Design, synthesis and evaluation of bioactivity of peptidomimetics based on chloroalkene dipeptide isosteres.

Ample biologically active peptides have been found, identified and modified for use in drug discovery to date. However, several factors, such as low metabolic stability due to proteolysis and non-specific interactions with multiple off-target molecules, might limit the therapeutic use of peptides. To enhance the stability and/or bioactivity of peptides, the development of "peptidomimetics," which mimick peptide molecules, is considered to be idealistic. Hence, chloroalkene dipeptide isosteres (CADIs) was designed, and their synthetic methods have been developed by us. Briefly, in a CADI an amide bond in peptides is replaced with a chloroalkene structure. CADIs might be superior mimetics of amide bonds because the Van der Waals radii (VDR) and the electronegativity value of a chlorine atom are close to those of the replaced oxygen atom. By a developed method of the "liner synthesis", N-tert-butylsulfonyl protected CADIs can be synthesized via a key reaction involving diastereoselective allylic alkylation using organocopper reagents. On the other hand, by a developed method of the "convergent synthesis", N-fluorenylmethoxycarbonyl (Fmoc)-protected carboxylic acids can be also constructed based on N- and C-terminal analogues from corresponding amino acid starting materials via an Evans syn aldol reaction and the Ichikawa allylcyanate rearrangement reaction involving a [3.3] sigmatropic rearrangement. Notably, CADIs can also be applied for Fmoc-based solid-phase peptide synthesis and therefore introduced into bioactive peptides including as the Arg-Gly-Asp (RGD) peptide and the amyloid ß fragment Lys-Leu-Val-Phe-Phe (KLVFF) peptide, which are correlated with cell attachment and Alzheimer's disease (AD), respectively. These CADI-containing peptidomimetics stabilized the conformation and enhanced the potency of the cyclic RGD peptide and the cyclic KLVFF peptide.

The Trend of Antibiotic Consumption After the COVID-19 Pandemic: Approach to Future Outbreaks.

Background: Earlier reports suggested high rates of antibiotic utilization among COVID-19 patients despite the lack of direct evidence of their activity against viral pathogens. Different trends in antibiotic consumption during 2020 compared to 2019 have been reported. Purpose: The objective of this study is to assess the impact of COVID-19 pandemic on antibiotic consumption in the presence of active Antibiotic Stewardship Program. Methods: This study represented a five years assessment of the consumption of the commonly prescribed antibiotics measured as DDDs/100-Bed Days. We analyzed the data by using nonparametric Friedman and Friedman tests to compare the antibiotic consumption before and during the three subsequent waves of COVID-19. Results: Antibiotic consumption through the DDDs/100-BD has shown reduction in the median of antibiotics consumption of most antibiotics during the period of COVID-19 as compared to the pre-COVID-19 period, which was significant for meropenem and ciprofloxacin, except colomycin that slightly increased. Significant reduction in the consumption of imipenem and meropenem during the second and third waves as compared to the pre-COVID period. Throughout the years, significant reductions were observed between 2018 and 2019 (p=<.001), 2018 and 2020 (p=0.008), and 2018 and 2022 (p=0.002). Conclusion: The reduction in antibiotic consumption is attributed to the strong influence if the ASP and the reluctance of people to visit hospitals during the COVID-19 pandemic. Other related COVID-19 precautions such as physical distance, good hand hygiene, facemasks, that resulted in the prevention of secondary bacterial infections have contributed to the reduction in antibiotic utilization during the pandemic.

A novel nomogram to predict testicular torsion in children with acute scrotal pain: a single-center retrospective study in western China.

