Development Process Research Articles

D-allose, a typical rare sugar: properties, applications, and biosynthetic advances and challenges.

D-allose, a C-3 epimer of D-glucose and an aldose-ketose isomer of D-allulose, exhibits 80% of sucrose's sweetness while being remarkably low in calories and nontoxic, making it an appealing sucrose substitute. Its diverse physiological functions, particularly potent anticancer and antitumor effects, render it a promising candidate for clinical treatment, garnering sustained attention. However, its limited availability in natural sources and the challenges associated with chemical synthesis necessitate exploring biosynthetic strategies to enhance production. This overview encapsulates recent advancements in D-allose's physicochemical properties, physiological functions, applications, and biosynthesis. It also briefly discusses the crucial role of understanding aldoketose isomerase structure and optimizing its performance in D-allose synthesis. Furthermore, it delves into the challenges and future perspectives in D-allose bioproduction. Early efforts focused on identifying and characterizing enzymes responsible for D-allose production, followed by detailed crystal structure analysis to improve performance through molecular modification. Strategies such as enzyme immobilization and implementing multi-enzyme cascade reactions, utilizing more cost-effective feedstocks, were explored. Despite progress, challenges remain, including the lack of efficient high-throughput screening methods for enzyme modification, the need for food-grade expression systems, the establishment of ordered substrate channels in multi-enzyme cascade reactions, and the development of downstream separation and purification processes.

Long-term administration of royal jelly regulates age-related disorders and improves gut function in naturally aging mice.

A natural aging mouse model can exhibit physiological characteristics that closely resemble those of human aging. Through long-term observation, it reflects the occurrence and development of the aging process more accurately. Although numerous beneficial effects of royal jelly (RJ) have been extensively demonstrated in multiple experimental models, the effects of RJ on naturally aging mice have not yet been investigated. In this study, middle-aged male C57BL/6J mice were given RJ for 9 consecutive months to investigate its impact on the intestinal barrier function, gut microbiota, short-chain fatty acids (SCFAs) content and possible mechanisms. The results confirmed that RJ modulated serum lipids by reducing the levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C). Additionally, it protected the liver by increasing antioxidant enzyme levels while decreasing inflammatory cytokines TNF-α (by 51.97%), IL-6 (by 29.73%), and IL-1β (by 43.89%). Furthermore, RJ inhibited the expression of cell cycle-dependent kinase inhibitors including p16, p21, and p53. Importantly, RJ ameliorated gut dysfunctions by inhibiting reduction of tight junction proteins and reducing inflammatory cytokines content in the colon. We also observed an alteration in gut microbiota characterized by an elevated ratio of Firmicutes to Bacteroides (F/B) along with increased abundance of beneficial bacteria, i.e., Lachnospiraceae NK4A136 and Akkermansia. Correlation analysis revealed positive associations between most bacterial genera and SCFAs production. Functional profiling of gut microbiota composition indicated that RJ intervention regulated amino acid metabolism, glycan biosynthesis, and cofactor/vitamin metabolism. Overall, our findings provide an effective dietary intervention strategy for modulating age-associated frailty through the modulation of the gut microbiota.

ABCD4 is associated with mammary gland development in mammals.

Mammary gland development is a critical process in mammals, crucial for their reproductive success and offspring nourishment. However, the functional roles of key candidate genes associated with teat number, including ABCD4, VRTN, PROX2, and DLST, in this developmental process remain elusive. To address this gap in knowledge, we conducted an in-depth investigation into the dynamic expression patterns, functional implications, and regulatory networks of these candidate genes during mouse mammary gland development. In this study, the spatial and temporal patterns of key genes were characterized in mammary gland development. Using time-series single-cell data, we uncovered differences in the expression of A bcd4, Vrtn, Prox2, and Dlst in cell population of the mammary gland during embryonic and adult stages, while Vrtn was not detected in any cells. We found that only overexpression and knockdown of Abcd4 could inhibit proliferation and promote apoptosis of HC11 mammary epithelial cells, whereas Prox2 and Dlst had no significant effect on these cells. Using RNA-seq and qPCR, further analysis revealed that Abcd4 can induce widespread changes in the expression levels of genes involved in mammary gland development, such as Igfbp3, Ccl5, Tlr2, and Prlr, which were primarily associated with the MAPK, JAK-STAT, and PI3K-AKT pathways by functional enrichment. These findings revealed ABCD4 as a candidate gene pivotal for regulating mammary gland development and lactation during pregnancy by influencing PRLR expression.

