Major Defects Research Articles

Is 26S proteasome non-ATPase regulatory subunit 6 a potential molecular target for intrahepatic cholangiocarcinoma?

In this editorial we comment on the article by Tang et al published in the recent issue of World Journal of Hepatology . Drug therapy of intrahepatic cholangiocarcinoma (iCCA) poses an enormous challenge since only a small proportion of patients demonstrate beneficial responses to therapeutic agents. Thus, there has been a sustained search for novel molecular targets for iCCA. The study by Tang et al evaluated the role of 26S proteasome non-ATPase regulatory subunit 6 (PSMD6), a 19S regulatory subunit of the proteasome, in human iCCA cells and specimens. The authors employed clustered regularly interspaced short palindromic repeat (CRISPR) knockout screening technology integrated with the computational CERES algorithm, and analyzed the human protein atlas (THPA) database and tissue microarrays. The results show that PSMD6 is a gene essential for the proliferation of 17 iCCA cell lines, and PSMD6 protein was overexpressed in iCCA tissues without a significant correlation with the clinicopathological parameters. The authors conclude that PSMD6 may play a promoting role in iCCA. The major limitations and defects of this study are the lack of detailed information of CRISPR knockout screening, in vivo experiments, and a discussion of plausible mechanistic cues, which, therefore, dampen the significance of the results. Further studies are required to verify PSMD6 as a molecular target for developing novel therapeutics for iCCA. In addition, the editorial article summarizes the latest advances in molecular targeted drugs and recently emerging immunotherapy in the clinical management of iCCA, development of proteasome inhibitors for cancer therapy, and advantages of CRISPR screening technology, computational methods, and THPA database as experimental tools for fighting cancer. We hope that these comments may provide some clues for those engaged in the field of basic and clinical research into iCCA.

Exposure to drinking water pollutants and non-syndromic birth defects: a systematic review and meta-analysis synthesis

ObjectivesTo evaluate the association between drinking water pollutants and non-syndromic birth defects.DesignSystematic review and meta-analysis synthesis.Data sourcesA search of MEDLINE, EMBASE and Google Scholar was performed to review relevant citations...

Improving the Classification of Defect Levels in Main Electrical Equipment Through Advanced Prompting on a Large Language Model

The stable operation of the power system is closely related to the national economy and people’s livelihoods. Therefore, the timely detection, qualitative assessment, and handling of major equipment defects are crucial. The classification of defect levels in main electrical equipment is a fundamental task in this process, which is often manually completed, supplemented by knowledge bases or expert systems. However, this approach is time-consuming, labor-intensive, involves challenging human–machine interaction, and relies on expert experience. Conversational large language models, such as ChatGPT, ERNIE Bot, ChatGLM, have garnered widespread recognition in various domains. However, these models may have errors in the reasoning process, resulting in biased or even erroneous outputs, which is referred to as the “hallucinations”. The hallucinations’ problem of large language models poses challenges in specific fields. To mitigate the hallucinations in large language models, researchers often seek to incorporate domain-specific knowledge into these models through methods like fine-tuning or prompt learning. In order to enhance model performance while minimizing computational costs, this study adopts the prompt learning approach. Specifically, we propose a large language model prompt learning framework based on knowledge graphs, aiming to provide the large language model with reasoning support by leveraging specific information stored within the knowledge graph and receive explainable reasoning result. Experimental results demonstrate that our module achieved superior results on the power defect dataset compared to the non-prompt method.

Temporal trends in the prevalence of major birth defects in China: a nationwide population-based study from 2007 to 2021.

