Immunomodulatory Effects of Vitamin D and Zinc on Viral Infection.

Several nutrients are crucial in enhancing the immune system and preserving the structural integrity of bodily tissue barriers. Vitamin D (VD) and zinc (Zn) have received considerable interest due to their immunomodulatory properties and ability to enhance the body's immune defenses. Due to their antiviral, anti-inflammatory, antioxidative, and immunomodulatory properties, the two nutritional powerhouses VD and Zn are crucial for innate and adaptive immunity. As observed with COVID-19, deficiencies in these micronutrients impair immune responses, increasing susceptibility to viral infections and severe disease. Ensuring an adequate intake of VD and Zn emerges as a promising strategy for fortifying the immune system. Ongoing clinical trials are actively investigating their potential therapeutic advantages. Beyond the immediate context of the pandemic, these micronutrients offer valuable tools for enhancing immunity and overall well-being, especially in the face of future viral threats. This analysis emphasizes the enduring significance of VD and Zn as both treatment and preventive measures against potential viral challenges beyond the current health crisis. The overview delves into the immunomodulatory potential of VD and Zn in combating viral infections, with particular attention to their effects on animals. It provides a comprehensive summary of current research findings regarding their individual and synergistic impacts on immune function, underlining their potential in treating and preventing viral infections. Overall, this overview underscores the need for further research to understand how VD and Zn can modulate the immune response in combatting viral diseases in animals.

Quality control of postoperative radiotherapy for non-small cell lung cancer: A study of mediastinal shift.

PURPOSE: This study aimed to assess the shifting patterns of the mediastinum, including the target volume and the isocenter point during the postoperative radiotherapy (PORT) process of non-small cell lung cancer (NSCLC), and to observe the occurrence of radiation injury. Additionally, we investigated the significance of mid-term assessment during the implementation of the PORT process. MATERIAL AND METHODS: We established coordinate axes based on bone anatomy and measured the mediastinum's three-dimensional direction and the shift of the isocenter point's shift in the PORT process. Statistical analysis was performed using Wilcoxon, Kruskal-Wallis, and the Chi-square test. P<0.05 was considered statistically significant. RESULTS: In this study, the analysis of patients revealed that the shift of anterior and posterior mediastinum (X), left and right mediastinum (Y), upper and lower mediastinum (Z), anterior and posterior isocenter point (Xi), and the left and right isocenter points (Yi) in the PORT process were 0.04-0.53, 0.00-0.84, 0.00-1.27, 0.01-0.86, and 0.00-0.66cm, respectively. The shift distance of the mediastinum was Z>Y>X, and the shift distance of the isocenter point was Xi>Yi. According to the ROC curve, the cut-off values were 0.263, 0.352, 0.405, 0.238, and 0.258, respectively, which were more significant than the cut-off values in 25 cases (25%), 30 cases (30%), 30 cases (30%), 17 cases (17%), and 15 cases (15%). In addition, there was a significant difference in the shift of the mediastinum and the isocenter point (all P=0.00). Kruskal-Wallis test showed no statistically significant difference between mediastinal shift and resection site in X, Y, and Z directions (P=0.355, P=0.239, P=0.256), surgical method (P=0.241, P=0.110, P=0.064). There was no significant difference in the incidence of RE and RP in PORT patients (P>0.05). No III-IV RP occurred. However, the incidence of ≥ grade III RE in the modified plan cases after M-S was significantly lower than in the original PORT patients, 0% and 7%, respectively (P=0.000). CONCLUSION: In conclusion, this study provides evidence that mediastinal shift is a potential complication during the PORT process for patients with N2 stage or R1-2 resection following radical resection of NSCLC. This shift affects about 20-30% of patients, manifesting as actual radiation damage to normal tissue and reducing the local control rate. Therefore, mid-term repositioning of the PORT and revision of the target volume and radiation therapy plan can aid in maintaining QA and QC during the treatment of NSCLC patients and may result in improved patient outcomes.

Nuclear factor E2-associated factor 2 and musculoaponeurotic fibrosarcoma K mediate regulation glutathione peroxidase of Cristaria plicata after microcystin-induced oxidative stress.

