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Johnson Chia-Shen Yang,1,2 Lien-Hung Huang,1,2 Shao-Chun Wu,3,4 Yi-Chan Wu,1,4 Chia-Jung Wu,1,4 Chia-Wei Lin,1,4 Pei-Yu Tsai,1,4 Peng-Chen Chien,1,4 Ching-Hua Hsieh1,2 1Division of Plastic and Reconstructive Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4Chang Gung University College of Medicine, Taoyuan, TaiwanCorrespondence: Ching-Hua HsiehGraduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, 123 Dapi Road, Niaosong District, Kaohsiung City, 833, Taiwan, Tel +886-7-7317123, ext.8002, Fax +886-7-7354309, Email prs581126@gmail.comPurpose: This study aims at profiling the expression of dysregulated genes in circulating monocytes of patients with cancer-related lower limb lymphedema before and after treatment with supermicrosurgical lymphaticovenous anastomosis (LVA).Materials and Methods: This prospective longitudinal cohort study enrolled 51 women with post-treatment gynecological cancer, including those with unilateral lymphedema (study group, n = 25) and those without (control group, n = 26). Venous blood samples obtained from the study group before and after LVA and those from the controls were sent for next-generation sequencing, which was validated by real-time PCR. Dysregulated gene expression in the study group, relative to expression in the controls, was recorded before LVA. After one month, postoperative changes in the expression of the identified genes were evaluated. Protein-protein interaction (PPI) was used to investigate dysregulated genes whose expression returned to baseline levels after LVA.Results: Of the 148 preoperative dysregulated genes, which comprised 108 up- and 40 down-regulated genes, 78 genes, consisting of 69 up- and 9 down-regulated genes, showed post-LVA recovery to baseline levels. Through PPI analysis, five functional modules involving immunity, lipid metabolism, oxidative stress, transcriptional regulators, and tumor suppression, as well as six hub genes (CCL2, LPL, PDK4, FOXO3, EGR1, and DUSP5), were identified. Cross-linking and co-regulated genes between modules were also identified.Conclusion: Localized lymphedema leads to dysregulated gene expression in circulating monocytes. The current study is the first to identify the hub genes related to lymphedema and demonstrate the recovery of some dysregulated genes after LVA.Keywords: transcriptome, NGS, real-time PCR, hub gene, functional modules

Segmentation of a fetal head from three-dimensional (3-D) ultrasound images is a critical step in the quantitative measurement of fetal craniofacial structure. However, two main issues complicate segmentation, including fuzzy boundaries and large variations in pose and shape among different ultrasound images. In this article, we propose a new registration-based method for automatically segmenting the fetal head from 3-D ultrasound images. The proposed method first detects the eyes based on Gabor features to identify the pose of the fetus image. Then, a reference model, which is constructed from a fetal phantom and contains prior knowledge of head shape, is aligned to the image via feature-based registration. Finally, 3-D snake deformation is utilized to improve the boundary fitness between the model and image. Four clinically useful parameters including inter-orbital diameter (IOD), bilateral orbital diameter (BOD), occipital frontal diameter (OFD) and bilateral parietal diameter (BPD) are measured based on the results of the eye detection and head segmentation. Ultrasound volumes from 11 subjects were used for validation of the method accuracy. Experimental results showed that the proposed method was able to overcome the aforementioned difficulties and achieve good agreement between automatic and manual measurements. [ABSTRACT FROM AUTHOR]

Background: Results on whether N-acetylcysteine (NAC) ameliorates depression in patients with psychiatric problems, such as bipolar disorder and major depressive disorder, remain inconsistent, and several new studies have recently been published. Thus, we conducted an uptodated meta-analysis to evaluate the efficacy of NAC against depression., Methods: This systematic review and meta-analysis included randomized controlled trials where NAC was used to treat depression. The present study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase (Ovid), and Cochrane were searched for relevant articles. A random-effects model was used to evaluate the primary outcome-efficacy of NAC in ameliorating depression., Results: This review included 12 studies (904 patients with depression). The daily dose of NAC in the included studies ranged from 1000 to 3000 mg. The duration of NAC treatment ranged from 8 to 24 weeks. A significant difference was noted between NAC and placebo in terms of the change in mean depression score from baseline to treatment conclusion (standardized mean difference = -0.24; 95 % confidence interval (CI) = -0.44 to -0.05; I 2  = 45 %; P = .02)., Conclusion: Our findings indicate that adjunctive NAC can ameliorate depressive symptoms in patients with psychiatric problems, particularly bipolar disorder. However, large-scale clinical trials were needed to substantiate our results due to the wide CI value., Competing Interests: Declaration of competing interest All authors declare no conflict to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Aims: Diabetic kidney disease (DKD) is a common complication of type 2 diabetes mellitus (T2DM) that leads to systemic inflammation. Maternally expressed gene 3 (MEG3) is a tumor suppressor that is involved in inflammation regulation. The current study investigated the association between DKD and the prevalence of the single-nucleotide polymorphisms (SNPs) of MEG3., Methods: A total of 706 and 735 patients were included in the DKD and non-DKD groups, respectively. The five SNPs of MEG3, namely rs4081134 (G/A), rs10144253 (T/C), rs7158663 (G/A), rs3087918 (T/G), and rs11160608 (A/C), were genotyped using TaqMan allelic discrimination., Results: Our results revealed that, in the DKD group, the distribution of the GG genotype of the MEG3 SNP rs3087918 was significantly lower than that of the wild-type genotype (AOR: 0.703, 95% CI: 0.506-0.975, P = 0.035). In addition, in the pre-ESRD DKD subgroup, the distribution of the TG + GG genotype of the MEG3 SNP rs3087918 was significantly lower than that of the wild-type genotype (AOR: 0.637, 95% CI: 0.421-0.962, P = 0.032). In addition, among men in the DKD subgroup, the distribution of the GG genotype of the MEG3 SNP rs3087918 was significantly lower than that of the wild-type genotype (AOR: 0.630, 95% CI: 0.401-0.990, P = 0.045). Glycated hemoglobin (HbA1c) level was significantly higher in all T2DM patients with the wild-type genotype of the MEG3 SNP rs3087918 (P = 0.020). In addition, HbA1c levels were significantly higher in male patients and male DKD patients with the wild-type genotype of the MEG3 SNP rs3087918 (P = 0.032 and 0.031, respectively)., Conclusion: MEG3 SNP rs3087918 is significantly less prevalent in patients with DKD, and the SNP rs3087918 of MEG3 is associated with lower HbA1c levels., (© 2024. The Author(s).)

