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To date, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) COVID-19 pandemic continues to be a potentially lethal disease. Although both vaccines and specific antiviral drugs have been approved, the search for more specific therapeutic approaches is still ongoing. The infection mechanism of SARS-CoV-2 consists of several stages, and each one can be selectively blocked to disrupt viral infection. Peptides are a promising class of antiviral compounds, which may be suitably modified to be more stable, more effective, and more selective towards a specific viral replication step. The latter two goals might be obtained by increasing the specificity and/or the affinity of the interaction with a specific target and often imply the stabilization of the secondary structure of the active peptide. This review is focused on modified antiviral peptides against SARS-CoV-2 acting at different stages of virus replication, including ACE2-RBD interaction, membrane fusion mechanism, and the proteolytic cleavage by different viral proteases. Therefore, the landscape presented herein provides a useful springboard for the design of new and powerful antiviral therapeutics., (© 2023 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

Capitellacin (1) is a 20-residue antimicrobial β-hairpin, produced by the marine polychaeta (segmented worms) Capitella teletai. Since its discovery in 2020, only very limited studies have been undertaken to understand capitellacin's structure–activity relationship (SAR). Using fast-flow Fmoc-SPPS, a focused library of capitellacin analogues was prepared to systematically study the influence of the two disulphide bridges on its structure and activity, and their replacement with a vinyl sulphide as a potential bioisostere. Upon studying the resulting peptides' antimicrobial activity and secondary structure, the most terminal disulphide emerged as the most critical element for maintaining both bioactivity and the secondary structure, properties which were demonstrated to be closely interlinked. The removal of the innermost disulphide bridge or disulphide replacement with a vinyl sulphide emerged as strategies with which to tune the activity spectrum, producing selectivity towards E. coli. Additionally, an enantiomeric d-capitellacin analogue revealed mechanistic insights, suggesting that chirality may be an inherent property of capitellacin's bacterial membrane target, or that a hitherto unknown secondary mechanism of action may exist. Additionally, we propose the Alloc protecting group as a more appropriate alternative to the common Dde group during fast-flow Fmoc-SPPS, in particular for short-chain diamino acids. [ABSTRACT FROM AUTHOR]

Background: Each year, 3,800 cases of snakebite envenomation are reported in Mexico, resulting in 35 fatalities. The only scientifically validated treatment for snakebites in Mexico is the use of antivenoms. Currently, two antivenoms are available in the market, with one in the developmental phase. These antivenoms, produced in horses, consist of F(ab')2 fragments generated using venoms from various species as immunogens. While previous studies primarily focused on neutralizing the venom of the Crotalus species, our study aims to assess the neutralization capacity of different antivenom batches against pit vipers from various genera in Mexico. Methodology: We conducted various biological and biochemical tests to characterize the venoms. Additionally, we performed neutralization tests using all three antivenoms to evaluate their effectiveness against lethal activity and their ability to neutralize proteolytic and fibrinogenolytic activities. Results: Our results reveal significant differences in protein content and neutralizing capacity among different antivenoms and even between different batches of the same product. Notably, the venom of Crotalus atrox is poorly neutralized by all evaluated batches despite being the primary cause of envenomation in the country's northern region. Furthermore, even at the highest tested concentrations, no antivenom could neutralize the lethality of Metlapilcoatlus nummifer and Porthidium yucatanicum venoms. These findings highlight crucial areas for improving existing antivenoms and developing new products. Conclusion: Our research reveals variations in protein content and neutralizing potency among antivenoms, emphasizing the need for consistency in venom characteristics as immunogens. While Birmex neutralizes more LD50 per vial, Antivipmyn excels in specific neutralization. The inability of antivenoms to neutralize certain venoms, especially M. nummifer and P. yucatanicum, highlights crucial improvement opportunities, given the medical significance of these species. Author summary: The annual incidence of snakebite in Mexico is about 3,800 cases, leading to 35 fatalities. Therefore, antivenoms, which are the primary treatment, are crucial. Two Mexican antivenoms are in therapeutic use, and a third is in development; all are made from horse-derived antibody fragments. Our study assesses antivenom's effectiveness in neutralizing the venom of several vipers in Mexico. We tested different antivenom batches, finding differences in neutralization capacity. Surprisingly, the Crotalus atrox venom is not well neutralized, and all antivenoms struggle against those of Metlapilcoatlus nummifer and Porthidium yucatanicum. Altogether, our work reveals crucial areas for antivenom improvement, stressing the need for better antivenoms, mainly due to the medical relevance of these species. [ABSTRACT FROM AUTHOR]