Background: Acute scrotal pain (ASP) is the most common urological emergency in pediatrics, and its causes include testicular torsion (TT), testicular appendage torsion, and epididymo-orchitis. Among them, TT requires prompt and accurate diagnosis and urgent surgical exploration to prevent testicular loss. Conservative anti-infective treatment is recommended for epididymo-orchitis, and surgery is considered only when scrotal abscess formation and sepsis occur. Improving the understanding of TT in primary care doctors, early diagnosis, and timely surgical exploration are essential to improve the survival rate of TT and avoid excessive treatment. This study aimed to explore the risk factors for TT in children with ASP and construct a predictive model. Methods: Clinical data of children who presented with ASP and underwent emergency scrotal exploration surgery were retrospectively analyzed, including general information, physical examination, laboratory tests, and color Doppler ultrasonography (CDU) findings. Based on surgical exploration, the outcomes were categorized as confirmed TT or not. Results: A total of 283 children were included in this study, among whom 134 had TT. The mean age of all patients was 105±47.9 months, with the majority being of Han ethnicity (87.6%) and residing in urban areas (83%). Most patients had normal C-reactive protein levels and negative results in urine routine white blood cell tests (63.3%). After conducting univariate and multivariate logistic regression analyses, we identified laterality, neutrophil count, mean erythrocyte sedimentation rate, epididymal blood flow signal, testicular parenchymal echogenicity, and testicular blood flow signal as independent risk factors influencing the occurrence of TT in ASP patients. Conclusions: This study is the report with the largest sample size on the construction of prediction models for ASP in children in southwestern China. The predictive model we developed demonstrated excellent performance and higher accuracy in predicting TT in children compared to the traditional Testicular Workup for Ischemia and Suspected Torsion (TWIST) score. It can assist pediatric surgeons in diagnosing and treating children with ASP.

Fabry disease caused by the GLA p.Gly183Asp (p.G183D) variant: Clinical profile of a serious phenotype.

Background: The detailed clinical phenotype of patients carrying the α-galactosidase gene (GLA) c.548 G > A/p.Gly183Asp (p.G183D) variant in Fabry disease (FD) has not been thoroughly documented in the existing literature. Methods: This paper offers a meticulous overview of the clinical phenotype and relevant auxiliary examination results of nine confirmed FD patients with the p.G183D gene variant from two families. Pedigree analysis was conducted on two male patients with the gene variant, followed by biochemical and genetic screening of all high-risk relatives. Subsequently, evaluation of multiple organ systems and comprehensive instrument assessment were performed on heterozygotes of the p.G183D gene variant. Results: The study revealed that all patients exhibited varying degrees of cardiac involvement, with two demonstrating left ventricular wall thickness exceeding 15 mm on echocardiography, and the remaining six exceeding 11 mm. Impaired renal function was evident in all six patients with available blood test data, two of whom underwent kidney transplantation. Eight cases reported neuropathic pain, and five experienced varying degrees of stroke or transient ischemic attack (TIA). Conclusion: This study indicates that the GLA p.G183D gene variant can induce premature organ damage, particularly affecting the heart, kidneys, and nervous system.

Identification of two plastid transit peptides for construction of pollen-inactivation system in rice.

Hybrid seed production technology (SPT) is achieved through the utilization of a recessive nuclear male-sterile mutant transformed with a transgenic cassette comprising three essential components: the wild-type gene to restore the fertility of the male-sterile mutant, an α-amylase gene to disrupt transgenic pollen grains, and red fluorescence protein gene DsRed to distinguish the transgenic seeds from the nontransgenic male sterile seeds. In rice, we establish the pollen disruption system by introducing an amyloplast targeting signal peptide (ASP) at the N-terminus of maize α-amylase protein ZM-AA1ΔSP (ZM-AA1 with the N-terminal signal peptide removed). The ASP facilitates the transport of ZM-AA1ΔSP protein into amyloplast where it degrades starch, resulting in disruption of the pollen fertility. To obtain such signal peptides for rice, we searched the rice proteins homologous to the defined wheat amyloplast proteins followed by protein-protein interaction network predictions and targeting signal peptides prediction. These analyses enabled the identification of four candidate ASPs in rice, which were designated as ASP1, ASP2, ASP3, and ASP4, respectively. ASP1 and ASP2, when linked with ZM-AA1ΔSP, exhibited the capability to disrupt transgenic pollen grains, whereas ASP3 and ASP4 did not produce this effect. Interestingly, the localization experiments showed that ASP3 and ASP4 were able to target the proteins into chloroplast. The ASP1 and ASP2 sequences provide valuable tools for genetic engineering of the rice male-sterile system, which will contribute to the hybrid rice breeding and production. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01471-y.