Birth defects constitute a significant public health issue worldwide, yet there is a lack of comprehensive population-based data for the Chinese population. Weanalyzed data from the China National Population-based Birth Defects Surveillance System from 2007 to 2021, we calculated the prevalence rates of selected birth defects, stratified by maternal residence, geographic region, maternal age, and infant sex. The Joinpoint regression model was utilized to assess trends and annual percent changes in prevalence. From 2007 to 2021, significant downward trends in prevalence were observed for neural tube defects (NTDs), hydrocephalus, cleft lip with or without palate (CL/P), limbreductiondefects (LRD), omphalocele, Down syndrome, and tetralogy of Fallot (TOF). Conversely, upward trends were identified for hypospadias, cleft palate (CP), microtia/anotia, polydactyly, syndactyly, ventricular septal defect (VSD), atrial septal defect/patent foramen ovale (ASD/PFO), and patent ductus arteriosus (PDA). Younger mothers exhibited a higher prevalence of hydrocephalus, gastroschisis, CL/P, and polydactyly, while anotia/microtia, Down syndrome, and congenital heart diseases (CHDs) were more common in mothers aged 35 years or older. Significant variations in the prevalence of anencephalus, spina bifida, CL/P, anorectal atresia/stenosis, hypospadias, polydactyly, syndactyly, VSD, ASD/PFO, and PDA were found across different maternal residences and geographic regions. This study highlights the diverse trends and prevalence patterns of major birth defects, underscoring the necessity for defect-specific public health interventions.

The global, regional, and national patterns of change in the burden of congenital birth defects, 1990–2021: an analysis of the global burden of disease study 2021 and forecast to 2040

Congenital birth defects (CBDs) present enormous challenges to global healthcare systems. These conditions severely impact patients' health and underscore issues related to socioeconomic development and healthcare accessibility and efficiency. Previous studies have been geographically limited and lacked comprehensive global analysis. This study provides global, regional, and national disability-adjusted life years (DALYs) data for four major congenital birth defects-congenital heart defects (CHD), neural tube defects (NTDs), digestive congenital anomalies (DCAs), and Down syndrome (DS) from 1990 to 2021, emphasizing health inequalities. The goal is to offer scientific evidence for optimizing resource allocation, focusing on high-burden populations, and reducing disease burden. This study systematically evaluated the global, regional, and national burden of CBDs and their changes from 1990 to 2021 using the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021. To conduct a more focused analysis, four specific CBDs were selected: CHD, NTDs, DCAs, and DS. DALYs were used as the metric, combined with the sociodemographic index (SDI). Analyses included the slope index of inequality and concentration index to measure health inequalities, frontier analysis to estimate achievable outcomes based on development levels, decomposition analysis to identify drivers of disease burden changes, Joinpoint regression analysis to assess temporal trends, and the Bayesian age-period-cohort (BAPC) model to predict future disease burden trends. Compared to 1990, the global burden of the CBDs in 2021 showed a downward trend. Males had a higher burden than females, with the highest burden observed in low-SDI regions. When examining CHD, NTDs, DCAs, and DS specifically, trends in burden changes varied across different CBDs at the global, regional, and national levels. Frontier analysis revealed potential for burden improvement in various countries and territories. Decomposition analysis highlighted differences in disease burden drivers across SDI regions, showing the greatest improvement observed in low-SDI regions. Joinpoint regression analysis indicated a downward trend in DALYs burden across SDI regions, and BAPC model predictions suggested that the burden of CBDs will continue to decline in the future. CBDs pose a major challenge to global public health. Despite an overall decline in disease burden, health inequalities remain prominent, particularly in countries and territories with lower levels of development. Future public health interventions should focus on countries and territories with low levels of development by optimizing healthcare resource allocation, improving basic health infrastructure, enhancing health education, and reducing disease burden inequalities. Global collaboration and data sharing are essential to promote a lifecycle management model for CBDs research and treatment, advancing global health development. This study was supported by the National Natural Science Foundation of China (No. 82270310) and the Jiangsu Provincial Key Research and Development Program (No. BE2023662).

Assessment of Acoustic and Nasalance Improvement in Maxillary Obturator Patients Using PRAAT Software: An In Vivo Study.