Disturbances in cholesterol homeostasis have been associated with ASD. Lipid rafts are central in many transmembrane signaling pathways (including mTOR) and changes in raft cholesterol content affect their order function. Cholesterol levels are controlled by several mechanisms, including endoplasmic reticulum associated degradation (ERAD) of the rate limiting HMGCoA reductase. A new approach to increase cholesterol via temporary ERAD blockade using a benign bacterial toxin-derived competitor for the ERAD translocon is suggested. A new lock and key model for cholesterol/lipid raft dependent signaling is proposed in which the rafts provide both the afferent and efferent 'tumblers' across the membrane to allow 'lock and key' receptor transmembrane signals. [ABSTRACT FROM AUTHOR]

Pain affects one-third of the global population and is a significant public health issue. The use of opioid drugs, which are the strongest painkillers, is associated with several side effects, such as tolerance, addiction, overdose, and even death. An increasing demand for novel, safer analgesic agents is a driving force for exploring natural sources of bioactive peptides with antinociceptive activity. Since the G protein-coupled receptors (GPCRs) play a crucial role in pain modulation, the discovery of new peptide ligands for GPCRs is a significant challenge for novel drug development. The aim of this review is to present peptides of human and animal origin with antinociceptive potential and to show the possibilities of their modification, as well as the design of novel structures. The study presents the current knowledge on structure-activity relationship in the design of peptide-based biomimetic compounds, the modification strategies directed at increasing the antinociceptive activity, and improvement of metabolic stability and pharmacodynamic profile. The procedures employed in prolonged drug delivery of emerging compounds are also discussed. The work summarizes the conditions leading to the development of potential morphine replacements. [ABSTRACT FROM AUTHOR]

Solid-phase peptide synthesis (SPPS) is the preferred strategy for synthesizing most peptides for research purposes and on a multi-kilogram scale. One key to the success of SPPS is the continual evolution and improvement of the original method proposed by Merrifield. Over the years, this approach has been enhanced with the introduction of new solid supports, protecting groups for amino acids, coupling reagents, and other tools. One of these improvements is the use of the so-called "safety-catch" linkers/resins. The linker is understood as the moiety that links the peptide to the solid support and protects the C-terminal carboxylic group. The "safety-catch" concept relies on linkers that are totally stable under the conditions needed for both α-amino and side-chain deprotection that, at the end of synthesis, can be made labile to one of those conditions by a simple chemical reaction (e.g., an alkylation). This unique characteristic enables the simultaneous use of two primary protecting strategies: tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). Ultimately, at the end of synthesis, either acids (which are incompatible with Boc) or bases (which are incompatible with Fmoc) can be employed to cleave the peptide from the resin. This review focuses on the most significant "safety-catch" linkers. [ABSTRACT FROM AUTHOR]