Angelica sinensis polysaccharide combined with cisplatin reverses cisplatin resistance of ovarian cancer by inducing ferroptosis via regulating GPX4.

Cisplatin (DDP) resistance poses a significant challenge in the treatment of ovarian cancer. Studies have shown that the combination of certain polysaccharides derived from plants with DDP is an effective approach to overcoming drug resistance in some cancers. Angelica sinensis (Oliv.) Diels has been used for centuries in China to treat gynecological ailments. Numerous studies indicate that Angelica sinensis polysaccharide (ASP), an extract from Angelica sinensis, can inhibit various forms of cancer. However, the impact of ASP on ovarian cancer remains unexplored. Through both in vitro and in vivo experiments, our study revealed the capability of ASP to effectively reversing DDP resistance in cisplatin-resistant ovarian cancer cells, while exhibiting acceptable safety profiles in vivo. To elucidate the mechanism underlying drug resistance reversal, we employed RNA-seq analysis and identified GPX4 as a key gene. Considering the role of GPX4 in ferroptosis, we conducted additional research to explore the effects of combining ASP with DDP on SKOV3/DDP cells. In summary, our findings demonstrate that the combination of ASP and DDP effectively suppresses GPX4 expression in SKOV3/DDP cells, thereby reversing their resistance to DDP.

Principles and practices of antimicrobial stewardship programs in Korea.

This review addresses the escalating challenge posed by antibiotic resistance, highlighting its profound impact on global public health, including increased mortality rates and healthcare expenditures. The review focuses on the need to adopt the One Health approach to effectively manage antibiotic usage across human, animal, and environmental domains. Antimicrobial stewardship programs (ASPs) are considered as comprehensive strategies that encompass both core and supplementary initiatives aimed at enhancing prudent antibiotic use. The 2021 "Guidelines on Implementing ASP in Korea" introduced such strategies, with a strong emphasis on fostering multidisciplinary and collaborative efforts. Furthermore, the "Core Elements for Implementing ASPs in Korean General Hospitals," established in 2022, provide a structured framework for ASPs, delineating leadership responsibilities, the composition of interdisciplinary ASP teams, a range of interventions, and continuous monitoring and reporting mechanisms. In addition, this review examines patient-centric campaigns such as "Speak Up, Get Smart" and emphasizes the pivotal role of a multidisciplinary approach and international cooperation in addressing the multifaceted challenges associated with antibiotic resistance.

Working and impacting local communities as establishing the start of a conservation initiative: American Society of Primatology conservation committee webinar.

Nonhuman primate species currently face human-induced pressures and will continue to face them in the modern landscape. These pressures require conservation projects in primate habitat countries to aid in protection, preservation, and conservation. Though there are several examples of primate conservation projects, starting up an initiative can be a daunting task. The American Society of Primatology (ASP) Conservation Committee hosted a video webinar presenting on the first steps of developing, running and continuing a primate conservation program. Dr. Christopher Shaffer, Rahayu Oktaviani, and Dr. Jill Pruetz presented their early program experiences establishing wild primate conservation projects to educate primatologists around the world. The running themes of the presentations included establishing community, working locally, impacting locally and preparing for the future.

Evaluating acute toxicity of amino acid ionic liquids towards Poecilia reticulata fish for designing sustainable chemical processes.

An acute toxicity study assessed the LC50 values for eight different amino acid ionic liquids (AAILs), featuring two cations, tetrabutylphosphonium [P4444] and tetrabutylammonium [N4444], coupled with four anions [PHE], [ASP], [SER], and [GLY]. According to the OECD 203 standard for acute fish toxicity tests with guppy fish (Poecilia reticulata, all the AAILs exhibited low toxicity levels, and were practically nontoxic and harmless. The LC50 values surpassed 100 mg/L and 1000 mg/L. This study provides valuable insights for industrial professionals in utilizing tetrabutylphosphonium-based amino acid ionic liquids [P4444] [AA] and tetrabutylammonium-based amino acid ionic liquids [N4444][AA] in chemical processes, indicating their safety in aquatic environments. These promising results highlight the potential of incorporating these AAILs into diverse chemical processes while ensuring minimal ecological impact.