Colorectal cancer (CRC) is one of the primary contributors to cancer-related fatalities, with up to 80% of advanced CRC cases exhibiting mutations in the p53 gene. Unfortunately, the development of new compounds targeting mutant p53 is quite limited. The anticancer effects of Dehydroepiandrosterone (DHEA) on various cancers have been reported. However, the suppressive effect of DHEA on CRC cells harboring wild-type or mutant p53 gene remains controversial. This study emphasized revealing the suppressive mechanism and the effect of DHEA on CRC cell tumorigenesis in the presence of wild-type or mutant p53 gene. We demonstrate that DHEA causes CRC cell death and cell cycle arrest in a dose and time-dependent manner. Notably, DHEA exhibits similar inhibitory effects on CRC cells regardless of the p53 gene status. Further study reveals that DHEA induces endoplasmic reticulum (ER) stress and triggers PERK/eIF2/ATF4/CHOP UPR signaling pathway to activate autophagy followed by apoptosis, which was confirmed by suppression of 4-phenylbutyric acid (an ER stress inhibitor) or knockdown either ATF4 or CHOP. DHEA-induced apoptosis was attenuated by silencing ATG5 gene in either p53 +/+ or p53 -/- CRC cells, indicating autophagy regulation of apoptosis. Furthermore, DHEA treatment accompanied by bafilomycin A1 (a blocker of autophagosome degradation) leads to the accumulation of ATF4, CHOP, DR5, and p21 levels in CRC cells, implying that the degradative autophagy machinery regulates these four molecules. Consistently, DHEA demonstrates its inhibitory effect by suppressing CRC tumor formation in vivo . Altogether, we provide compelling evidence that DHEA is a potential therapeutic candidate for CRC patient treatment regardless of the p53 status through ER stress-PERK-autophagy-apoptosis axis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nguyen, Ko, Tsai, Cheng, Tran, Doan, Hsiao, Chang, Liu, Hong and Huang.)

Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The placenta experiences a low-oxygen stage during early pregnancy. Aspirin is an effective preventative treatment for preeclampsia if applied early in pregnancy. Elevation of fibronectin (FN) level has been reported to be associated with preeclampsia; however, the role of FN in the physiological hypoxic phase and whether aspirin exerts its effect on FN at this hypoxic stage remain unknown. We determined pregnancy outcomes by injecting saline or recombinant FN protein into C57BL/6 pregnant mice and one group of FN-injected mice was fed aspirin. The effects of FN, the underlying pathways on trophoblast biology, and cilia formation under hypoxia were investigated in FN-pretreated or FN-knockdown HTR-8/SVneo cells in a hypoxic chamber (0.1 % O 2 ). Preeclampsia-like phenotypes, including blood pressure elevation and proteinuria, developed in FN-injected pregnant mice. The fetal weight of FN-injected mice was significantly lower than that of non-FN-injected mice (p < 0.005). Trophoblast FN expression was upregulated under hypoxia, which could be suppressed by aspirin treatment. FN inhibited trophoblast invasion and migration under hypoxia, and this inhibitory effect occurred through downregulating ZEB1/2, MMP 9 and the Akt and MAPK signaling pathways. Ciliogenesis of trophoblasts was stimulated under hypoxia but was inhibited by FN treatment. Aspirin was shown to reverse the FN-mediated inhibitory effect on trophoblast invasion/migration and ciliogenesis. In conclusion, FN overexpression induces preeclampsia-like symptoms and impairs fetal growth in mice. Aspirin may exert its suppressive effect on FN upregulation and FN-mediated cell function in the hypoxic stage of pregnancy and therefore provides a preventative effect on preeclampsia development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes, whose complex etiology involves a genetic component. Growth arrest-specific 5 (GAS5), a long noncoding RNA (lncRNA) gene, has been recently shown to regulate renal fibrosis. Here, we aimed to explore the potential role of GAS5 gene polymorphisms in the predisposition to DKD. One single-nucleotide (rs55829688) and one insertion/deletion polymorphism (rs145204276) of GAS5 gene were surveyed in 778 DKD cases and 788 DKD-free diabetic controls. We demonstrated that diabetic subjects who are heterozygous at rs55829688 (TC; AOR, 1.737; 95% CI, 1.028-2.937; p=0.039) are more susceptible to advanced DKD but not early-staged DKD, as compared to diabetic subjects who are homozygous for the major allele of rs55829688 (TT). Carriers of at least one minor allele (C) of rs55829688 (TC and CC; AOR, 1.317; 95% CI, 1.023-1.696; p=0.033) more frequently suffer from advanced DKD than do those homozygotes for the major allele (TT). Furthermore, in comparison to those who do not carry the minor allele of rs55829688 (TT), advanced DKD patients possessing at least one minor allele of rs55829688 (TC and CC) exhibited a lower glomerular filtration rate, revealing an impact of rs55829688 on renal co-morbidities of diabetes. In conclusion, our data indicate an association of GAS5 gene polymorphisms with the progression of DKD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric symptoms. Currently, there is no cure, and only limited treatments are available to manage the symptoms and to slow down the disease's progression. The molecular and cellular mechanisms of HD's pathogenesis are complex, involving immune cell activation, altered protein turnover, and disturbance in brain energy homeostasis. Microglia have been known to play a dual role in HD, contributing to neurodegeneration through inflammation but also enacting neuroprotective effects by clearing mHTT aggregates. However, little is known about the contribution of microglial metabolism to HD progression. This study explores the impact of a microglial metabolite transporter, equilibrative nucleoside transporter 3 (ENT3), in HD. Known as a lysosomal membrane transporter protein, ENT3 is highly enriched in microglia, with its expression correlated with HD severity. Using the R6/2 ENT3 -/- mouse model, we found that the deletion of ENT3 increases microglia numbers yet worsens HD progression, leading to mHTT accumulation, cell death, and disturbed energy metabolism. These results suggest that the delicate balance between microglial metabolism and function is crucial for maintaining brain homeostasis and that ENT3 has a protective role in ameliorating neurodegenerative processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Perturbation of gut microbiota has been linked to chronic kidney disease (CKD), which was correlated with a sophisticated milieu of metabolic and immune dysregulation., Methods: To clarify the underlying host-microbe interaction in CKD, we performed multi-omics measurements, including systems-level gut microbiome, targeted serum metabolome and deep immunotyping, in a cohort of patients and non-CKD controls., Results: Our analyses on functional profiles of the gut microbiome showed a decrease in the diversity and abundance of carbohydrate-active enzyme (CAZyme) genes but an increase in the abundance of antibiotic resistance, nitrogen cycling enzyme and virulence factor genes in CKD. Moreover, models generated using measurements of serum metabolites (amino acids, bile acids and short-chain fatty acids) or immunotypes were predictive of renal impairment but less so than many of the functional profiles derived from gut microbiota, with the CAZyme genes being the top-performing model to accurately predict the early stage of diseases. In addition, co-occurrence analyses revealed coordinated host-microbe relationships in CKD. Specifically, the highest fractions of significant correlations were identified with circulating metabolites by several taxonomic and functional profiles of gut microbiome, while immunotype features were moderately associated with the abundance of microbiome-encoded metabolic pathways and serum levels of amino acids (e.g. B cell cluster tryptophan and B cell cluster tryptophan metabolism)., Conclusion: Overall, our multi-omics integration revealed several signatures of systems-level gut microbiome in robust associations with host-microbe co-metabolites and renal function, which may have aetiological and diagnostic implications in CKD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Lymphedema is a debilitating condition that significantly affects quality of life due to its chronic nature and visible symptoms. Lymphaticovenous anastomosis (LVA) has emerged as a promising surgical intervention, yet its effects on body image and spiritual health alongside physical symptoms have not been thoroughly examined. This study evaluates the efficacy of LVA in improving symptoms, quality of life (QOL), body image, and spiritual well-being in lymphedema patients., Methods: A prospective cohort study was conducted at Kaohsiung Chang Gung Memorial Hospital, Taiwan, involving 44 patients with lymphedema undergoing LVA surgery. Evaluations were made pre-surgery, one month post-surgery, and six months post-surgery using the 36-Item Short Form Health Survey (SF-36), Multidimensional Body-Self Relations Questionnaire-Appearance Scales (MBSRQ-AS), and a spiritual health scale. Statistical analysis was performed using one-way repeated measures ANOVA., Results: Significant improvements were observed in lymphedema symptoms and QOL measures at six months post-operation. SF-36 results showed enhanced scores in nearly all domains, particularly in physical functioning and role-physical. The appearance orientation scores from the MBSRQ-AS significantly increased, indicating improved perceptions in some dimensions of body image., Conclusions: LVA surgery significantly enhances physical and psychological outcomes in patients with lymphedema, with marked improvements in symptoms, QOL, and body image perceptions. The findings suggest that while LVA is effective in addressing the physical and psychological aspects of lymphedema, it does not impact spiritual dimensions. This underscores the need for holistic approaches in the management of lymphedema to address all facets of patient well-being.