Impact of contextual factors on new product development process: evidence from a large company in Thailand

Impact of contextual factors on new product development process: evidence from a large company in Thailand

Neighborhood Gentrification and Food Insecurity among Urban Older Adults: Evidence from New York City.

Gentrification is a prevalent neighborhood development process in urban areas across the United States. Prior studies have identified the influence of gentrification on late-life health and quality of life, yet little is known about its relationship with food insecurity, an important public health issue for older adult populations. Using New York City as a case study, this study investigated associations between living in a gentrifying neighborhood and food insecurity, as well as the mediating roles of neighborhood environment factors-social cohesion, public transportation, and food environment. This study adopted two waves of annual data from the Poverty Tracker Study (2015-16; N = 703) merged with American Community Survey and spatial datasets to measure gentrification and neighborhood factors. Adjusted logistic regressions were used to examine the associations between gentrification and food insecurity. Further mediation analyses were conducted to test the mechanisms of such associations. Older adults in gentrifying neighborhoods were more likely to have food insecurity than those in moderate- to high-income neighborhoods. Compared to low-income neighborhoods, older adults in gentrifying neighborhoods had a lower likelihood of reporting food insecurity. Two significant mediators were found when comparing gentrification with moderate- to high-income neighborhoods: social cohesion and healthy food outlets. This study highlights the importance of gentrification in determining late-life food insecurity and identified possible mechanisms with policy and social service implications to reduce the risk of food insecurity in urban areas.

Comparative proteomic analysis of dental pulp from supernumerary and normal permanent teeth.

To obtain and compare the protein profiles of supernumerary and normal permanent dental pulp tissues. Dental pulp tissues were obtained from supernumerary and normal permanent teeth. Proteins were extracted and analyzed by liquid chromatography-tandem mass spectrometry (LC/MS-MS). Protein identification and quantification from MS data was performed with MaxQuant. Statistical analysis was conducted using Metaboanalyst to identify differentially expressed proteins (DEPs) (P-value < 0.05, fold-change > 2). Gene Ontology enrichment analyses were performed with gProfiler. A total of 3,534 proteins were found in normal dental pulp tissue and 1,093 in supernumerary dental pulp tissue, with 174 DEPs between the two groups. This analysis revealed similar functional characteristics in terms of cellular component organization, cell differentiation, developmental process, and response to stimulus, alongside exclusive functions unique to normal permanent dental pulp tissues such as healing, vascular development and cell death. Upon examination of DEPs, these proteins were associated with the processes of wound healing and apoptosis. This study provides a comprehensive understanding of the protein profile of dental pulp tissue, including the first such profiling of supernumerary permanent dental pulp. There are functional differences between the proteomic profiles of supernumerary and normal permanent dental pulp tissue, despite certain biological similarities between the two groups. Differences in protein expression were identified, and the identified DEPs were linked to the healing and apoptosis processes. This discovery enhances our knowledge of supernumerary and normal permanent pulp tissue, and serves as a valuable reference for future studies on supernumerary teeth.

Advancing Drug Safety in Drug Development: Bridging Computational Predictions for Enhanced Toxicity Prediction.