The purpose of this study was to evaluate the improvement in acoustic and nasalance in patients with maxillary obturators, using PRAAT software. The current study comprised a total of 16 patients who had acquired maxillary defects. Regardless of gender, the age range of these patients was 40-75 years old. The total number of patients were randomly divided into two groups (8 participants in each group) namely (A) Interim obturator group and (B) Definitive obturator group. Analysis was done using PRAAT software for two speech parameters namely nasalance and acoustic value. The first stage of speech analysis was completed without the use of an obturator, whereas the second stage involved inserting the obturator on the same day. The third stage occurred 2 months after the usage of the obturator. The data were recorded and statistically analyzed. In definitive obturator group, mean value for relative nasalance increases from before prosthesis (60.93 ± 3.34 db) to after 2 months of prosthesis (70.53 ± 2.24 db) while in interim group increased from 57.55 ± 4.31 db (before prosthesis) to 63.77 ± 3.66 db (after 2 months of prosthesis). This improvement was more marked with definitive obturator than interim obturator. The F2-F1 comparative mean value changed from before prosthesis to immediate after prosthesis in definitive group for /a/, /e/, and /u/ vowels was 9.77, 22, and 24.38, respectively. F2-F1 comparative mean changes from before prosthesis to after 2 months of prosthesis was 102, 75.75, and 87 for three vowels /a/, /e/, and /u/, respectively. Similarly, F2-F1 mean value in interim prosthesis group changes from before to after 2 months of prosthesis was 62.25, 27.62, and 1.75 for /a/, /e/, and /u/, respectively. On conclusion, the definitive obturators were well-tolerated by patients with major defects and the results show that maxillary resection significantly impairs speech and definitive obturator rehabilitation is effective in regaining nasalance and acoustic speech components. Speech disorders in maxillectomy patients are a significant clinical issue since the surgery results in hypernasality, which impairs a person's ability to understand their own speech. Either surgical techniques or prosthetic rehabilitation are used to correct these abnormalities. Certain people require prosthetics to fix their speech even after surgery. How to cite this article: Bhushan P, Thenumkal E, Khosla E, et al. Assessment of Acoustic and Nasalance Improvement in Maxillary Obturator Patients Using PRAAT Software: An In Vivo Study. J Contemp Dent Pract 2024;25(7):656-660.

Optimization of aloe vera‐sodium alginate composite coating using L16 orthogonal design for extension of shelf life of mushroom

AbstractWhite button mushrooms are highly nutritive, rich in various macro and micro nutrients, however, have a short shelf life with weight loss (WL), enzymatic browning, and loss in firmness as the major quality defects. The present study was carried out to investigate the effect of aloe vera‐sodium alginate (AV‐SA) composite coating on the quality attributes of mushroom. The development of coating formulations containing 2% sodium alginate along with varying concentration of aloe vera gel 20%–80% and storage time 4–16 days was planned using a 2‐factor 4‐level orthogonal array (L16) design of Taguchi technique. The influence of both the process parameters on the WL, total soluble solids (TSS), respiration rate (RR), browning index (BI), firmness, electrolyte leakage rate (EL), malondialdehyde (MDA), ascorbic acid (AA), total phenolic content (TPC), enzymes activity (polyphenol oxidase and peroxidase), and yeast and mold count (YMC) were evaluated and the optimized level of parameters was determined on the basis of the highest S/N ratios of the responses. The results indicated that 60% AV‐SA composite coating could extend the shelf life of white button mushrooms for up to 8 days with retarded loss in weight, firmness, AA, and TPC and reduced increase in TSS, BI, EL, MDA with controlled enzymatic activity, RR, and YMC.

The progress of Mycobacterium tuberculosis drug targets.

Tuberculosis (TB) has been troubling humans for hundreds of years, is a highly infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, Mtb can infect almost all organs of the body and is one of the deadly infectious diseases in the world. At present, the first-line treatment regimen has a long treatment cycle and is prone to multiple drug resistance. Anti-tuberculosis drugs and latent tuberculosis infection (LTBI) resistance are increasing year by year, and new targets and new bioactive compounds are urgently needed to treat this disease. This review focuses on the latest reported anti-TB drug targets and related compounds in recent years, reviews the current TB drug regimen and major defects, outlines the key drug targets developed to date in Mtb, and the current situation of newly discovered anti-TB resistant forms of drugs. To provide a reference for the research and development of new anti-TB drugs and bring new treatment strategies for TB patients.