Psychological stress increases risk of gastrointestinal tract diseases. However, the mechanism behind stress-induced gastrointestinal injury is not well understood. The objective of our study is to elucidate the putative mechanism of stress-induced gastrointestinal injury and develop an intervention strategy. To achieve this, we employed the restraint stress mouse model, a well-established method to study the pathophysiological changes associated with psychological stress in mice. By orally administering gut-nonabsorbable Evans blue dye and monitoring its plasma levels, we were able to track the progression of gastrointestinal injury in live mice. Additionally, flow cytometry was utilized to assess the viability, death, and inflammatory status of splenic leukocytes, providing insights into the stress-induced impact on the innate immune system associated with stress-induced gastrointestinal injury. Our findings reveal that neutrophils represent the primary innate immune leukocyte lineage responsible for stress-induced inflammation. Splenic neutrophils exhibited elevated expression levels of the pro-inflammatory cytokine IL-1, cellular reactive oxygen species, mitochondrial burden, and cell death following stress challenge compared to other innate immune cells such as macrophages, monocytes, and dendritic cells. Regulated cell death analysis indicated that NETosis is the predominant stress-induced cell death response among other analyzed regulated cell death pathways. NETosis culminates in the formation and release of neutrophil extracellular traps, which play a crucial role in modulating inflammation by binding to pathogens. Treatment with the NETosis inhibitor GSK484 rescued stress-induced neutrophil extracellular trap release and gastrointestinal injury, highlighting the involvement of neutrophil extracellular traps in stress-induced gastrointestinal inflammation. Our results suggest that neutrophil NETosis could serve as a promising drug target for managing psychological stress-induced gastrointestinal injuries.

Background: Contraction-type lymphatic vessels (LV) are considered suboptimal for lymphaticovenous anastomosis (LVA). However, despite these pathological changes, their functionality and link to outcomes have not been fully elucidated. The aim of this study was to determine the impact on outcomes when contraction-type LVs were used for LVA compared to the noncontraction-type (normal + ectatic) counterpart for treating lower limb lymphedema., Study Design: Eighty-three patients with gynecologic cancer-related unilateral lower-limb lymphedema who underwent LVA as their primary treatment were enrolled in this study. The study group included 20 patients who used only contraction-type LVs. An additional 63 patients (control group) received noncontraction-type LVs only. Patients with a history of LVA, liposuction, or excisional therapy were excluded. Patient characteristics, intraoperative findings, functional parameters, and pre-LVA and post-LVA volume changes were recorded and matched using propensity scores. The primary endpoint was the volume change at 6/12 months after LVA., Results: After matching, 20 patients were included in each group. All parameters were matched, except that the study group still had a significantly inferior indocyanine green (ICG)-positive ratio, lymph flow-positive ratio, and washout-positive ratios ( P <0.001, P =0.003, and P <0.001, respectively) when compared to the control group after matching. However, at 1-year follow-up, the postoperative percentage volume reduction was comparable between the groups ( P= 0.619)., Conclusion: The use of contraction-type LVs for LVA is encouraged when no other LVs are available., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease., Competing Interests: Drs. Wendy Broom and Leila Noetzli are employees and shareholders of Alnylam Pharmaceuticals, with multiple patent applications pending. All other authors declare no competing interests., (Copyright: © 2024 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A pregnancy booster dose significantly reduces the risk and severity of COVID-19, and it is widely recommended. A prospective cohort study was conducted to compare the transplacental passage of maternal antibodies from vaccination or infection during three trimesters against both the vaccine-targeted Wuhan strain and the Omicron strain of SARS-CoV-2. Maternal-infant dyads from vaccinated mothers were collected between 6 June 2022 and 20 September 2022. We analyzed 38 maternal-infant dyads from mothers who had been infected with COVID-19 and 37 from mothers without any previous infection. Pregnant women who received their last COVID-19 vaccine dose in the third trimester exhibited the highest anti-spike protein antibody levels and neutralizing potency against both the Wuhan strain and Omicron BA.2 variant in their maternal and cord plasma. Both second- and third-trimester vaccination could lead to a higher level of neutralization against the Wuhan and Omicron strains. COVID-19 infection had a negative effect on the transplacental transfer ratio of SARS-CoV-2 antibodies. A booster dose during the second or third trimester is encouraged for the maximum transplacental transfer of humoral protection against COVID-19 for infants.

Preparing Cd 3 As 2 , which is a three-dimensional (3D) Dirac semimetal in certain crystal orientation, on Si is highly desirable as such a sample may well be fully compatible with existing Si CMOS technology. However, there is a dearth of such a study regarding Cd 3 As 2 films grown on Si showing the chiral anomaly. Here, for the first time , we report the novel preparation and fabrication technique of a Cd 3 As 2 (112) film on a Si (111) substrate with a ZnTe (111) buffer layer which explicitly shows the chiral anomaly with a nontrivial Berry's phase of π . Despite the Hall carrier density (n3D≈9.42×1017cm -3 ) of our Cd 3 As 2 film, which is almost beyond the limit for the portents of a 3D Dirac semimetal to emerge, we observe large linear magnetoresistance in a perpendicular magnetic field and negative magnetoresistance in a parallel magnetic field. These results clearly demonstrate the chiral magnetic effect and 3D Dirac semimetallic behavior in our silicon-based Cd 3 As 2 film. Our tailoring growth of Cd 3 As 2 on a conventional substrate such as Si keeps the sample quality, while also achieving a low carrier concentration., (© 2024 IOP Publishing Ltd.)

Recurrent miscarriage is defined as more than three pregnancy failures occurring before 20 weeks of gestation. Poor differentiation of the endometrial stroma or defective trophoblast cell invasion at the maternal-fetal interface leads to recurrent miscarriages. Several miRNAs, including miR-20b-5p, are aberrantly regulated in recurrent miscarriages; however, the underlying molecular mechanisms remain unclear. Primary cilia are antenna-like organelles that coordinate signaling during development and differentiation. Defective primary cilia formation leads to complications, such as recurrent miscarriage or preeclampsia. Here, we demonstrated that miR-20b-5p inhibited trophoblast cell invasion by blocking primary cilia formation. Mechanistically, miR-20b-5p targeted and inhibited ATG16L1 and ATG7 expression, thereby blocking autophagy. Defective autophagy reduced primary cilia formation and stopped ERK activation, which is a crucial signaling pathway for trophoblast invasion. Aspirin is used to prevent recurrent miscarriages in clinical settings. Treatment with aspirin inhibited miR-20b-5p levels, thus restoring primary cilia formation and trophoblast invasion. Thus, our findings uncovered the molecular mechanism by which miR-20b-5p suppressed primary cilia formation and trophoblast invasion by reducing the expression of ATG16L1 and ATG7. Moreover, we found that the defective phenotypes could be rescued by aspirin in recurrent miscarriages., Competing Interests: Declaration of Competing Interest No competing interests are declared., (Copyright © 2023. Published by Elsevier Inc.)