Nuclear factor E2-associated factor 2 (Nrf2)/Antioxidant Response Element (ARE) signaling pathway is an endogenous antioxidant pathway that protects cells from oxidative damage. This pathway is triggered when aquatic organisms are exposed to environmental toxicants. In this study, CpMafK (musculoaponeurotic fibrosarcoma K of Cristaria plicata) mRNA expression in hepatopancreas and gills were up regulated after Cristaria plicata (C. plicata) was exposed to microcystin (MC), which showed that CpMafK protected C. plicata from MC. After MC treatment and CpNrf2 (Nrf2 of Cristaria plicata) knockdown, the mRNA expression of CpMafK was down regulated. After MC treatment and CpMafK knockdown, the mRNA expression of CpNrf2 was down regulated. Indicating that the expression of CpNrf2 was positively correlated with CpMafK. CpGPx (GPx of Cristaria plicata) mRNA was also down regulated with the down regulation of CpMafK and CpNrf2. CpGPx promoter contains a variety of transcription factor binding sites, including Nrf2, ARE elements, etc. Gel blocking experiments showed that CpNrf2/CpMafK heterodimers were bound to CpGPx promoters in vitro. Dual luciferase reporter assay showed that CpNrf2/CpMafK heterodimer negatively regulated CpGPx promoter in cells. In conclusion, Nrf2 and MafK mediate regulation of GPx play a crucial role in protecting bivalves from MC.

Detoxification and antioxidant functions and regulatory mechanisms of two Delta-class GSTs in paddy crayfish (Procambarus clarkii) after imidacloprid stress.

Glutathione S-transferases (GSTs) are phase II metabolic detoxification enzymes, which are widely found in organisms, and play an important role in helping organisms to resist toxic compounds. In this study, the two Delta-class GSTs cDNA sequences were cloned from Procambarus clarkii (designated as PcGSTD1 and PcGSTD2). Tissue specific expression profile showed that PcGST1,2 were expressed in all 6 tissues, with the highest expression in hepatopancreas. Subcellular localization assay showed that PcGSTD1, 2 were mainly expressed in the cytoplasm of HEK-293 T cells. Recombinant PcGSTD1, 2 showed the highest catalytic activity to the GST model substrate 1-chloro-2,4-dinitrobenzene (CDNB) at 20 and 30 °C, pH 8 and 7, respectively. The mRNA expression of PcGSTD1, 2 and the GSTs activity varied with the time of imidacloprid challenge. The BL21(DE3) expressing PcGSTD1, 2 proteins could more resistant to H2O2. The dsRNA experiments showed that PcKeap1b, PcNrf1, and PcMafK affected the transcription levels of PcGSTD1, 2. The GST-Pulldown results revealed that PcbZIP and PcMafK recombinant proteins could bind to each other in vitro. The gel mobility shift assay demonstrated that PcMafK recombinant protein had affinity with the promoter of PcGSTD2. The Dual luciferase assays analyzed the activity of the promoters after different truncations, the core region of PcGSTD1 promoter was at -440 bp to +54 bp, and that of PcGSTD2 promoter was between -1609∼-1125 bp. These results suggested that PcGSTD1, 2 respond positively to imidacloprid stress in P. clarkii, and the transcriptional expressions of PcGSTD1, 2 were influenced by the factors of PcKeap1b/PcNrf1/PcMafK.

Prx5 of Cristaria plicata has antioxidant function and is regulated by Nrf2/ARE signaling pathway.