The attrition rate of drugs in clinical trials is generally quite high, with estimates suggesting that approximately 90% of drugs fail to make it through the process. The identification of unexpected toxicity issues during preclinical stages is a significant factor contributing to this high rate of failure. These issues can have a major impact on the success of a drug and must be carefully considered throughout the development process. These late-stage rejections or withdrawals of drug candidates significantly increase the costs associated with drug development, particularly when toxicity is detected during clinical trials or after market release. Understanding drug-biological target interactions is essential for evaluating compound toxicity and safety, as well as predicting therapeutic effects and potential off-target effects that could lead to toxicity. This will enable scientists to predict and assess the safety profiles of drug candidates more accurately. Evaluation of toxicity and safety is a critical aspect of drug development, and biomolecules, particularly proteins, play vital roles in complex biological networks and often serve as targets for various chemicals. Therefore, a better understanding of these interactions is crucial for the advancement of drug development. The development of computational methods for evaluating protein-ligand interactions and predicting toxicity is emerging as a promising approach that adheres to the 3Rs principles (replace, reduce, and refine) and has garnered significant attention in recent years. In this review, we present a thorough examination of the latest breakthroughs in drug toxicity prediction, highlighting the significance of drug-target binding affinity in anticipating and mitigating possible adverse effects. In doing so, we aim to contribute to the development of more effective and secure drugs.

Diffusion-driven fed-batch fermentation in perforated ring flasks.

Simultaneous membrane-based feeding and monitoring of the oxygen transfer rate shall be introduced to the newly established perforated ring flask, which consists of a cylindrical glass flask with an additional perforated inner glass ring, for rapid bioprocess development. A 3D-printed adapter was constructed to enable monitoring of the oxygen transfer rate in the perforated ring flasks. Escherichia coli experiments in batch were performed to validate the adapter. Fed-batch experiments with different diffusion rates and feed solutions were performed. The adapter and the performed experiments allowed a direct comparison of the perforated ring flasks with Erlenmeyer flasks. In batch cultivations, maximum oxygen transfer capacities of 80mmolL-1h-1 were reached with perforated ring flasks, corresponding to a 3.5 times higher capacity than in Erlenmeyer flasks. Fed-batch experiments with a feed reservoir concentration of 500gglucoseL-1 were successfully conducted. Based on the oxygen transfer rate, an ammonium limitation could be observed. By adding 40gammonium sulfateL-1 to the feed reservoir, the limitation could be prevented. The membrane-based feeding, an online monitoring technique, and the perforated ring flask were successfully combined and offer a new and promising tool for screening and process development in biotechnology.

Comparison of kinematics and pedobarography findings between the unaffected foot of patients with unilateral clubfoot and controls.

Idiopathic clubfoot (ICF) involves structural abnormalities in the lower extremities. Approximately half of patients have unilateral ICF, which could be due to differences in limb formation. The contralateral unaffected foot may have subclinical ICF. The objectives were to compare ankle and foot kinematics and pedobarography findings between the unaffected foot of patients with unilateral ICF and controls. Eleven children with unilateral ICF (11 unaffected feet, 11.7 ± 3.8years) and 15 age-matched controls (30 control feet, 11.1 ± 3.0years) were enroled. Five complete gait trials were performed. Data were collected using ten cameras and a twom long Footscan system and compared between groups using the Wilcoxon rank sum test. All children with ICF underwent the selective soft tissue release procedure. The unaffected feet showed limited ranges in inversion-eversion and dorsiflexion-plantar flexion on kinematic analysis. There was a delay in landing time in all regions of the foot during heel rise and propulsion. The peak time was achieved significantly later in the unaffected feet compared to the controls. Although plantar pressure parameters were comparable, unaffected feet showed a larger contact area in the midfoot region. Gait data on the unaffected foot in unilateral ICF patients do not correspond to those of controls despite an indistinguishable clinical appearance. This could be due to the effect of treatment, the process of foot development, or a combination. The relationship between genetics and gait deviation in patients with unilateral ICF needs further evaluation. The unaffected foot should receive similar attention during follow-up.