Background: Paxlovid is an oral drug composed of nirmatrelvir and ritonavir that has been demonstrated to be effective in decreasing the risk of severe coronavirus disease 2019 (COVID-19). Here, we report the use of paxlovid in pregnant women with COVID-19., Methods: Pregnant women attending a tertiary referral hospital in Taiwan from 29 April to 30 July 2022 were enrolled in the study. We compared baseline characteristics, clinical manifestations, and adverse events between paxlovid-treated women and those without paxlovid use. Maternal and neonatal outcomes were analysed in women who delivered during the study period., Results: A total of 30 paxlovid-treated pregnant women and 55 women without paxlovid use were included in the analysis. The mean duration of COVID-19-associated symptoms in the paxlovid-treated women was shorter than that in the control group (10.10 days versus 15.59 days, p = 0.04). No severe adverse events due to paxlovid use were observed. Dysgeusia and diarrhoea were the most common adverse effects. Thirteen paxlovid-treated and 28 untreated women delivered during the study period. More pregnant women in the paxlovid group who delivered during the study period underwent caesarean delivery compared to the group without antiviral treatment (10 of 13 [76.92%] versus 12 of 28 [42.86%], p = 0.042), and insignificantly more newborns were born small for gestational age in the paxlovid group compared to the control group (3 of 13 [23.08%] versus 1 of 28 [3.57%], p = 0.086)., Conclusion: Our study showed that paxlovid was effective and safe for pregnant women during the Omicron wave of the COVID-19 pandemic. A higher proportion of caesarean delivery rates was observed among paxlovid-treated women. Long-term follow-up of pregnant women exposed to paxlovid and their offspring is needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The COVID-19 pandemic has had an enormous impact on society and the medical environment in Taiwan in 2022. As pregnant women with COVID-19 are at higher risk for multiple complications, Taiwan needs a COVID-19 specialized maternity unit to improve the quality of maternal and neonatal care., Materials and Methods: We share our experience with specialized maternity unit for pregnant women with COVID-19 at the National Cheng Kung University Hospital, where we can have careful evaluation, safe birth, and comprehensive postpartum care., Results: Our COVID-19 specialized maternity unit enrolled 253 pregnant women with COVID-19, 90 (35.6%) pregnant women were admitted to the specialized maternity unit, and 71 (28.1%) pregnant women gave birth during hospitalization in two months. All pregnant women recovery well and real-time polymerase chain reaction tests on all infants were negative for COVID-19., Conclusion: A specialized maternity unit can provide pregnant women with a safe birth environment, immediate maternity care, and high medical quality. It can also help health workers in non-specialized maternity units deal with COVID-19-related psychological stress. Therefore, setting up one specialized maternity unit in the city during the pandemic should be guardedly considered., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023. Published by Elsevier B.V.)

The immune synapse, a highly organized structure formed at the interface between T lymphocytes and antigen-presenting cells (APCs), is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although the roles of ciliary proteins on the immune synapse remain elusive. Here, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, is enriched at the immune synapse in Jurkat T-cells during superantigen-mediated conjugation or antibody-mediated crosslinking of TCR complexes, and forms a complex with CD3ζ, ZAP-70, and Lck. Silencing INPP5E in Jurkat T-cells impairs the polarized distribution of CD3ζ at the immune synapse and correlates with a failure of PI(4,5)P 2 clearance at the center of the synapse. Moreover, INPP5E silencing decreases proximal TCR signaling, including phosphorylation of CD3ζ and ZAP-70, and ultimately attenuates IL-2 secretion. Our results suggest that INPP5E is a new player in phosphoinositide manipulation at the synapse, controlling the TCR signaling cascade., (© 2023. Springer Nature Limited.)

