtypes. The (89)Zr-ACKR3-mAb was produced in 80% ± 5% radiochemical yields with greater than 98% radiochemical purity. In vitro cell uptake of (89)Zr-ACKR3-mAb correlated with gradient levels of cell surface ACKR3 expression observed by flow cytometry. In vivo PET imaging and ex vivo biodistribution studies in mice with breast, lung, and esophageal cancer xenografts consistently showed enhanced (89)Zr-ACKR3-mAb uptake in high-ACKR3-expressing tumors. SPECT imaging of (125)I-ACKR3-mAb showed the versatility of ACKR3-mAb for in vivo monitoring of ACKR3 expression., Conclusion: Data from this study suggest ACKR3 to be a viable diagnostic marker and demonstrate the utility of radiolabeled ACKR3-mAb for in vivo visualization of ACKR3-overexpressing malignancies., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

The sex chromosomes in Sauropsida (reptiles and birds) have evolved independently many times. They show astonishing diversity in morphology ranging from cryptic to highly differentiated sex chromosomes with male (XX/XY) and female heterogamety (ZZ/ZW). Comparing such diverse sex chromosome systems thus provides unparalleled opportunities to capture evolution of morphologically differentiated sex chromosomes in action. Here, we describe chromosomal mapping of 18 microsatellite repeat motifs in eight species of Sauropsida. More than two microsatellite repeat motifs were amplified on the sex-specific chromosome, W or Y, in five species (Bassiana duperreyi, Aprasia parapulchella, Notechis scutatus, Chelodina longicollis, and Gallus gallus) of which the sex-specific chromosomes were heteromorphic and heterochromatic. Motifs (AAGG)n and (ATCC)n were amplified on the W chromosome of Pogona vitticeps and the Y chromosome of Emydura macquarii, respectively. By contrast, no motifs were amplified on the W chromosome of Christinus marmoratus, which is not much differentiated from the Z chromosome. Taken together with previously published studies, our results suggest that the amplification of microsatellite repeats is tightly associated with the differentiation and heterochromatinization of sex-specific chromosomes in sauropsids as well as in other taxa. Although some motifs were common between the sex-specific chromosomes of multiple species, no correlation was observed between this commonality and the species phylogeny. Furthermore, comparative analysis of sex chromosome homology and chromosomal distribution of microsatellite repeats between two closely related chelid turtles, C. longicollis and E. macquarii, identified different ancestry and differentiation history. These suggest multiple evolutions of sex chromosomes in the Sauropsida.

The insole shape and the resulting plantar stress distribution have a pivotal impact on overall health. In this paper, by Finite Element Method, maximum stress value and stress distribution of plantar were studied for different insoles designs, which are the flat surface and the custom-molded (conformal) surface. Moreover, insole thickness, heel's height, and different materials were used to minimize the maximum stress and achieve the most uniform stress distribution. The foot shape and its details used in this paper were imported from online CT-Scan images. Results show that the custom-molded insole reduced maximum stress 40% more than the flat surface insole. Upon increase of thickness in both insole types, stress distribution becomes more uniform and maximum stress value decreases up to 10%; however, increase of thickness becomes ineffective above a threshold of 1 cm. By increasing heel height (degree of insole), maximum stress moves from heel to toes and becomes more uniform. Therefore, this scenario is very helpful for control of stress in 0.2° to 0.4° degrees for custom-molded insole and over 1° for flat insole. By changing the material of the insole, the value of maximum stress remains nearly constant. The custom-molded (conformal) insole which has 0.5 to 1 cm thickness and 0.2° to 0.4° degrees is found to be the most compatible form for foot.

Sex determination in animals is amazingly plastic. Vertebrates display contrasting strategies ranging from complete genetic control of sex (genotypic sex determination) to environmentally determined sex (for example, temperature-dependent sex determination). Phylogenetic analyses suggest frequent evolutionary transitions between genotypic and temperature-dependent sex determination in environmentally sensitive lineages, including reptiles. These transitions are thought to involve a genotypic system becoming sensitive to temperature, with sex determined by gene-environment interactions. Most mechanistic models of transitions invoke a role for sex reversal. Sex reversal has not yet been demonstrated in nature for any amniote, although it occurs in fish and rarely in amphibians. Here we make the first report of reptile sex reversal in the wild, in the Australian bearded dragon (Pogona vitticeps), and use sex-reversed animals to experimentally induce a rapid transition from genotypic to temperature-dependent sex determination. Controlled mating of normal males to sex-reversed females produces viable and fertile offspring whose phenotypic sex is determined solely by temperature (temperature-dependent sex determination). The W sex chromosome is eliminated from this lineage in the first generation. The instantaneous creation of a lineage of ZZ temperature-sensitive animals reveals a novel, climate-induced pathway for the rapid transition between genetic and temperature-dependent sex determination, and adds to concern about adaptation to rapid global climate change.