Development of Efficient and Scalable Production Process of Analytical Grade Sodium Chloride at Laboratory Scale

Development of Efficient and Scalable Production Process of Analytical Grade Sodium Chloride at Laboratory Scale

A Systemic Approach to the Product Life Cycle for the Product Development Process in Agriculture

A Systemic Approach to the Product Life Cycle for the Product Development Process in Agriculture

Global research landscape and trends of cancer stem cells from 1997 to 2023: A bibliometric analysis.

Cancer stem cells (CSCs) are a subset of cells with self-renewal ability and tumor generating potential. Accumulated evidence has revealed that CSCs were shown to contribute to tumorigenesis, metastasis, recurrence and resistance to chemoradiotherapy. Therefore, CSCs were regarded as promising therapeutic targets in cancer. This study is the first to reveal the development process, research hotspots, and trends of entire CSCs research field through bibliometric methods. All relevant publications on CSCs with more than 100 citations (notable papers) and the 100 most cited papers (top papers) during 1997 to 2023 were extracted and analyzed. Cancer research published the largest number of papers (184 papers). The USA accounted for the most publications (1326 papers). Rich, JN was the author with the most publications (56 papers) and the highest M-index (3.111). The most contributive institution was the University of Texas System (164 papers). Before 2007, research mainly focused on the definition and recognition of CSCs. Between 2007 and 2016, with the emergence of the terms such as "sonic hedgehog," "metabolism," "oxidative phosphorylation," and "epithelial mesenchymal transition," research began to shift toward exploring the mechanisms of CSCs. In 2016, the focus transitioned to the tumor microenvironment and the ecological niches. The analysis of papers published in major journals since 2021 showed that "transcription," "inhibition," and "chemoresistance" emerged as new focused issues. In general, the research focus has gradually shifted from basic biology to clinical transformation. "Tumor microenvironment" and "chemo-resistance" should be given more attention in the future.

The Evolution Mechanism of Correctness for Cyber-Physical System

Cyber-physical Systems (CPS) are widely used in all areas of life. Ensuring the correctness of CPS remains an enduring challenge during its development and design phases. One approach to ascertain the correctness of CPS is behavior equivalence based on bisimulation. However, whether the implementation development process develops in the right direction has an important impact on obtaining the correct system implementation. Especially, the development process of complex CPS often yields a multitude of implementation versions, the correlation among these versions partly signifies the correctness of the development process. This paper formalizes the relationship between the implementation versions and establishes a formal description of the development process progressing in the correct direction, leveraging the concept of a “limit idea.” Initially, we introduce the concept of “limit bisimulation” for CPS systems to delineate implementations acquired during the CPS development process. Specific limit bisimulations are demonstrated to represent distinct scenarios within the development process. Subsequently, the convergence mechanism of implementations is modeled through bisimulation limits, encapsulating the CPS’s specification as the ultimate goal of obtained implementations during the development process. Finally, the congruence property of the bisimulation limit is proved, which accounts for the relation between specification and implementation versions can be decomposed into a refinement hierarchy. The limit theorem of bisimulation in CPS can help the designer and developer of CPS to comprehend the development course better.

A review of nanotechnology in enzyme cascade to address challenges in pre-treating biomass.

Nanotechnology has become a revolutionary technique for improving the preliminary treatment of lignocellulosic biomass in the production of biofuels. Traditional methods of pre-treatment have encountered difficulties in effectively degrading the intricate lignocellulosic composition, thereby impeding the conversion of biomass into fermentable sugars. Nanotechnology has enabled the development of enzyme cascade processes that present a potential solution for addressing the limitations. The focus of this review article is to delve into the utilization of nanotechnology in the pretreatment of lignocellulosic biomass through enzyme cascade processes. The review commences with an analysis of the composition and structure of lignocellulosic biomass, followed by a discussion on the drawbacks associated with conventional pre-treatment techniques. The subsequent analysis explores the importance of efficient pre-treatment methods in the context of biofuel production. We thoroughly investigate the utilization of nanotechnology in the pre-treatment of enzyme cascades across three distinct sections. Nanomaterials for enzyme immobilization, enhanced enzyme stability and activity through nanotechnology, and nanocarriers for controlled enzyme delivery. Moreover, the techniques used to analyse nanomaterials and the interactions between enzymes and nanomaterials are introduced. This review emphasizes the significance of comprehending the mechanisms underlying the synergy between nanotechnology and enzymes establishing sustainable and environmentally friendly nanotechnology applications.