Objective: The activation of non-shivering thermogenesis (NST) has strong potential to combat obesity and metabolic disease. The activation of NST however is extremely temporal and the mechanisms surrounding how the benefits of NST are sustained once fully activated, remain unexplored. The objective of this study is to investigate the role of 4-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like 1 (Nipsnap1) in NST maintenance, which is a critical regulator identified in this study., Methods: The expression of Nipsnap1 was profiled by immunoblotting and RT-qPCR. We generated Nipsnap1 knockout mice (N1-KO) and investigated the function of Nipsnap1 in NST maintenance and whole-body metabolism using whole body respirometry analyses. We evaluate the metabolic regulatory role of Nipsnap1 using cellular and mitochondrial respiration assay., Results: Here, we show Nipsnap1 as a critical regulator of long-term thermogenic maintenance in brown adipose tissue (BAT). Nipsnap1 localizes to the mitochondrial matrix and increases its transcript and protein levels in response to both chronic cold and β3 adrenergic signaling. We demonstrated that these mice are unable to sustain activated energy expenditure and have significantly lower body temperature in the face of an extended cold challenge. Furthermore, when mice are exposed to the pharmacological β3 agonist CL 316, 243, the N1-KO mice exhibit significant hyperphagia and altered energy balance. Mechanistically, we demonstrate that Nipsnap1 integrates with lipid metabolism and BAT-specific ablation of Nipsnap1 leads to severe defects in beta-oxidation capacity when exposed to a cold environmental challenge., Conclusion: Our findings identify Nipsnap1 as a potent regulator of long-term NST maintenance in BAT., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Non-shivering thermogenesis (NST) has strong potential to combat obesity; however, a safe molecular approach to activate this process has not yet been identified. The sulfur amino acid taurine has the ability to safely activate NST and confer protection against obesity and metabolic disease in both mice and humans, but the mechanism of this action is unknown. In this study, we discover that a suite of taurine biosynthetic enzymes, especially that of cysteamine dioxygenase (ADO), significantly increases in response to β 3 adrenergic signaling in inguinal adipose tissue (IWAT) in order to increase intracellular concentrations of taurine. We further show that ADO is critical for thermogenic mitochondrial respiratory function as its ablation in adipocytes significantly reduces taurine levels, which leads to declines in mitochondrial oxygen consumption rates. Finally, we demonstrate via assay for transposase-accessible chromatin with sequencing (ATAC-seq) that taurine supplementation in beige adipocytes has the ability to remodel the chromatin landscape to increase the chromatin accessibility and transcription of genes, such as glucose-6-phosphate isomerase 1 (Gpi1), which are critical for NST. Taken together, our studies highlight a potential mechanism for taurine in the activation of NST that can be leveraged toward the treatment of obesity and metabolic disease.

Background and Purpose: A reliable neuroimaging biomarker to predict language improvement after neuromodulation in post-stroke aphasia is lacking. It is hypothesized that aphasic patients with stroke injuries in the left primary language circuits but with sufficient right arcuate fasciculus (AF) integrity might respond to low-frequency repetitive transcranial magnetic stimulation (LF-rTMS), leading to language improvement. This study aimed to assess the microstructural indices of the right AF before LF-rTMS treatment and further correlate with language improvement after the treatment., Methods: Thirty-three patients with at least 3 months after stroke in the left hemisphere and nonfluent aphasia were recruited in this randomized double-blind study. All patients received real 1-Hz LF-rTMS (n = 16) or sham stimulation (n = 17) at the right pars triangularis for 10 consecutive weekdays. Fractional anisotropy, axial diffusivity, radial diffusivity and apparent diffusion coefficient of the right AF were extracted using diffusion tensor imaging before the rTMS treatment and correlated with the measured functional improvement by the Concise Chinese Aphasia Test., Results: The Concise Chinese Aphasia Test change scores revealed a stronger language improvement in auditory/reading comprehension and expression in the rTMS group than in the sham group. Regression analysis showed that the pre-treatment fractional anisotropy, axial diffusivity and apparent diffusion coefficient of the right AF significantly correlated with the expression abilities (R 2  > 0.700, p < 0.044) and comprehension abilities (R 2  > 0.702, p < 0.039) in the rTMS group., Conclusions: It was concluded that the right AF could be a predictor in language recovery induced by LF-rTMS after the injuries of primary language circuits., (© 2023 European Academy of Neurology.)

Currently available intrathymic injection techniques cause postoperative complications or difficulties in equipment acquisition. Here, we describe a standardized intrathymic injection protocol that requires only basic equipment with a minimally invasive procedure. We detail steps to identify injection sites for intrathymic delivery. We then describe how to visualize a successful intrathymic injection by including Indian ink in the injected solution. For complete details on the use and execution of this protocol, please refer to Tsai et al. (2022). 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

An increasing amount of evidence emphasizes the role of metabolic reprogramming in immune cells to fight infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of equilibrative nucleoside transporter 3 (ENT3, encoded by solute carrier family 29 member 3, Slc29a3) is part of the innate immune response, which is rapidly upregulated upon pathogen invasion. The transcription of Slc29a3 is directly regulated by type I interferon-induced signaling, demonstrating that this metabolite transporter is an interferon-stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS-CoV-2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of Slc29a3 expression is sufficient to significantly decrease viral replication in vitro and in vivo. Our study reveals that ENT3 is a pro-viral ISG co-opted by some viruses to gain a survival advantage., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background and Aim: A better understanding of irreversible prognoses in palliative care is crucial for improving patients' quality of life and their sense of dignity. We examined whether measurements of meridian electrical conductance can noninvasively and objectively predict survival time in a hospice patient population., Experimental Procedure: This was a single-center cohort study. Between 2019 and 2020, we measured skin conductance from 24 representative acupoints of 12 meridians on both sides of the body in 181 advanced cancer patients within 48 h of hospitalization and monitored their survival time. The Palliative Prognostic Score (PaP Score) was calculated for each patient, classifying them into one of three prognosis groups: Group A, B, or C. Factors associated with short-term and long-term survival were identified using multivariate regression analysis. Statistical differences in survival times were analyzed between the meridian electrical conductance measurements and PaP Scores., Results and Conclusion: Analyses of the clinicopathological data from terminal cancer patients revealed that male sex, mean meridian electrical conductance measurements of ≤8.8 μA, and PaP Scores in Group C were independent predictors of short-term survival. Mean meridian electrical conductance measurements of ≤8.8 μA demonstrated good sensitivity (85.1%) and adequate specificity (60.6%) for short-term survival. A survival curve analysis revealed a mortality rate of 90.6% at 30 days among patients with meridian electrical conductance measurements of ≤8.8 μA. A mean meridian electrical conductance measurement of ≤8.8 μA can objectively assess short-term survival with advanced cancer and reduce nonbeneficial medical treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this paper., (© 2023 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Preeclampsia is a severe gestational hypertensive disorder that may lead to maternal multiple organ dysfunction and adverse fetal outcomes. Aspirin provides a protective effect by reducing the risk of preeclampsia; however, its mechanism of action is unclear. Fibronectin (FN) is a key factor in cell motility and is associated with preeclampsia. Here, we demonstrated that cellular FN expression was elevated in the placenta of preeclamptic patients. The functional roles of plasma and cellular FN in trophoblasts were investigated by treating HTR-8/SVneo cells with exogenous recombinant human FN protein (rhFN) and siRNA, respectively. Trophoblast migration and invasion were inhibited by rhFN and facilitated by FN knockdown. Moreover, rhFN activated ERK and Akt signaling in trophoblasts, and FN-suppressed cell motility was rescued by ERK and/or Akt inhibitors. In this study, aspirin suppressed trophoblast cellular FN expression and reversed FN-mediated cell functions, including cell migration, invasion, and ERK/Akt signal changes. Taken together, the results of this study revealed the effects of FN on trophoblast motility and signaling; aspirin inhibits FN expression and reverses FN-mediated trophoblast biology. These results provide a drug mechanism for disease prevention and a target for preeclampsia intervention.