Characterisation of protective vaccine antigens from the thiol-containing components of excretory/secretory material of Ostertagia ostertagi.

Previous vaccination trials have demonstrated that thiol proteins affinity purified from Ostertagia ostertagi excretory-secretory products (O. ostertagi ES-thiol) are protective against homologous challenge. Here we have shown that protection induced by this vaccine was consistent across four independent vaccine-challenge experiments. Protection is associated with reduced cumulative faecal egg counts across the duration of the trials, relative to control animals. To better understand the diversity of antigens in O. ostertagi ES-thiol we used high-resolution shotgun proteomics to identify 490 unique proteins in the vaccine preparation. The most numerous ES-thiol proteins, with 91 proteins identified, belong to the sperm-coating protein/Tpx/antigen 5/pathogenesis-related protein 1 (SCP/TAPS) family. This family includes previously identified O. ostertagi vaccine antigens O. ostertagi ASP-1 and ASP-2. The ES-thiol fraction also has numerous proteinases, representing three distinct classes, including: metallo-; aspartyl- and cysteine proteinases. In terms of number of family members, the M12 astacin-like metalloproteinases, with 33 proteins, are the most abundant proteinase family in O. ostertagi ES-thiol. The O. ostertagi ES-thiol proteome provides a comprehensive database of proteins present in this vaccine preparation and will guide future vaccine antigen discovery projects.

Peptide-Based Mass Spectrometry for the Investigation of Protein Complexes.

In the last two decades, biological mass spectrometry has become the gold standard for the identification of proteins in biological samples. The technological advancement of mass spectrometers and the development of methods for ionization, gas phase transfer, peptide fragmentation as well as for acquisition of high-resolution mass spectrometric data marked the success of the technique. This chapter introduces peptide-based mass spectrometry as a tool for the investigation of protein complexes. It provides an overview of the main steps for sample preparation starting from protein fractionation, reduction, alkylation and focus on the final step of protein digestion. The basic concepts of biological mass spectrometry as well as details about instrumental analysis and data acquisition are described. Finally, the most common methods for data analysis and sequence determination are summarized with an emphasis on its application to protein-protein complexes.

Evaluation of Hospital Antimicrobial Stewardship Programs: Implementation, Process, Impact, and Outcomes, Review of Systematic Reviews.

Antimicrobial Stewardship Programs (ASP) were introduced in healthcare as a public health priority to promote appropriate prescribing of antimicrobials, to reduce adverse events related to antimicrobials, as well as to control the escalating challenges of antimicrobial resistance. To deliver aimed outcome objectives, ASPs involve multiple connected implementation process measures. A systematic review was conducted to evaluate both concepts of ASPs. Guided by PRISMA frames, published systematic reviews (SR) focusing on ASPs restricted to secondary and tertiary healthcare were evaluated over the past 10 years involving all age groups. Out of 265 identified SR studies, 63 met the inclusion criteria. The majority were conducted in Europe and North America, with limited studies from other regions. In the reviewed studies, all age groups were examined, although they were conducted mainly on adults when compared to children and infants. Both process and outcomes measures of ASPs were examined equally and simultaneously through 25 different concepts, dominated by efficacy, antimicrobial resistance, and economic impact, while information technology as well as role of pharmacy and behavioral factors were equally examined. The main broad conclusions from the review were that, across the globe, ASPs demonstrated effectiveness, proved efficacy, and confirmed efficiency, while focused evaluation advocated that developed countries should target medium- and small-sized hospitals while developing countries should continue rolling ASPs across healthcare facilities. Additionally, the future of ASPs should focus on embracing evolving information technology to bridge the gaps in knowledge, skills, and attitude, as well as to enhance appropriate decision making.

Short-term effects of antimicrobial stewardship programs on antibiotics usage, clinical outcomes, and multidrug resistant organisms in the post COVID-19 era.