The emerging role and mechanism of HMGA2 in breast cancer.

High mobility group AT-hook 2 (HMGA2) is a member of the non-histone chromosomal high mobility group (HMG) protein family, which participate in embryonic development and other biological processes. HMGA2 overexpression is associated with breast cancer (BC) cell growth, proliferation, metastasis, and drug resistance. Furthermore, HMGA2 expression is positively associated with poor prognosis of patients with BC, and inhibiting HMGA2 signaling can stimulate BC cell progression and metastasis. In this review, we focus on HMGA2 expression changes in BC tissues and multiple BC cell lines. Wnt/β-catenin, STAT3, CNN6, and TRAIL-R2 proteins are upstream mediators of HMGA2 that can induce BC invasion and metastasis. Moreover, microRNAs (miRNAs) can suppress BC cell growth, invasion, and metastasis by inhibiting HMGA2 expression. Furthermore, long noncoding RNAs (LncRNAs) and circular RNAs (CircRNAs) mainly regulate HMGA2 mRNA and protein expression levels by sponging miRNAs, thereby promoting BC development. Additionally, certain small molecule inhibitors can suppress BC drug resistance by reducing HMGA2 expression. Finally, we summarize findings demonstrating that HMGA2 siRNA and HMGA2 siRNA-loaded nanoliposomes can suppress BC progression and metastasis.

Immediate effects of Ramadan on objective time asleep in male youth football players from the Middle East: an interrupted time-series study.

To examine the abrupt effects of Ramadan onset on actigraphy-based time asleep in male youth Muslim football players. We adopted a quasi-experimental, interrupted time-series research design and tracked objective time asleep over a minimum of 12 consecutive nights in the two weeks prior to and immediately after Ramadan onset, respectively. Twenty-two, male academy student-athletes (chronological age range: 12.6 to 16.2 years) participated in the study (464 individual observations). Segmented generalized mixed-effects modelling estimated the effects of Ramadan onset on time asleep during the first period of night sleep only. Ramadan onset led to an immediate mean reduction of 89 min (95% confidence interval [CI], 54 to 123 min) in time asleep during the first period of night sleep compared to pre-Ramadan sleep patterns. Model-adjusted estimated marginal means for time asleep were ~ 5.7 h (95%CI, 5.1 to 6.2 h) before and ~ 4.2 h (95%CI, 3.6 to 4.7 h) after Ramadan onset. Night sleep interruptions resulting in two or more fragmented periods accounted for 8% (95%CI, 2 to 21%) to 19% (95%, 11 to 29%) of sleep observations before and after Ramadan onset, respectively. The onset of Ramadan determined an abrupt reduction in time asleep of ~ 1 h 30 min in the first period of a night cycle and contributed to additional problems of heterogeneous sleep fragmentation that can impact optimal school learning and youth athlete performance development processes.

The development process of ‘fit-for-purpose’ imaging biomarkers to characterize the tumor microenvironment

The development process of ‘fit-for-purpose’ imaging biomarkers to characterize the tumor microenvironment

Clinical Practice Guidelines to Support Capacity Building in Orthopaedic Surgical Outreach: An International Consensus Building Approach.