Myeloid sarcoma (MS) is a rare hematological neoplasm with poor prognosis, posing a significant clinical challenge due to the absence of effective and standardized treatments. We conducted a retrospective analysis of 162 MS patients treated at 12 centers to compare outcomes between intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our analysis revealed that allo-HSCT demonstrated superior overall survival (OS) within the initial 36 months compared to intensive chemotherapy alone (p = 0.037). However, beyond 36 months (36-60 months), a reverse trend was observed (p = 0.056). Subgroup analysis revealed potential benefit for isolated MS patients with allo-HSCT, but not for those with leukemic MS. Additionally, in patients achieving first complete remission (CR1) after induction chemotherapy, allo-HSCT did not significantly improve 5-year OS compared with intensive chemotherapy alone (p = 0.25). Conversely, allo-HSCT significantly improved 5-year OS in non-CR1 patients (p < 0.001). Notably, HLA-matched HSCT and haploidentical HSCT showed comparable outcomes in terms of OS, disease-free survival, and cumulative incidence of relapse. In conclusion, allo-HSCT improved outcomes for MS patients within 36 months of disease onset, and haploidentical HSCT emerged as a viable treatment option for patients without matched donors., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Adrenocorticotropic hormone (ACTH), in addition to the renin-angiotensin-aldosterone axis, is a potent aldosterone stimulator, suggesting a potential contribution to conditions associated with increased ACTH concentrations. This study aims to systematically review and synthesize the scientific evidence of alterations of plasma aldosterone concentrations in response to ACTH stimulation during the cosyntropin (Synacthen) test and define the range of aldosterone response., Methods: A systematic search of PubMed, Medline, and Google Scholar databases according to PRISMA guidelines was performed. Only studies that assessed the alterations in plasma aldosterone concentrations following ACTH stimulation in healthy individuals were included. We incorporated studies that utilized the doses of 1 μg, 250 μg, 0.125 μg/m 2 , or 0.5 μg/m 2 of ACTH. Out of 1599 initially assessed articles, 17 were deemed relevant to our research. The selected articles were assessed by two independent investigators based on the predetermined inclusion and exclusion criteria. Finally, eight full-text articles were included., Results: The analyzed studies revealed a significant increase in plasma aldosterone concentrations in healthy subjects after ACTH stimulation, irrespective of the ACTH dose. The peak aldosterone concentration after the 250 μg dose occurred at 30 min, whereas smaller doses exhibited an earlier peak, at around 15 min. On average, plasma aldosterone concentration increased by 125.5% after the 1 μg and 0.5 μg/m 2 doses, and by 189.6% after 250 μg., Conclusion: The presented evidence strongly supports the contribution of ACTH to aldosterone secretion regulation beyond the renin-angiotensin-aldosterone axis. Establishing a normal aldosterone response threshold following standardized ACTH stimulation could aid in identifying individuals with ACTH-dependent aldosterone hypersecretion and guide personalized and effective treatment strategies., (© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Peptides continue to gain significance in the pharmaceutical arena. Since the unveiling of insulin in 1921, the Food and Drug Administration (FDA) has authorised around 100 peptides for various applications. Peptides, although initially derived from endogenous sources, have evolved beyond their natural origins, exhibiting favourable therapeutic effectiveness. Medicinal chemistry has played a pivotal role in synthesising valuable natural peptide analogues, providing synthetic alternatives with therapeutic potential. Furthermore, key chemical modifications have enhanced the stability of peptides and strengthened their interactions with therapeutic targets. For instance, selective modifications have extended their half-life and lessened the frequency of their administration while maintaining the desired therapeutic action. In this review, I analyse the FDA approval of natural peptides, as well as engineered peptides for diabetes treatment, growth-hormone-releasing hormone (GHRH), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), and α-melanocyte stimulating hormone (α-MSH) peptide analogues. Attention will be paid to the structure, mode of action, developmental journey, FDA authorisation, and the adverse effects of these peptides. [ABSTRACT FROM AUTHOR]