Cristaria plicata is one of the more important freshwater pearl bivalves in China, which is susceptible to pathogen infection, and greatly impacts the ability of breeding pearls. Nrf2/ARE signaling pathway and its downstream target gene Prx5 have endogenous antioxidant functions to protect cells from oxidative damage. The full-length cDNA of Prx5 was cloned from C. Plicata, which was 1420 bp, encoding a total of 189 amino acids and had two conserved cysteine residues (Cys78 and Cys179). The amino acid sequence of CpPrx5 was highly similar to Prx5 of other species. Real-time fluorescence quantitative PCR showed that CpPrx5 was distributed in various tissues of mussels, and the highest expression was in hepatopancreas. The expression of CpPrx5 up-regulated in hepatopancreas and gills after LPS, PGN and Poly:I:C stimulation. The recombinant plasmid DE3-PGEX-4T-1-CpPrx5 was expressed in Escherichia coli BL21 and showed antioxidant activity. With the increase of CpPrx5 protein concentration, the superhelical form of DNA was protected. The expression of CpPrx5 was up-regulated after interference CpKeap1 and down-regulated after interference CpNrf2. Gel block assay showed that CpNrf2 and CpMafK proteins blocked CpPrx5 promoter. Subcellular localization showed that CpPrx5 was located in 293T nucleus and cytoplasm and CpMafK was located in 293T nucleus. GST-Pull down verified that CpMafK and CpPrx5 could bind in vitro. These results indicated that Prx5 had antioxidant function and could protects DNA from oxidative damage, and participated in transcriptional regulation by combining with the transcription factor MafK. In addition, MafK could combine with Nrf2 to regulate the downstream target gene Prx5.

Facile and Scalable Synthesis of Metal- and Nitrogen-Doped Carbon Nanotubes for Efficient Electrochemical CO2 Reduction.

Metal- and nitrogen-doped carbon (M-N-C) is a promising material to catalyze electrochemical CO2 reduction reaction (CO2RR). However, most M-N-C catalysts in the literature require complicated synthesis procedures and produce small quantities per batch, limiting the commercialization potential. In this work, we developed a simple and scalable synthesis method to convert metal-impurity-containing commercial carbon nanotubes (CNTs) and nitrogen-containing organic precursors into M-N-C via one-step moderate-temperature (650 °C) pyrolysis without any other treatment nor the need to add metal precursors. Batches of catalysts in varied mass up to 10 g (150 mL in volume) per batch were synthesized, and repeatable catalytic performances were demonstrated. To the best of our knowledge, the 10 g batch is one of the largest batches of CO2RR catalysts synthesized in the literature while requiring minimal synthesis steps. The catalyst possessed single-atomic iron-nitrogen (Fe-N) sites, enabling a high performance of >95% CO product selectivity at a high current density of 400 mA/cm2 and high stability for 45 h at 100 mA/cm2 in a flow cell testing. The catalyst outperformed a benchmark noble-metal nanoparticle catalyst and achieved longer stability than many other reported M-N-C catalysts in the literature. The scalable and cost-effective synthesis developed in this work paves a pathway toward practical CO2RR applications. The direct utilization of metal impurities from raw CNTs for efficient catalyst synthesis with minimal treatment is a green and sustainable engineering approach.

MafG-like contribute to copper and cadmium induced antioxidant response by regulating antioxidant enzyme in Procambarus clarkii.

Avian musculoaponeurotic fibrosarcoma (Maf) proteins play an important role in Nrf2/Keap1 signaling pathway, which mainly resist the oxidant stress. The members of sMaf have a high homology basic leucine zipper (bZIP) and lack trans activation domain, and could interact with other transcriptional regulatory factors as a molecular chaperone. In this study, a full-length MafG-like gene was cloned from Procambarus Clarkii, designated as PcMafG-like, which consisted of an ORF length of 246 bp encoding 82 amino acids, a 5' untranslated region (UTR) of 483 bp, and a 3' UTR of 111 bp. The domain of PcMafG-like had a bZIP-Maf domain that binds to DNA. The cDNA sequence of PcMafG-like was 99 % similar to that of Penaeus vannamei. The mRNA of PcMafG-like was expressed in all tested tissues, and the highest expression was in muscle tissue. Under stimulation of Cu2+ and Cd2+, PcMafG-like was significantly up-regulated in hepatopancreas and gill, and the same result was testified by situ hybridization. The representative antioxidant genes, CAT, GPx and CZ-SOD, were significantly induced by Cu2+; CAT and GPx was induced by Cd2+. PcMafG-dsRNA significantly inhibited the expression of these up-regulated genes, but also inhibited the expression of other detected genes CZ-SOD, GST-θ and GST-1like. The antioxidant effect of PcMafG-like was further verified by oxidative stress markers (T-SOD, CuZnSOD, GPx, CAT, GSH and MDA) kits. Cu2+ and Cd2+ could induce the contents of these oxidative stress markers (MDA, GSH, CZ-SOD, CAT in Cu2+/Cd2+ treated group, and GSH-Px in Cd2+ group), while interference of PcMafG-like significantly inhibited the up-regulation. Furthermore, hematoxylin-eosin staining experiments showed that the degree of pathological damage was dose-dependent and time-dependent, and the pathological damage was more serious after dsRNA interfered with PcMafG-like. In addition, subcellular localization showed that PcMafG-like gene existed in nucleus. The recombinant protein PcMafG-like was expressed and purified in prokaryotic expression. The affinity analysis of promoter by agarose gel electrophoresis suggested that PcMafG-like could bind with CAT promoter in vitro. This indicated that PcMafG-like could activate antioxidant genes.