Surgical outreach to low- and middle-income countries (LMICs) by organizations from high- income countries is on the rise to help address the growing burden of conditions warranting surgery. However, concerns remain about the impact and sustainability of such outreach. Leading organizations (e.g., the World Health Organization) advocate for a capacity-building approach to ensure the safety, quality, and sustainability of the local health-care system. Despite this, to our knowledge, no guidelines exist to inform such efforts. We aimed to develop clinical practice guidelines (CPGs) to support capacity-building in orthopaedic surgical outreach utilizing a multistakeholder and international voting panel. We followed a modified American Academy of Orthopaedic Surgeons (AAOS) CPG development process. We systematically reviewed the existing literature across 7 predefined capacity-building domains (partnership, professional development, governance, community impact, finance, coordination, and culture). A writing panel composed of 6 orthopaedic surgeons with extensive experience in surgical outreach reviewed the existing literature and developed a consensus-based CPG for each domain. We created an international voting panel of orthopaedic surgeons and administrators who have leadership roles in outreach organizations or hospitals with which outreach organizations partner. Members individually reviewed the CPGs and voted to approve or disapprove each guideline. A CPG was considered approved if >80% of panel members voted to approve it. An international voting panel of 14 surgeons and administrators from 6 countries approved all 7 of the CPGs. Each CPG provides recommendations for capacity-building in a specific domain. For example, in the domain of partnership, the CPG recommends the development of a documented plan for ongoing, bidirectional partnership between the outreach organization and the local team. In the domain of professional development, the CPG recommends the development of a needs-based curriculum focused on both surgical and nonsurgical patient care utilizing didactic and hands-on techniques. As orthopaedic surgical outreach grows, best-practice CPGs to inform capacity-building initiatives can help to ensure that resources and efforts are optimized to support the sustainability of care delivery at local sites. These guidelines can be reviewed and updated in the future as evidence that supports capacity-building in LMICs evolves.The global burden of disease warranting surgery is substantial, and morbidity and mortality from otherwise treatable conditions remain disproportionately high in low- and middle-income countries (LMICs)1,2. It is estimated that up to 2 million (about 40%) of injury-related deaths in LMICs could be avoided annually if mortality rates were reduced to the level of those in high-income countries (HICs)3. Despite this, progress toward improved access to safe, timely surgery in resource-poor areas has been slow. Historically, nongovernmental organizations (NGOs) have tried to address unmet surgical needs through short-term outreach trips; however, growing criticism has highlighted the limitations of short-term trips, including limited follow-up, an increased burden on the local workforce, and further depletion of local resources4-6. In light of ongoing concerns, public health priorities have shifted toward models that emphasize long-term capacity-building rather than short-term care delivery. Capacity-building is an approach to health-care development that builds independence through infrastructure development, sustainability, and enhanced problem-solving while taking context into account7,8.

The impacts of undetected nonadherence in phase II, III and post-marketing clinical trials: An overview.

This research aims to provide an overview of the consequences of undiagnosed nonadherence (noninitiation, suboptimal implementation, nonpersistence) in randomized clinical trials (RCTs). This research was conducted by combining a literature review and qualitative semistructured interviews with key opinion leaders. Based on this groundwork, the consequences of undiagnosed nonadherence in RCTs were summarized and reported in a figure. This study focused on phases II, III and post-marketing in ambulatory settings across a variety of therapeutic areas and indications. Various consequences of nonadherence in RCTs were investigated. In phase II, drug efficacy may be underestimated, variability in the outcomes may be high and a distorted picture of side effects could be reported, resulting in an uncertain impression of the investigational product's profile and complicating decision-making. The sponsor may need to increase the sample size of the upcoming phase III study to improve its power, representing additional costs, or even terminate the study. In phase III, similar phenomena may be observed, making demonstration of efficacy to the regulatory bodies more difficult. Lastly, after commercialization, a distortion in pharmacometrics may occur: the drug may underperform, prescriptions may be refilled less often than expected or extra expenses may be incurred by the payers. This can result in post-marketing dose reduction, new competitors coming into the market and, eventually, product withdrawal. This research highlighted the many potential adverse consequences of undiagnosed nonadherence in RCTs, including additional costs. Collecting accurate data appeared to be crucial for decision-making throughout the drug development process.

Early Kilogram Scale Delivery of MK-7845 as a Potential COVID-19 Therapy: Rapid Process Development of Key Intermediates

Early Kilogram Scale Delivery of MK-7845 as a Potential COVID-19 Therapy: Rapid Process Development of Key Intermediates