Geographical variability of commercial traits of sable skins in the Irkutsk region

The purpose of the research was to consider the infl uence of the geographical distribution of sable on the main commercial properties of its skins in the Irkutsk region. It is noted that the number of the species in 2023 was 266.7 thousand individuals. An analysis of 750 sable skins obtained in the western and northern parts of the region was carried out. The dependence of the fur quality on the geographical distribution of the species was analyzed. It was confi rmed that in batches of skins from the Nizhneudinsky, Tulunsky, Katangsky districts of the Irkutsk region, the share of light sables predominated (67–75 %). In the Kirensky and Kazachinsko-Lensky districts of the Irkutsk region, the share of dark sables was 58 and 59 %, respectively. It is indicated that in the Cisbaikalia region the general lightening of sable fur continues, explained by the proximity of the Katangsky, Nizhneudinsky and Tulunsky districts to the neighboring populations of lighter strains of the Krasnoyarsk Territory and the Republic of Tuva. The majority of the total batch of harvested sable skins were of the especially large size 46.5 %, the share of large sables was 22.1 %, 31.3 % of the skins of the studied batch were classifi ed as medium and small goods. The percentage of especially large skins was found in the Kirensky and Kazachinsko-Lensky districts of the Irkutsk region and was more than 50 %. The analysis of fur defects showed that the share of the norm among the model regions was almost equal and was 33–36 %. Most sable skins (38.7 %) had a small defect, the share of skins with a medium defect was 22.7 %, large was 4.3 %. The highest percentage of sable skins with major defects was found in the Kazachinsko-Lensky region.

Two conserved arginine residues facilitate C-S bond cleavage and persulfide transfer in Suf family cysteine desulfurases.

Under conditions of oxidative stress or iron starvation, iron-sulfur cluster biogenesis in E. coli is initiated by the cysteine desulfurase, SufS, via the SUF pathway. SufS is a type II cysteine desulfurase that catalyzes the PLP-dependent breakage of an L-cysteine C-S bond to generate L-alanine and a covalent active site persulfide as products. The persulfide is transferred from SufS to SufE and then to the SufBC 2 D complex, which utilizes it in iron-sulfur cluster biogenesis. Several lines of evidence suggest two conserved arginine residues that line the solvent side of the SufS active site could be important for function. To investigate the mechanistic roles of R56 and R359, the residues were substituted using site-directed mutagenesis to obtain R56A/K and R359A/K SufS variants. Steady state kinetics indicated R56 and R359 have moderate defects in the desulfurase half reaction but major defects in the transpersulfurase step. Fluorescence polarization binding assays showed that the loss of activity was not due to a defect in forming the SufS/SufE complex. Structural characterization of R56A SufS shows loss of electron density for the α3-α4 loop at the R56/G57 positions, consistent with a requirement of R56 for proper loop conformation. The structure of R359A SufS exhibits a conformational change in the α3-α4 loop allowing R56 to enter the active site and mimics the residue's position in the PLP-cysteine aldimine structure. Taken together, the kinetic, binding, and structural data support a mechanism where R359 plays a role in linking SufS catalysis with modulation of the α3-α4 loop to promote a close-approach interaction of SufS and SufE conducive to persulfide transfer.

Incidence of Congenital Posterior Arch Defects of the Atlas in Chinese Population

To study the incidence of congenital posterior arch defects of the atlas and in combination with other congenital variations in the Chinese population. 1405 images of cervical three-dimensional computed tomography (3D CT) and 1284 images of head and cervical three-dimensional computed tomography angiography (3D CTA) were retrospectively reviewed, including images of 1539 males and 1150 females. These images of cervical 3D CT and head and cervical 3D CTA were obtained in the Department of Radiology of two hospitals, Second and Third People's Hospital of Jingzhou, China, from January 2020 to October 2023. And congenital posterior arch defects of the atlas were classified according to the criteria of Currarino et al. Congenital posterior arch defects of the atlas combined with other congenital variations including occipitalization of the atlas, the ponticulus posticus variation of the vertebral artery groove of the atlas, cervical fusion, and the transversal foramen of the atlas variant were also observed. A total of 2689 subjects were included in this study. The overall prevalence of congenital posterior arch defects of the atlas was 0.74% (20/2689). There was no statistically significant difference in incidence between males (0.78%,12/1539) and females (0.70%,8/1150) (P >0.05). Among all posterior defects, type A and B defects were found in 0.6% (16/2689) and 0.15% (4/2689) cases, respectively. There were no type C, D, and E defects and no anterior arch defects. But in 20 cases of congenital posterior arch defects of atlas, 40%(8/20) combined with other congenital variations including occipitalization of atlas in 4 type A cases, bilateral complete ponticus posticus variation of atlas vertebral groove in one type A case, C2-3 fusion in one type A case, coexistence of unilateral complete ponticulus posticus variation of the vertebral artery groove of the atlas and unilateral unclosed transverse foramen in one type B case, and coexistence of unilateral unclosed transverse foramen in one type A case. The incidence of congenital posterior arch defects of the atlas was low in Chinese population. There was no difference between males and females. Type A and B were the two major defects in Chinese population, and the prevalence of type A and B combined with other congenital cervical variations were higher than those of type C, D, and E.