Giant cervical goiter in Hashimoto's thyroiditis: A case report.

A giant cervical goiter, defined as a thyroid mass larger than 8 cm in diameter, is usually a nodular or adenomatous goiter. A giant cervical goiter can also be caused by hyperthyroidism (i.e., Hashimoto's thyroiditis). The surgical indications for patients with Hashimoto's disease include suspected malignant tumors, persistent symptoms related to the disease, or persistent enlargement of the goiter. We herein describe a woman who developed symptoms of compression from a thyroid tumor, the volume of which was almost the largest reported in the relevant literature to date. The bilateral lobes of the giant thyroid tumor were removed by total en bloc excision. We protected the bilateral recurrent laryngeal nerve and preserved the bilateral upper and lower parathyroid glands in situ. The excised left lobe tumor was 16 × 9 × 5.5 cm, whereas the right lobe tumor was 12 × 8 × 4 cm. The pathological diagnosis was Hashimoto's thyroiditis. Although surgical excision is difficult, it is still the main treatment modality for giant goiters in patients with Hashimoto's thyroiditis and can help to reduce the occurrence of complications.

MAPK/MAK/MRK overlapping kinase mediated apoptosis through caspase signaling pathway from Cristaria plicata.

MAPK/MAK/MRK Overlapping Kinase (MOK) belongs to MAP kinase superfamily, which plays an important role in regulating cell growth, division, and differentiation. Caspase-3, as the final executor of apoptosis, has an important position in the caspase-mediated apoptotic signaling pathway. The full-length cDNA of MOK and caspase-3 were cloned from Cristaria plicata (designated CpMOK and CpCaspase-3). The CpMOK gene was sequence with a full-length of 1413 bp, encoding a total of 470 amino acids, and containing an S_TKc structural domain. CpCaspase-3 has a sequence of 2425 bp, encoding 322 amino acids, containing a CASc domain. Real-time fluorescence quantitative PCR analysis showed that CpMOK and CpCaspase-3 distributed in various tissues of C. plicata, and the highest expression of CpMOK and CpCaspase-3 mRNA was in hepatopancreas. The expression of CpMOK was significantly changed in hepatopancreas, gills, and kidneys by the construction of wound model as well as stimulation of LPS, PGN, Poly I: C and Aeromonas hydrophila. Subcellular localization experiments confirmed that CpMOK was localized in the nucleus. Furthermore, the double-stranded RNA (dsRNA) of CpMOK was constructed for interference experiment, and the results showed that the mRNA expression of apoptotic gene signals caspase-1, caspase-3, caspase-7, caspase-8, and caspase-9 were increased. The expression of caspase-1, -3, -7, -9, cytochrome C (Cyt-c) and tumor necrosis factor-α (TNF-α) was detected by ELISA. Fluorescent staining of apoptotic cells using the Tunnel method revealed an increase in the number of apoptotic cells after interference. These results suggested that CpMOK knockdown could induce caspase-mediated apoptosis in C. plicata, and the phosphorylation of the kinase was disrupted during the process.

PLHPP2 inhibits the stemness of colorectal cancer by inactivating the Nrf2 signaling pathway.

Pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase 2 (PHLPP2) is a critical regulator of cellular homeostasis and acts as a tumor suppressor in multiple human cancers. However, its exact biological function in colorectal cancer (CRC) and the underlying molecular mechanism remain poorly understood. The correlation between the transcription and protein abundance of PHLPP2 was analyzed using proteomic and corresponding transcriptional data. Immunohistochemistry was used to validate the protein expression and the role of PHLPP2 in patient prognosis. In addition, a series of experiments in vitro and in vivo were performed to investigate the underlying molecular mechanism. Immunohistochemical staining of a CRC tissue microarray revealed that PHLPP2 protein expression was significantly downregulated compared to that in adjacent normal tissues. Low expression of PHLPP2 was an independent prognostic risk factor for poor survival. A nomogram established by integrating PHLPP2 expression and traditional clinicopathological factors achieved more reliable prognostic assessment in CRC patients. Additionally, PHLPP2 overexpression suppressed CRC cell migration, invasion and stemness in vitro as well as tumorigenesis in vivo. Further experiments revealed that upregulation of PHLPP2 increased ROS levels by suppressing the Nrf2-ARE signaling pathway, which inhibited the stemness of CRC cells. Moreover, incubation with sulforaphane, a selective chemical agonist of Nrf2, reversed this inhibitory effect in CRC. PHLPP2 acts as a tumor suppressor gene in CRC by restraining the Nrf2-ARE signaling pathway and increasing ROS levels, affecting the stemness of CRC cells. These anticancer molecular mechanisms indicate PHLLPP2's significant clinical value in prognosis prediction and targeted therapy.

Does serum progesterone level impact the ongoing pregnancy rate in frozen embryo transfer under artificial preparation with vaginal progesterone? Study protocol for a randomized controlled trial.

BACKGROUND: In previous retrospective studies, low serum progesterone level on the embryo transfer day is associated with lower clinical pregnancy and ongoing pregnancy rates. Whether adding progesterone in low serum progesterone patients can rescue the outcome, there is no sufficient evidence from randomized controlled studies. METHODS: This trial is a clinical randomized controlled study (high serum progesterone vs low serum progesterone 1:1, 1:1 randomization ratio of intervention vs the control group with low serum progesterone). The eligible hormone replacement therapy-frozen embryo transfer (HRT-FET) cycles, will be recruited and randomly assigned to two parallel groups when serum progesterone is < 7.24µg/l on the day of embryo transfer for D3. The intervention group will be extrally given intramuscular progesterone 40 mg per day from D3 to 8 weeks of gestation if clinical pregnancy. The primary outcome is the ongoing pregnancy (beyond 12 weeks of gestation) rate. DISCUSSION: The findings of this study will provide strong evidence for whether the progesterone addition from the D3 in low serum progesterone patients can improve the outcome in the HRT-FET cycle. TRIAL REGISTRATION: ClinicalTrials.gov NCT04248309 . Registered on January 28, 2020.

Construction of wound repair model and function of recombinant TIMP from Hyriopsis cumingii.

Metalloproteinase tissue inhibitors (TIMPs) have the activity of inhibiting matrix metalloproteinases (MMPs), which can promote cell growth, bind to the matrix, inhibit angiogenesis, and play a key role in extracellular matrix (ECM) metabolism regulation. In this study, TIMP-1, 2 from Hyriopsis cumingii (designated as HcTIMP-1, 2) were cloned and identified. Full-length cDNA of HcTIMP-1, 2 was 1160 bp and 729 bp, encoding 235 and 150 amino acid residues, respectively. The predicted molecular weight of HcTIMP-1 and 2 protein was 27.26 and 16.58 kDa, with isoelectric points of 8.89 and 8.72, respectively. HcTIMP-2 contained only one netrin (NTR) domain at the N-terminal but lacked a C-terminal domain. The mRNA of HcTIMP-1, 2 was expressed in hepatopancreas, gills, muscles, hemocytes, and mantles, which had the highest expression in hemocytes and muscles. The expression of HcTIMP-1, 2 had increased remarkably in hemocytes after bacterial challenge. After trauma, HcTIMP-1, 2 genes had the highest expression level in the first day. This indicated that HcTIMP-1 and 2 were involved in the immune response of H. cumingii. The soluble recombinant proteins HcTIMP-1, 2 were expressed efficiently in Escherichia coli BL21 (DE3) by constructing pET32a-TIMP1, 2 recombinant plasmids. The concentration of the recombinant was 0.14 and 0.31 mg/mL, respectively. The recombinant HcTIMP-1, 2 proteins were shown to inhibit human MMP2 activity and promoted the growth of NBL-7 and HUVE cells.