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Background: Parents and survivors of retinoblastoma often hold misconceptions about the disease and desire more extensive and detailed information about its genetic nature. The aim of this study was to co-develop and evaluate a genetic education booklet for retinoblastoma., Methods: A human-centered design approach was employed, in which the study team consulted with clinician and patient knowledge user groups to design, produce, and refine an educational booklet. Over three phases of consultation, the study team met with each knowledge user group to review booklet prototypes and collect feedback for its further refinement. A preliminary evaluation using quantitative and qualitative methods was completed with six mothers of children with retinoblastoma., Results: The iterative, phased design process produced an educational booklet rich in images and stories, with complex genetic topics described in simplified terms. The preliminary evaluation showed an average improvement in knowledge between pre- and post-test questionnaire of 10%. Participants were satisfied with content and comprehensiveness of the information included in the booklet., Conclusion: A novel educational tool for families affected by retinoblastoma was developed through collaboration with health care and patient knowledge users. Preliminary evaluation results indicate it is feasible to implement and study the booklet in a prospective, pragmatic trial to evaluate its efficacy., (© 2024 The Author(s). Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Automated recognition of heart shunts using saline contrast transthoracic echocardiography (SC-TTE) has the potential to transform clinical practice, enabling non-experts to assess heart shunt lesions. This study aims to develop a fully automated and scalable analysis pipeline for distinguishing heart shunts, utilizing a deep neural network-based framework. The pipeline consists of three steps: (1) chamber segmentation, (2) ultrasound microbubble localization, and (3) disease classification model establishment. The study's normal control group included 91 patients with intracardiac shunts, 61 patients with extracardiac shunts, and 84 asymptomatic individuals. Participants' SC-TTE images were segmented using the U-Net model to obtain cardiac chambers. The segmentation results were combined with ultrasound microbubble localization to generate multivariate time series data on microbubble counts in each chamber. A classification model was then trained using this data to distinguish between intracardiac and extracardiac shunts. The proposed framework accurately segmented heart chambers (dice coefficient = 0.92 ± 0.1) and localized microbubbles. The disease classification model achieved high accuracy, sensitivity, specificity, F1 score, kappa value, and AUC value for both intracardiac and extracardiac shunts. For intracardiac shunts, accuracy was 0.875 ± 0.008, sensitivity was 0.891 ± 0.002, specificity was 0.865 ± 0.012, F1 score was 0.836 ± 0.011, kappa value was 0.735 ± 0.017, and AUC value was 0.942 ± 0.014. For extracardiac shunts, accuracy was 0.902 ± 0.007, sensitivity was 0.763 ± 0.014, specificity was 0.966 ± 0.008, F1 score was 0.830 ± 0.012, kappa value was 0.762 ± 0.017, and AUC value was 0.916 ± 0.006. The proposed framework utilizing deep neural networks offers a fast, convenient, and accurate method for identifying intracardiac and extracardiac shunts. It aids in shunt recognition and generates valuable quantitative indices, assisting clinicians in diagnosing these conditions., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Background: The outcome of extramedullary infiltration (EMI) in pediatric acute myeloid leukemia (AML) is controversial, and little is known about the implications of stem cell transplantation (SCT) and gemtuzumab ozogamicin (GO) treatment on patients with EMI., Methods: We retrieved the clinical data of 713 pediatric patients with AML from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset, and analyzed the clinical and prognostic characteristics of patients with EMI at diagnosis and relapse., Results: A total of 123 patients were identified to have EMI at diagnosis and 64 presented with EMI at relapse. The presence of EMI was associated with age ≤2 years, M5 morphology, abnormal karyotype, and KMT2A rearrangements. Hyperleukocytosis and complex karyotype were more prevalent in patients with EMI at relapse. Additionally, patients with EMI at diagnosis had a reduced incidence of FLT3 ITD - /NPM1 + , whereas those with EMI at relapse displayed a lower frequency of FLT3 ITD + . Patients with EMI at diagnosis exhibited a lower complete remission (CR) rate at the end of Induction Course 1 and higher relapse incidence. Importantly, EMI at diagnosis independently predicted both shorter event-free survival (EFS) and overall survival (OS). Regarding relapse patients, the occurrence of EMI at relapse showed no impact on OS. However, relapse patients with myeloid sarcoma (MS)/no central nervous system (CNS) exhibited poorer OS compared to those with CNS/no MS. Furthermore, regarding patients with EMI at diagnosis, SCT failed to improve the survival, whereas GO treatment potentially enhanced OS., Conclusion: EMI at diagnosis is an independent adverse prognostic risk factor for pediatric AML, and GO treatment potentially improves survival for patients with EMI at diagnosis., (© 2024 Wiley Periodicals LLC.)

Neurological diseases are a major global health challenge, affecting hundreds of millions of people worldwide. Ultrasound therapy plays an irreplaceable role in the treatment of neurological diseases due to its noninvasive, highly focused, and strong tissue penetration capabilities. However, the complexity of brain and nervous system and the safety risks associated with prolonged exposure to ultrasound therapy severely limit the applicability of ultrasound therapy. Ultrasound-sensitive intelligent nanosystems (USINs) are a novel therapeutic strategy for neurological diseases that bring greater spatiotemporal controllability and improve safety to overcome these challenges. This review provides a detailed overview of therapeutic strategies and clinical advances of ultrasound in neurological diseases, focusing on the potential of USINs-based ultrasound in the treatment of neurological diseases. Based on the physical and chemical effects induced by ultrasound, rational design of USINs is a prerequisite for improving the efficacy of ultrasound therapy. Recent developments of ultrasound-sensitive nanocarriers and nanoagents are systemically reviewed. Finally, the challenges and developing prospects of USINs are discussed in depth, with a view to providing useful insights and guidance for efficient ultrasound treatment of neurological diseases., (© 2023 Wiley‐VCH GmbH.)

Around 48 million couples and 186 million people worldwide have infertility; of these, approximately 85% have an identifiable cause, the most common being ovulatory dysfunctions, male infertility, polycystic ovary syndrome, and tubule disease. The remaining 15% have infertility for unknown reasons, including lifestyle and environmental factors. The regulation of the hypothalamic- pituitary-adrenal axis (HPA) is crucial for the secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which are essential for female reproductive functions. GnRH is the primary reproductive axis regulator. The pattern of GnRH, FSH, and LH release is determined by its pulsatile secretion, which in turn controls endocrine function and gamete maturation in the gonads. Peptides called Kisspeptin (KP), Neurokinin-B (NKB), and Orexin influence both positive and negative feedback modulation of GnRH, FSH, and LH secretion in reproduction. This review article mainly focuses on the historical perspective, isoform, and signaling pathways of KP, NKB, and Orexin novel peptide-based targets including clinical and preclinical studies and having a promising effect in the management of infertility., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)