A Longitudinal Observation of Antenatal Milk Expression in Mothers of Infants with Congenital Anomalies.

Background: For mothers of infants with congenital anomalies, antenatal milk expression (AME), known as hand expression during late pregnancy, allows mothers to contribute to their newborn's care through colostrum collection. However, research is limited by self-report of AME adherence and colostrum volume. Objective: This study examined the ability of participants to adhere to a recommended protocol on AME for any removal and measurement of colostrum during late pregnancy. Materials and Methods: A prospective, longitudinal, observational design was used. Our recommended protocol involved hand expression of 5 minutes per breast for a total of 10 minutes for each AME session twice per 24 hours for any colostrum from 37 0/7 weeks gestation until birth. Women received AME education, completed milk logs, and attempted AME. The study team verified all colostrum volumes. Results: Nineteen women (10 nulliparous) participated, with 13 (68%) carrying infants with major organ system defects and 6 (32%) carrying infants with congenital heart defects. Most participants (52.6%) completed more than half but fewer than all AME sessions. Seven participants (36.8%) fully adhered, completing two AME sessions daily until hospital admission. Eighteen participants (94.7%) could remove milk (80-100% of the time). The 24-hour colostrum volume (median 0.35 mL, interquartile range [IQR] 0.065-0.845) and the total colostrum volume (median 3.99 mL, IQR 1.35-6.82) from AME varied. Conclusions: Among a small group of women of infants with congenital anomalies, adherence to a recommended protocol is feasible but varied by AME session frequency. Most women could collect colostrum for future infant feeding.

Pelvic Floor Muscle Evaluation in Older Women with Urinary Incontinence: A Feasibility Study.

The objective of this feasibility study was to characterize the pelvic floor muscles (PFMs) in older women with urinary incontinence (UI) via clinical and magnetic resonance imaging (MRI) evaluation. This cross-sectional study included women aged ≥ 70years with symptomatic UI confirmed by a 3-day bladder diary. Clinical evaluation of the PFMs included the Modified Oxford Scale strength assessment (grade 0-5). PFM defects were also characterized as none/normal, minor, and major based on MRI evaluation. Descriptive statistics were utilized. Spearman's correlation with 95% confidence intervals was calculated between PFMs strength, MRI defects, and age. Participants (n = 20) were 76.6 ± 4.7years. Clinical evaluation demonstrated poor PFM strength in 95% (n = 19) of participants with the following grades: 15% (n = 3) grade 0, 45% (n = 9) grade 1, and 35% (n = 7) grade 2. MRI evaluation demonstrated PFMs= defects in 100% of participants with 45% (n = 9) minor and 55% (n = 11) major defects. The correlation coefficients between PFM strength and MRI defects, MRI defects and age, and PFM strength and age were -0.29 (95% CI -0.64, 0.18; p = 0.22), -0.01 (95% CI = -0.44, 0.44; p = 0.99), and 0.04 (95% CI = -0.41, 0.47; p = 0.88) respectively. Clinical and MRI evaluation of PFMs in older women with UI is feasible. Clinical evaluation of PFMs demonstrated poor strength in 95% of women, and MRI revealed PFM defects in all participants.

Symptom trajectories in infancy for the prediction of subsequent wheeze and asthma in the BILD and PASTURE cohorts: a dynamic network analysis