Treated with interferon and the gene polymorphism of CGRP and its receptor.

OBJECTIVE: This case-control study aims to investigate the relationship of polymorphisms of four gene loci (CGRP rs155209 and rs3781719, RAMP1 rs3754701 and rs7590387) with the prognosis of interferon therapy for chronic hepatitis B (CHB). MATERIALS AND METHODS: A total of 317 CHB patients receiving interferon alone for the first time were recruited in northern China, and peripheral blood samples were obtained. The single-nucleotide polymorphisms (SNPs) in rs155209, rs3781719, rs3754701, and rs7590387 were genotyped using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS). Univariate and multivariate logistic regression methods were employed to assess the correlation between CHB prognosis treated with interferon and polymorphisms of these gene loci. RESULTS: The study clearly demonstrated the relevance of polymorphisms of rs155209, rs3781719, rs3754701, and rs7590387 with DNA response and ALT response after interferon treatment. CHB patients with CGRP rs155209C had a lower risk of developing DNA response (CT vs. TT: OR = 0.159, 95% CI = 0.086-0.294, Padj < 0.001; CC vs. TT: OR = 0.131, 95% CI = 0.059-0.288, Padj < 0.001), as well as a lower risk of developing ALT response (CT vs. TT: OR = 0.530, 95% CI = 0.323-0.869, Padj < 0.05). Moreover, CHB patients with RAMP1 rs3754701T allele were more prone to develop DNA response (AT vs. AA: OR = 2.061, 95% CI = 1.237-3.435, Padj < 0.05; TT vs. AA: OR = 5.676, 95% CI =1.247-25.837, Padj < 0.05), and they also more likely to develop ALT response (AT vs. AA: OR = 1.766, 95% CI = 1.098-2.840, Padj < 0.05). We did not find a significant association between CGRP rs3781719 or RAMP1 rs7590387 and DNA response or ALT response. CONCLUSION: This study revealed that CGRP rs155209 and RAMP1 rs3754701 polymorphisms, but not CGRP rs3781719 and RAMP1 rs7590387, were correlated with interferon therapy prognosis for CHB in Han Chinese population, and RAMP1 rs3754701T was a protective factor for ALT response and DNA response, but CGRP rs155209C carriers were less prone to DNA and ALT responses.

Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition should be a key strategy for treatment, especially considering the recent development of specific KRAS inhibitors. Nevertheless, the effects of KRAS inhibition can be increased through the co-inhibition of other nodes important for cancer development. One of them could be the hexosamine biosynthetic pathway (HBP), whose enhancement is considered fundamental for PDAC. Here, we demonstrate that PDAC cells expressing oncogenic KRAS, owing to an increase in the HBP flux, become strongly reliant on HBP for both proliferation and survival. In particular, upon treatment with two different compounds, 2-deoxyglucose and FR054, inhibiting both HBP and protein N-glycosylation, these cells undergo apoptosis significantly more than PDAC cells expressing wild-type KRAS. Importantly, we also show that the combined treatment between FR054 and the pan-RAS inhibitor BI-2852 has an additive negative effect on cell proliferation and survival by means of the suppression of both Akt activity and cyclin D1 expression. Thus, co-inhibition of HBP and oncogenic RAS may represent a novel therapy for PDAC patients.

Coronavirus disease 2019 in pregnancy.