Acinetobacter baumannii is a well-known nosocomial pathogen that can survive in different environments through the use of intricate networks to regulate gene expression. Two-component systems (TCS) form an important part of such regulatory networks, and in this study, we describe the identification and characterization of a novel EmaSR TCS in A. baumannii . We constructed a Tn 5 -tagged mutagenesis library, from which an emaS sensor kinase gene and emaR response regulator gene were identified. We found that emaS / emaR single-mutants and double-mutants were unable to replicate in M9 medium with 1% ethanol as the single carbon source. Motility and biofilm formation were negatively affected in double-mutants, and transcriptomic analysis showed that mutation of emaSR dysregulated genes required for carbon metabolism. In addition, emaS / emaR single-mutants and double-mutants were unable to survive in acetic acid- and sodium acetate-containing medium, indicating that the EmaSR TCS is also important for acetate metabolism. Furthermore, virulence against Galleria mellonella was diminished in emaS / emaR single- and double-mutants. Taken together, these results show that this novel EmaSR TCS is involved in the regulation of A. baumannii ethanol metabolism and acetate metabolism, with important implications on motility, biofilm formation, and virulence if mutated. Further research on the underlying mechanisms is warranted.

Methamphetamine use disorder (MUD) is an illness associated with severe health consequences. Virtual reality (VR) is used to induce the drug-cue reactivity and significant EEG and ECG abnormalities were found in MUD patients. However, whether a link exists between EEG and ECG abnormalities in patients with MUD during exposure to drug cues remains unknown. This is important from the therapeutic viewpoint because different treatment strategies may be applied when EEG abnormalities and ECG irregularities are complications of MUD. We designed a VR system with drug cues and EEG and ECG were recorded during VR exposure. Sixteen patients with MUD and sixteen healthy subjects were recruited. Statistical tests and Pearson correlation were employed to analyze the EEG and ECG. The results showed that, during VR induction, the patients with MUD but not healthy controls showed significant [Formula: see text] and [Formula: see text] power increases when the stimulus materials were most intense. This finding indicated that the stimuli are indiscriminate to healthy controls but meaningful to patients with MUD. Five heart rate variability (HRV) indexes significantly differed between patients and controls, suggesting abnormalities in the reaction of patient's autonomic nervous system. Importantly, significant relations between EEG and HRV indexes changes were only identified in the controls, but not in MUD patients, signifying a disruption of brain-heart relations in patients. Our findings of stimulus-specific EEG changes and the impaired brain-heart relations in patients with MUD shed light on the understanding of drug-cue reactivity and may be used to design diagnostic and/or therapeutic strategies for MUD., (© 2022 The Authors.)