Host and environment early-life risk factors are associated with progression of wheezing symptoms over time; however, their individual contribution is relatively small. We hypothesised that the dynamic interactions of these factors with an infant's developing respiratory system are the dominant factor for subsequent wheeze and asthma. In this dynamic network analysis we used data from term healthy infants from the Basel-Bern Infant Lung Development (BILD) cohort (435 neonates aged 0-4 weeks recruited in Switzerland between Jan 1, 1999, and Dec 31, 2012) and replicated the findings in the Protection Against Allergy Study in Rural Environments (PASTURE) cohort (498 infants aged 0-12 months recruited in Germany, Switzerland, Austria, France, and Finland between Jan 1, 2002, and Oct 31, 2006). BILD exclusion criteria for the current study were prematurity (<37 weeks), major birth defects, perinatal disease of the neonate, and incomplete follow-up period. PASTURE exclusion criteria were women younger than 18 years, a multiple pregnancy, the sibling of a child was already included in the study, the family intended to move away from the area where the study was conducted, and the family had no telephone connection. Outcome groups were subsequent wheeze, asthma, and healthy. The first outcome was defined as ever wheezed between the age of 2 years and 6 years. Week-by-week correlations of the determining factors with cumulative symptom scores (CSS) were calculated from weeks 2 to 52 (BILD) and weeks 8 to 52 (PASTURE). The complex dynamic interaction between the determining factors and the CSS was assessed via dynamic host-environment correlation network, quantified by a simple descriptor: trajectory function G(t). Wheeze outcomes at age 2-6 years were compared in 335 infants from BILD and 437 infants from PASTURE, and asthma outcomes were analysed at age 6 years in a merged cohort of 783 infants. CSS was significantly different for wheeze and asthma outcomes and became increasingly important during infancy in direct comparison with all determining factors. Weekly symptoms were tracked for groups of infants, showing a non-linear increase with time. Using logistic regression classification, G(t) distinguished between the healthy group and wheeze or asthma groups (area under the curve>0·97, p<0·0001; sensitivity analysis confirmed significant CSS association with wheeze [BILD p=0·0002 and PASTURE p=0·068]) and G(t) was also able to distinguish between the farming and non-farming exposure groups (p<0·0001). Similarly to other risk factors, CSS had weak sensitivity and specificity to identify risks at the individual level. At group level however, the dynamic host-environment correlation network properties (G(t)) showed excellent discriminative ability for identifying groups of infants with subsequent wheeze and asthma. Results from this study are consistent with the 2018 Lancet Commission on asthma, which emphasised the importance of dynamic interactions between risk factors during development and not the risk factors per se. The Swiss National Science Foundation, the Kühne Foundation, the EFRAIM study EU research grant, the FORALLVENT study EU research grant, and the Leibniz Prize.

Consanguinity and Occurrence of Monogenic Diseases in a Single Tertiary Centre in Riyadh, Saudi Arabia: A 2 Years Cross-Sectional Study.

Consanguinity, or the practice of marrying close relatives, is a common cultural tradition in Saudi Arabia, with rates among the highest in the world. This practice has significant implications for the prevalence and distribution of major single genetic defects and chromosomal abnormalities within the Saudi population. Herein, using the BESTCare electronic medical record system (designed to streamline hospital operations, enhance patient care, and improve the overall efficiency of healthcare services; bestcare.ezcaretech.com) in a single tertiary centre, King Abdullah Specialized Children Hospital (KASCH) in Riyadh, Saudi Arabia, we performed a cross-sectional study for all patients referred to the hospital from the 1st January 2020 until 1st January 2022. The present study, which included 1100 individuals, found a high prevalence of consanguinity (64%) and a significant proportion of third-degree relatives (69%). The mean age of participants was 12.24 years, and the diagnostic rate using advanced molecular genetics techniques was 45%, with whole exome sequencing (WES) being the most common method (43%). The study also noted a significant delay in diagnosis for more than a year in 16% of cases, with a common neurodevelopmental phenotype (18%). In conclusion, we revealed the prevalence of consanguineous marriages in the KASCH hospital in Riyadh, Saudi Arabia. We also highlighted the most frequently referred phenotype. These findings are consistent with previous research on the prevalence and impact of consanguinity on rare genetic disorders.

Cooperation Between Platelet β1 and β3 Integrins in the Arrest of Bleeding Under Inflammatory Conditions in Mice-Brief Report.