BACKGROUND: Antimicrobial resistance is associated with increasing mortality rates and the emergence of multidrug-resistant (MDR) organisms. There is scarcity of data on the short-term impact of Antimicrobial Stewardship Programs (ASP) on antibiotic usage, clinical outcome and MDR organisms' pattern following the COVID-19 pandemic. This study evaluated the short-term effects of ASP on antibiotic usage, clinical outcomes and MDR organisms' pattern in the post COVID-19 era. METHODS: Conducted at a tertiary academic health center, this observational study involved adult patients (≥18 years) in the general medical unit, treated with oral or intravenous antibiotics from May 1, 2021, to April 30, 2022. The applied ASP strategy was a prospective audit and feedback where a weekly meeting was held to discuss the antimicrobial therapy of admitted patient, after which recommendations were made regarding antimicrobial use. RESULTS: The study included 301 patients with 166 (55.1%) pre-ASP and 135 (44.9%) post-ASP. The median (IQR) age was 69 (55-77) years with 56.1% were female. Antibiotic usage dropped by 25.2% post-ASP. The length of hospital stay (LOS) was longer post-ASP (7 days vs. 7.9 days, p = 0.001), with MDR infections being a significant predictor (OR: 0.486, p < 0.001). There were no significant differences in 28-day readmission, recurrence of infections and all-cause mortality. Post-ASP, MDR pathogens increased (17.0% vs. 6.6%, p = 0.013), however, after separating post-ASP into two three-months periods, MDROs numbers decreased slightly (13 vs. 10). CONCLUSION: Short-term ASP implementation post COVID-19 reduced antibiotic usage while other clinical outcomes remained unchanged. Nonetheless an increase in MDR pathogens and LOS was observed. Further research is required to assess ASP's long-term impact on MDR infections rates and specific patient group outcomes.

[MACULOPAPULAR CUTANEOUS MASTOCYTOSIS HARBORING A KIT MUTATION (ASP419DEL): A CASE REPORT].

A 2-year-old, male patient presented with an 18-month history of scattered, brown macules and nodules up to 2 cm in size on his trunk and extremities. These macules were accompanied by pruritus and were positive for Darier's sign. A skin biopsy of a brown macule on the left thigh revealed a dense accumulation of CD117-positive, round or oval cells with amphophilic cytoplasm within the upper to middle dermis. The patient was otherwise healthy and had normal laboratory and imaging test results. Sequence analysis of genomic DNA from a skin biopsy demonstrated the presence of an Asp419del mutation in exon 8 of the KIT gene. Based on these findings, maculopapular cutaneous mastocytosis (MPCM) was diagnosed. The patient received H 1-antihistamine. Although the pruritus resolved, the brown macules remained for one year after the initial treatment. To the best of our knowledge, only three cases of cutaneous mastocytosis (CM) with an Asp419del mutation, including the present case, have been reported in the Japanese literature to date; moreover, while the previous two cases were of DCM, the present case was the first instance of MPCM. Normally, the symptoms of childhood-onset MPCM are dormant until puberty. However, a recent study reported that many MPCM patients may experience persistent or exacerbated symptoms. The present study therefore evaluated 53 Japanese cases of childhood onset MPCM with a KIT gene mutation and discussed the patients' clinical outcomes.

A gluco-mindful approach to diabetic gastroparesis.

Diabetes gastroparesis is a common manifestation of autonomic neuropathy in persons with long-standing, uncontrolled diabetes. Most discussion about its management revolves around the mitigation of symptoms. Here, we share tips on choosing the right glucose-lowering medication, based upon predominant symptomatology of gastroparesis. We highlight about insulin preparations, and their timing of administration, can be tailored according to need. We also emphasize the need to choose oral glucose lowering drugs with care.

Closing the antimicrobial stewardship gap - a call for LMICs to embrace the global antimicrobial stewardship accreditation scheme.

The escalating challenge of antimicrobial resistance (AMR) poses a considerable concern for global health, particularly impacting low- and middle-income countries (LMICs). This article highlights the critical importance of tackling AMR in LMICs by adopting the Global Antimicrobial Stewardship Accreditation Scheme (GAMSAS). GAMSAS is portrayed as a holistic and sustainable strategy for antimicrobial stewardship, extending beyond accreditation to include educational programs, capacity enhancement, improved surveillance, and support for AMS policy research. While acknowledging the global uptake of the scheme, the article highlights its preliminary phase of adoption in LMICs, particularly in high-AMR burden regions like Sub-Saharan Africa. The piece stresses the imperative for LMICs to integrate GAMSAS, underscoring its significance in optimizing antimicrobial usage and patient health outcomes. It advocates for an all-encompassing approach that leverages international cooperation and sustained financial backing, crucial for the effective deployment and enduring success of antimicrobial stewardship efforts in these key areas.