Background: In addition to antegrade anastomosis, retrograde anastomosis has been thought to offer further improvements after lymphaticovenous anastomosis (LVA) by bypassing the retrograde lymphatic flow. However, this concept has yet to be validated. The aim of this study was to determine the impacts on outcomes of performing both retrograde and antegrade anastomosis, as compared to antegrade-only anastomosis for treating lower limb lymphedema., Study Design: This was a retrospective cohort propensity score-matched study. Eighty-seven patients with gynecologic cancer-related lower limb lymphedema were enrolled, including 58 patients who had received both antegrade and retrograde anastomoses (Group I) and 29 patients who had received antegrade-only anastomoses (Group II) as the control group. LVA was the primary treatment. Patients who had previous LVA, liposuction, or excisional therapy were excluded. Patient characteristics, intraoperative findings, and functional parameters including the ratio of indocyanine green-enhanced and flow-positive lymphatic vessels were recorded. Magnetic resonance volumetry was used for outcome assessments. The primary endpoint was the volume change at 6 months after LVA., Results: After matching, a total of 26 patients have remained in each group. All parameters were matched except that Group I still had significantly more median LVA performed compared to Group II (8 [IQR: 5.3-10.0] vs. 5.5 [4.3-6.0], p = 0.001, respectively). Group II showed more post-LVA improvements at six-month and one-year follow-up compared to Group I but without statistically significant differences., Conclusion: The use of supplementary retrograde anastomoses is discouraged since it may lead to inferior post-LVA outcome compared to antegrade-only anastomoses., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/purpose: Clarithromycin-based standard triple therapy is still commonly adopted by 81.4% of physicians in real-world practice but yields low eradication rates. Therefore, we conducted this study to compare the efficacy of gastric juice-guided therapy for first-line eradication with the standard triple therapy, in order to provide an alternative to real-world practice., Methods: A total of 182 treatment-naïve Hp-infected patients were included and randomly allocated to either susceptibility-guided therapy (SGT) with gastric juice PCR or Clarithromycin-based standard triple therapy (STT) for 7 days., Results: The intention-to-treat eradication rates were 89% (81/91) in SGT and 75.8% in STT (p < 0.031). The per-protocol eradication rates were 91.0% (81/89) in SGT and 79.3% (69/87) in STT (p < 0.034). Among the subgroups of different antibiotic resistance, patients with SGT demonstrated superior eradication rates (91.7% vs 45.5%, p < 0.027) in the subgroup of both clarithromycin resistance and levofloxacin resistance., Conclusion: This prospective randomized controlled trial demonstrated the reliable efficacy of susceptibility-guided therapy via gastric juice PCR for the first-line Hp eradication. In Asia-Pacific area, where standard triple therapy is still adopted by the majority of the physicians, it is a recommended alternative to overcome the increasing antibiotic resistance., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2021. Published by Elsevier B.V.)

Background: Although satisfactory volume reduction in secondary unilateral lower limb lymphedema after lymphaticovenous anastomosis (LVA) in the affected limb has been well reported, alleviation of muscle edema and the impact of LVA on the contralateral limb have not been investigated., Study Design: This retrospective cohort study enrolled patients who underwent supermicrosurgical LVA between November 2015 and January 2017. Pre- and post-LVA muscle edema were assessed using fractional anisotropy (FA) and apparent diffusion coefficient (ADC). The primary endpoint was changes in limb/subfascial volume assessed with magnetic resonance volumetry at least 6 months after LVA., Results: Twenty-one patients were enrolled in this study. Significant percentage reductions in post-LVA muscle edema were found in the affected thigh (83.6% [interquartile range = range of Q1 to Q3; 29.8-137.1] [FA], 53.3% [27.0-78.4] [ADC]) as well as limb (21.7% [4.4-26.5]) and subfascial (18.7% [10.7-39.1]) volumes. Similar findings were noted in the affected lower leg: 71.8% [44.0-100.1] (FA), 59.1% [45.8-91.2] (ADC), 21.2% [6.8-38.2], and 28.2% [8.5-44.8], respectively (all p < 0.001). Significant alleviation of muscle edema was also evident in the contralateral limbs (thigh: 25.1% [20.4-57.5] [FA]; 10.7% [6.6-17.7] [ADC]; lower leg: 47.1% [35.0-62.8] [FA]; 14.6% [6.5-22.1] [ADC]; both p < 0.001), despite no statistically significant difference in limb and subfascial volumes., Conclusions: Our study found significant reductions in muscle edema and limb/subfascial volumes in the affected limb after LVA. Our findings regarding edema in the contralateral limb were consistent with possible lymphedema-associated systemic influence on the unaffected limb, which could be surgically relieved., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Surgeons.)

Tissue-resident macrophages (TRMs) are heterogeneous cell populations found throughout the body. Depending on their location, they perform diverse functions maintaining tissue homeostasis and providing immune surveillance. To survive and function within, TRMs adapt metabolically to the distinct microenvironments. However, little is known about the metabolic signatures of TRMs. The thymus provides a nurturing milieu for developing thymocytes yet efficiently removes those that fail the selection, relying on the resident thymic macrophages (TMφs). This study harnesses multiomics analyses to characterize TMφs and unveils their metabolic features. We find that the pentose phosphate pathway (PPP) is preferentially activated in TMφs, responding to the reduction-oxidation demands associated with the efferocytosis of dying thymocytes. The blockade of PPP in Mφs leads to decreased efferocytosis, which can be rescued by reactive oxygen species (ROS) scavengers. Our study reveals the key role of the PPP in TMφs and underscores the importance of metabolic adaptation in supporting Mφ efferocytosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Methamphetamine use disorder (MUD) is a brain disease that leads to altered regional neuronal activity. Virtual reality (VR) is used to induce the drug cue reactivity. Previous studies reported significant frequency-specific neuronal abnormalities in patients with MUD during VR induction of drug craving. However, whether those patients exhibit neuronal abnormalities after VR induction that could serve as the treatment target remains unclear. Here, we used an integrated VR system for inducing drug related changes and investigated the neuronal abnormalities after VR exposure in patients. Fifteen patients with MUD and ten healthy subjects were recruited and exposed to drug-related VR environments. Resting-state EEG were recorded for 5 minutes twice-before and after VR and transformed to obtain the frequency-specific data. Three self-reported scales for measurement of the anxiety levels and impulsivity of participants were obtained after VR task. Statistical tests and machine learning methods were employed to reveal the differences between patients and healthy subjects. The result showed that patients with MUD and healthy subjects significantly differed in Θ, α, and γ power changes after VR. These neuronal abnormalities in patients were associated with the self-reported behavioral scales, indicating impaired impulse control. Our findings of resting-state EEG abnormalities in patients with MUD after VR exposure have the translational value and can be used to develop the treatment strategies for methamphetamine use disorder.