OBJECTIVES: This study aimed to compare clinical courses and outcomes between pregnant and reproductive-aged non-pregnant women with COVID-19, and to assess the vertical transmission potential of COVID-19 in pregnancy. METHODS: Medical records of pregnant and reproductive-aged non-pregnant women hospitalized with COVID-19 from January 15 to March 15, 2020 were retrospectively reviewed. The severity of disease, virus clearance time, and length of hospital stay were measured as the primary objective, while the vertical transmission potential of COVID-19 was also assessed. RESULTS: Eighty-two patients (28 pregnant women, 54 reproductive-aged non-pregnant women) with laboratory-confirmed COVID-19 were enrolled in this study. Univariate regression indicated no association between pregnancy and severity of disease (OR 0.73, 95% CI 0.08-5.15; p=0.76), virus clearance time (HR 1.16, 95% CI 0.65-2.01; p=0.62), and length of hospital stay (HR 1.10, 95% CI 0.66-1.84; p=0.71). Of the pregnant women, 22 delivered 23 live births, either by cesarean section (17, 60.7%) or vaginal delivery (5, 17.9%), and no neonate was infected with SARS-CoV-2. CONCLUSIONS: Pregnant women have comparable clinical courses and outcomes with reproductive-aged non-pregnant women when infected with SARS-CoV-2. No evidence supported vertical transmission of COVID-19 in the late stage of pregnancy, including vaginal delivery.

Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation.

Different evidence has indicated metabolic rewiring as a necessity for pancreatic cancer (PC) growth, invasion, and chemotherapy resistance. A relevant role has been assigned to glucose metabolism. In particular, an enhanced flux through the Hexosamine Biosynthetic Pathway (HBP) has been tightly linked to PC development. Here, we show that enhancement of the HBP, through the upregulation of the enzyme Phosphoacetylglucosamine Mutase 3 (PGM3), is associated with the onset of gemcitabine (GEM) resistance in PC. Indeed, mRNA profiles of GEM sensitive and resistant patient-derived tumor xenografts (PDXs) indicate that PGM3 expression is specifically increased in GEM-resistant PDXs. Of note, PGM3 results also overexpressed in human PC tissues as compared to paired adjacent normal tissues and its higher expression in PC patients is associated with worse median overall survival (OS). Strikingly, genetic or pharmacological PGM3 inhibition reduces PC cell growth, migration, invasion, in vivo tumor growth and enhances GEM sensitivity. Thus, combined treatment between a specific inhibitor of PGM3, named FR054, and GEM results in a potent reduction of xenograft tumor growth without any obvious side effects in normal tissues. Mechanistically, PGM3 inhibition, reducing protein glycosylation, causes a sustained Unfolded Protein Response (UPR), a significant attenuation of the pro-tumorigenic Epidermal Growth Factor Receptor (EGFR)-Akt axis, and finally cell death. In conclusion this study identifies the HBP as a metabolic pathway involved in GEM resistance and provides a strong rationale for a PC therapy addressing the combined treatment with the PGM3 inhibitor and GEM.

Atomically Dispersed Iron-Nitrogen Sites on Hierarchically Mesoporous Carbon Nanotube and Graphene Nanoribbon Networks for CO2 Reduction.

Atomically dispersed metal and nitrogen co-doped carbon (M-N/C) catalysts hold great promise for electrochemical CO2 conversion. However, there is a lack of cost-effective synthesis approaches to meet the goal of economic mass production of single-atom M-N/C with desirable carbon support architecture for efficient CO2 reduction. Herein, we report facile transformation of commercial carbon nanotube (CNT) into isolated Fe-N4 sites anchored on carbon nanotube and graphene nanoribbon (GNR) networks (Fe-N/CNT@GNR). The oxidization-induced partial unzipping of CNT results in the generation of GNR nanolayers attached to the remaining fibrous CNT frameworks, which reticulates a hierarchically mesoporous complex and thus enables a high electrochemical active surface area and smooth mass transport. The Fe residues originating from CNT growth seeds serve as Fe sources to form isolated Fe-N4 moieties located at the CNT and GNR basal plane and edges with high intrinsic capability of activating CO2 and suppressing hydrogen evolution. The Fe-N/CNT@GNR delivers a stable CO Faradaic efficiency of 96% with a partial current density of 22.6 mA cm-2 at a low overpotential of 650 mV, making it one of the most active M-N/C catalysts reported. This work presents an effective strategy to fabricate advanced atomistic catalysts and highlights the key roles of support architecture in single-atom electrocatalysis.

The emerging role of circulating tumor cells in cancer management.