VWD domain stabilization by autocatalytic Asp-Pro cleavage.

Domains known as von Willebrand factor type D (VWD) are found in extracellular and cell-surface proteins including von Willebrand factor, mucins, and various signaling molecules and receptors. Many VWD domains have a glycine-aspartate-proline-histidine (GDPH) amino-acid sequence motif, which is hydrolytically cleaved post-translationally between the aspartate (Asp) and proline (Pro). The Fc IgG binding protein (FCGBP), found in intestinal mucus secretions and other extracellular environments, contains 13 VWD domains, 11 of which have a GDPH cleavage site. In this study, we investigated the structural and biophysical consequences of Asp-Pro peptide cleavage in a representative FCGBP VWD domain. We found that endogenous Asp-Pro cleavage increases the resistance of the domain to exogenous proteolytic degradation. Tertiary structural interactions made by the newly generated chain termini, as revealed by a crystal structure of an FCGBP segment containing the VWD domain, may explain this observation. Notably, the Gly-Asp peptide bond, upstream of the cleavage site, assumed the cis configuration in the structure. In addition to these local features of the cleavage site, a global organizational difference was seen when comparing the FCGBP segment structure with the numerous other structures containing the same set of domains. Together, these data illuminate the outcome of GDPH cleavage and demonstrate the plasticity of proteins with VWD domains, which may contribute to their evolution for function in a dynamic extracellular environment.

Acylation stimulating protein/C3adesArg in the metabolic states: role of adipocyte dysfunction in obesity complications.

Adipose tissue, as an endocrine organ, secretes several adipocyte-derived hormones named 'adipokines' that are implicated in regulating energy haemostasis. Substantial evidence shows that white adipose tissue-derived adipokines mediate the link between obesity-related exogenous factors (like diet and lifestyle) and various biological events (such as pre- and postmenopausal status) that have obesity consequences (cardiometabolic disorders). One of the critical aetiological factors for obesity-related diseases is the dysfunction of adipokine pathways. Acylation-stimulating protein (ASP) is an adipokine that stimulates triglyceride synthesis and storage in adipose tissue by enhancing glucose and fatty acid uptake. ASP acts via its receptor C5L2. The primary objective of this review is to address the existing gap in the literature regarding ASP by investigating its diverse responses and receptor interactions across multiple determinants of obesity. These determinants include diet composition, metabolic disorders, organ involvement, sex and sex hormone levels. Furthermore, this article explores the broader paradigm shift from solely focusing on adipose tissue mass, which contributes to obesity, to considering the broader implications of adipose tissue function. Additionally, we raise a critical question concerning the clinical relevance of the insights gained from this review, both in terms of potential therapeutic interventions targeting ASP and in the context of preventing obesity-related conditions, highlighting the potential of the ASP-C5L2 interaction as a pharmacological target. In conclusion, these findings validate that obesity is a low-grade inflammatory status with multiorgan involvement and sex differences, demonstrating dynamic interactions between immune and metabolic response determinants.

Roles and signaling pathways of CITED1 in tumors: overview and novel insights.

CBP/p300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (CITED1) is a transcriptional activator belonging to the non-DNA-binding transcription co-regulator family. It regulates diverse pathways, including the transforming growth factor/bone morphogenetic protein/SMAD, estrogen, Wnt-ß-catenin, and androgen-AR signaling pathways, by binding to CBP/p300 co-activators through its conserved transactivation domain CR2. CITED1 plays an important role in embryonic development and a certain regulatory role in the occurrence and development of various tumors. In this article, the biological characteristics, expression regulation, participating signaling pathways, and potential roles of CITED1 in the clinical diagnosis and treatment of tumors are reviewed.