Platelets prevent bleeding in a variety of inflammatory settings, the adhesion receptors and activation pathways involved being highly context-dependent and functionally redundant. In some situations, platelets recruited to inflammatory sites act independently of aggregation. The mechanisms underlying stable platelet adhesion in inflamed microvessels remain incompletely understood, in particular, whether and if so, how β1 and β3 integrins are involved. The impact of isolated or combined platelet deficiency in β1 and β3 integrins on inflammation-associated hemostasis was investigated in 3 models of acute inflammation: immune complex-based cutaneous reverse passive Arthus reaction, intranasal lipopolysaccharide-induced lung inflammation, and cerebral ischemia-reperfusion following transient (2-hour) occlusion of the middle cerebral artery. Mice with platelet-directed inactivation of Itgb1 (PF4Cre-β1-/-) displayed no bleeding in any of the inflammation models, while mice defective in platelet Itgb3 (PF4Cre-β3-/-) exhibited bleeding in all 3 models. Remarkably, the bleeding phenotype of PF4Cre-β3-/- mice was exacerbated in the reverse passive Arthus model by the concomitant deletion of β1 integrins, PF4Cre-β1-/-/β3-/- animals presenting increased bleeding. Intravital microscopy in reverse passive Arthus experiments highlighted a major defect in the adhesion of PF4Cre-β1-/-/β3-/- platelets to inflamed microvessels. Unlike PF4Cre-β1-/- and PF4Cre-β3-/- mice, PF4Cre-β1-/-/β3-/- animals developed early hemorrhagic transformation 6 hours after transient middle cerebral artery occlusion. PF4Cre-β1-/-/β3-/- mice displayed no more bleeding in lipopolysaccharide-induced lung inflammation than PF4Cre-β3-/- animals. Altogether, these results show that the requirement for and degree of functional redundancy between platelet β1 and β3 integrins in inflammation-associated hemostasis vary with the inflammatory situation.

Monocyte and macrophage profiles in patients with inherited long-chain fatty acid oxidation disorders

Patients with inherited disorders of the long-chain fatty acid oxidation (lcFAO) machinery present with a heterogeneous profile of disease manifestations and aggravation of symptoms is often triggered by inflammatory activation. Monocytes and macrophages are innate immune cells that play a major role in the onset and resolution of inflammation. These cells undergo metabolic rewiring upon activation including the regulation of the FAO rate. The rewiring of FAO and the effect of lcFAO disorders (lcFAOD) on human monocyte and macrophage phenotype and function remain largely unknown. Here, we performed extensive phenotyping of circulating monocytes and analyzed plasma cytokine levels in 11 lcFAOD patients and 11 matched control subjects. In patients with lcFAOD, we observed induced plasma levels of the inflammatory cytokines IL-1β and IL-6, and enhanced CD206 and CD62L surface marker expression in circulating monocyte subsets. To mimic the most common lcFAOD very-long-chain acyl-CoA dehydrogenase disorder (VLCADD), we used siRNA-mediated knockdown of the ACADVL gene (encoding VLCAD) in macrophages derived from healthy volunteers. Hereby, we found that siVLCAD affected IL-4-induced alternative macrophage activation while leaving LPS responses and cellular metabolism intact. In the same line, monocyte-derived macrophages from lcFAOD patients had elevated levels of the IL-4-induced alternative macrophage markers CD206 and CD200R. Still, they did not show major metabolic defects or changes in the LPS-induced inflammatory response. Our results indicate that monocytes and macrophages from lcFAOD patients present no major inflammatory or metabolic differences and show that IL-4-induced surface markers are intertwined with lcFAO in human macrophages.

PSVI-18 Association between residual feed intake and reproductive-related traits in young bulls