Circulating tumor cells (CTCs) are cells that are shed from the primary tumor and circulate in the blood, and their metastasis and formation of a secondary tumor are closely associated with cancer-related death. Therefore, regulating tumor metastasis through CTCs can be a novel strategy to fight cancer. It has been demonstrated that CTCs can reflect the profile of the primary tumor and provide valuable information about intratumoral heterogeneity and their evolution over time. Moreover, the revelation of the relationship between metastasis and CTCs suggests that CTC regulation represents a promising novel anticancer strategy. Above all, at the molecular level, genetic analysis might be vital in the new era of gene-targeted cancer therapies and contribute to personalized anti-metastasis tumor treatments. In this review, we will focus on the biological significance of CTCs in the peripheral blood and discuss their potential clinical implications in cancer management.

Systematic Review and Meta-Analysis of Genetic Risk of Developing Chronic Postsurgical Pain.

Chronic postsurgical pain (CPSP) is a significant detriment to postsurgical recovery and a risk factor for prolonged opioid use. Emerging evidence suggests the estimated heritability for chronic pain is 45% and that genetic factors partially explain individual susceptibility to CPSP. The aim of this study was to systematically review, assess quality, and summarize the studies in humans that have investigated genetic factors associated with CPSP. We also conducted a meta-analysis to derive a single effect size for evaluable genetic associations with CPSP. Our comprehensive literature search included review of 21 full-text articles evaluating variants of 69 genes for association with CPSP. We found significant gene variant associations reported for variants/haplotypes of 26 genes involved in neurotransmission, pain signaling, immune responses and neuroactive ligand-receptor interaction, with CPSP. Six variants of 5 genes (COMT: rs4680 and rs6269, OPRM1: rs1799971, GCH1: rs3783641, KCNS1: rs734784 and TNFA: rs1800629), were evaluated by more than one study and were included in the meta-analysis. At rs734784 (A>G) of KCNS1, presence of G allele marginally increased risk of CPSP (Additive genetic model; Odds ratio: 1.511; 95% CI 1-2.284; P value: .050), while the other variants did not withstand meta-analyses criteria. Our findings demonstrate the role of genetic factors with different functions in CPSP, and also emphasize that single genetic factors have small effect sizes in explaining complex conditions like CPSP. Heterogeneity in surgical cohorts, population structure, and outcome definitions, as well as small number of available studies evaluating same variants, limit the meta-analysis. There is a need for large-scale, homogenous, replication studies to validate candidate genes, and understand the underlying biological networks underpinning CPSP. PERSPECTIVE: Our systematic review comprehensively describes 21 studies evaluating genetic association with CPSP, and limitations thereof. A meta-analysis of 6 variants (5 genes) found marginally increased risk for CPSP associated with rs734784 A>G of the potassium voltage-gated channel gene (KCNS1). Understanding genetic predisposition for CPSP will enable prediction and personalized management.

A hybrid fault diagnosis methodology with support vector machine and improved particle swarm optimization for nuclear power plants.

The safety and public health during nuclear power plant operation can be enhanced by accurately recognizing and diagnosing potential problems when a malfunction occurs. However, there are still obvious technological gaps in fault diagnosis applications, mainly because adopting a single fault diagnosis method may reduce fault diagnosis accuracy. In addition, some of the proposed solutions rely heavily on fault examples, which cannot fully cover future possible fault modes in nuclear plant operation. This paper presents the results of a research in hybrid fault diagnosis techniques that utilizes support vector machine (SVM) and improved particle swarm optimization (PSO) to perform further diagnosis on the basis of qualitative reasoning by knowledge-based preliminary diagnosis and sample data provided by an on-line simulation model. Further, SVM has relatively good classification ability with small samples compared to other machine learning methodologies. However, there are some challenges in the selection of hyper-parameters in SVM that warrants the adoption of intelligent optimization algorithms. Hence, the major contribution of this paper is to propose a hybrid fault diagnosis method with a comprehensive and reasonable design. Also, improved PSO combined with a variety of search strategies are achieved and compared with other current optimization algorithms. Simulation tests are used to verify the accuracy and interpretability of research findings presented in this paper, which would be beneficial for intelligent execution of nuclear power plant operation.