Until the 19th century, medicine in Persia is mainly based on the humoral theory. According to some authors, the introduction of anatomical pathology principles is due to the particular political and health circumstances of this century and the intellectual evolution of Persian physicians. By making a comparison between the text of Shirazi, the prominent Persian physician of the 19th century, and the writings of Avicenna on cholera and heyze (acute diarrhea), this article tests this hypothesis.

Early detection enables improved prognosis for prostate cancer (PCa). A promising target for imaging and therapy of PCa is the prostate-specific membrane antigen (PSMA), which exhibits both expression within the epithelium of PCa cells, and becomes internalized upon ligand binding. Here we report the synthesis of a PSMA-targeted bionized nanoferrite (BNF) nanoparticle and its biological evaluation in an experimental model of PCa. The BNF nanoparticle formulation exhibits properties conducive to targeted imaging such as stealth, prolonged circulation time and enhanced clearance from non-target sites. Optical imaging of the targeted BNF in vivo indicates preferential accumulation in PSMA+ tumors 4 h post-injection, suggesting target specificity. On the other hand, non-targeted nanoparticles exhibit lower uptake with similar accumulation in both PSMA+ and PSMA- tumors indicating tumor access without preferential accumulation. Imaging with single photon emission computed tomography (SPECT) and biodistribution studies of a modified construct indicate highest tumor accumulation at 48 h post-injection [4.3 ± 0.4 percentage injected dose per gram of tissue (%ID g(-1))], with tumor/blood and tumor/muscle ratios of 7.5 ± 2.4 and 11.6 ± 1.2 %ID g(-1), respectively. Ex vivo fluorescence microscopy, Prussian blue staining, immunohistochemistry and biodistribution studies confirm enhanced nanoparticle uptake in PSMA+ tumors compared to those not expressing PSMA. The BNF nano-formulation described is promising for PSMA-targeted imaging applications in vivo.

The CXCR4 chemokine receptor is integral to several biological functions and plays a pivotal role in the pathophysiology of many diseases. As such, CXCR4 is an enticing target for the development of imaging and therapeutic agents. Here we report the evaluation of the POL3026 peptidomimetic template for the development of imaging agents that target CXCR4. Structural and conformational analyses of POL3026 and two of its conjugates, DOTA (POL-D) and PEG12-DOTA (POL-PD), by circular dichroism, two-dimensional NMR spectroscopy and molecular dynamics calculations are reported. In silico observations were experimentally verified with in vitro affinity assays and rationalized using crystal structure-based molecular modeling studies. [(111)In]-labeled DOTA conjugates were assessed in vivo for target specificity in CXCR4 expressing subcutaneous U87 tumors (U87-stb-CXCR4) through single photon emission computed tomography (SPECT/CT) imaging and biodistribution studies. In silico and in vitro studies show that POL3026 and its conjugates demonstrate similar interactions with different micelles that mimic cellular membrane and that the ε-NH2 of lysine(7) is critical to maintain high affinity to CXCR4. Modification of this group with DOTA or PEG12-DOTA led to the decrease of IC50 value from 0.087 nM for POL3026 to 0.47 nM and 1.42 nM for POL-D and POL-PD, respectively. In spite of the decreased affinity toward CXCR4, [(111)In]POL-D and [(111)In]POL-PD demonstrated high and significant uptake in U87-stb-CXCR4 tumors compared to the control U87 tumors at 90 min and 24 h post injection. Uptake in U87-stb-CXCR4 tumors could be blocked by unlabeled POL3026, indicating specificity of the agents in vivo. These results suggest POL3026 as a promising template to develop new imaging agents that target CXCR4.