Abstract Enhancement of feed efficiency (FE) along with reproductive performance is critical to maximize profitability of beef production systems. Residual feed intake (RFI) is a measure of FE, assessing differences between expected and actual feed intake. Published data suggest a negative impact of RFI on reproductive performance. The objective of this experiment was to establish the relationship between RFI and reproductive parameters related with puberty in young bulls. Growing, Brangus bulls (n = 58; 10 to 12 mo of age) were tested for FE over 56 d and ranked as low RFI (LRFI) and high RFI (HRFI). Scrotal circumference (SC) was measured at the greatest diameter of the testicles by the same operator using a scrotal measuring tape, and semen samples were collected by electroejaculation at the beginning and at the end of the test. Fresh semen was visually evaluated (VE) for visual motility (VM), morphology [major defects (MAD)], minor defects (MID), total defects (TD)], plasma membrane integrity (PMI) via Eosin-nigrosin stain and sperm concentration (Con). Sperm kinematics were objectively determined simultaneously via computer-assisted sperm analysis (CASA-IVOS II System, Hamilton Thorne, Beverly, MA) within 6 h of collection in a medium designed specifically for holding sperm. Statistical analysis included repeated measures to assess interactions between Group (LRFI, HRFI) and Time (0 and 56 d of RFI measurement). Results are presented as mean ± SEM in Table 1. The main effect of Group did not affect CASA derived traits, while MAD and TD were affected among VE traits. A Time effect was observed in the amplitude of lateral head displacement (ALH), beat cross frequency (BCF), curvilinear velocity (VCL) and linearity (LIN). A tendency was indicated for total motility (TM), and average path velocity (VAP) among CASA derived traits, while all VE traits were affected by Time except for visual motility (VM). Finally, an interaction effect (Group x Time) was observed in LIN and plasma membrane integrity (PMI). In conclusion, age at puberty as determined by VM, Con, and SC (Group: P = 0.12, Day: P &amp;lt; 0.001, Group x Day: P = 0.79) was not associated with RFI. Overall, fertility-related measurements were not influenced by RFI, with time emerging as the primary influencing factor across evaluated parameters. Evaluation of reproductive parameters following d 56 FE testing may be a useful determinant for identifying differences in seminal characteristics of young bulls.

Cost-based performance optimization of a single system under a hierarchical imperfect maintenance policy

Abstract Due to the influence from external factors such as repair sites and seasonal climate change, it is difficult to restore the system performance to any intermediate level between perfect maintenance and minimal maintenance through imperfect maintenance. This article first categorizes the states of the system just before repair into three classes based on its internal degradation level: failure, major defect, and minor defect, with three corresponding thresholds. Subsequently, the corresponding repairs are carried out to dwindle the system’s degradation to different levels. In detail, if the internal degradation level of the system just before repair is recognized as minor defect, an imperfect repair, termed as type I imperfect repair, is implemented to scale down the degradation level below the minor defect threshold. If the degradation level is identified as major defect, an upgraded imperfect repair, termed as type II imperfect repair, is executed to only lower the degradation to the level between the minor defect threshold and major defect threshold. Otherwise, if the degradation before repair is beyond the failure threshold, replacement will be carried out instead of these imperfect repairs. Thus, a novel hierarchical imperfect maintenance structure is introduced. Then, a multi-variable repair cost model is constructed when considering the related costs incurred from inspection, type I imperfect repair, type II imperfect repair, replacement, and even system downtime. Finally, with the aid of the stationary law of Markov chains and the semi-regenerative process, the cost-based performance optimization with three parameters, including the inspection interval, minor defect threshold, and major defect threshold, is explored through a numerical experiment, and the closed expression of the optimal cost rate is provided.

Fuzzy assessment of process parameter interactions on warpage defect modeling in plastic injection molding

AbstractStudying the interactions among major plastic injection molding process parameters is necessary to understand how they collectively influence major defects such as warpage hence enabling optimization of the process for improved product quality. Existing process parameter interaction studies have used statistical approximations, which have limitations such as reduced predictive power and limited accuracy. To overcome these limitations, this study presents an alternative method of analysis of the interactions among process parameters based on fuzzy logic intelligent algorithm. Through computer aided engineering, factorial design of experiment and fuzzy logic modelling, the study evaluated the effects of major injection molding process parameter interactions on warpage. The results obtained indicated a general increase in warpage with increase in parameters such as melt temperature, mold temperature, injection pressure and cool time whereas an increase in parameters such as ambient temperature and packing pressure decreased warpage. Parameter interactions were obtained both statistically and based on fuzzy logic model and their significance tested through ANOVA. Ambient temperature (30.6%) and melt temperatures (18.7%) had the greatest effect on warpage all with P-values of 0.000 whereas cooling time (0.1%) had the least effect with P-value of 0.250. The largest two way interaction affecting warpage involved melt temperature and cooling time with a contribution of 12.2% whereas the largest three way interaction involves ambient temperature, packing pressure and injection pressure with a contribution of 2.7%. Also, despite cooling time having the least mains effect, most interaction terms with greater effect on warpage involved cooling time and melt temperature. The results from this study provides an insight on targeted injection molding process parameter control for defect minimization.