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Cephalopod molluscs exhibit sophisticated colour changes that allow them to camouflage themselves in a dynamic environment, and to communicate with conspecifics, prey or predators. The present study reports the description of previously undescribed three chromatic body components that were observed by coincidence during prey attack by young cuttlefish. These three components are formed by several units in the form of dark spots located inside the white square on the mantle (L1), between the eyes along the white head bar (L2) and on the arms (L3). They were called the "Leopard spots." They appeared very transiently during the attack of a shrimp, alone or in group, and their expression was variable within and between individuals. We hypothesise that the Leopard spots play a role in reducing the risk of cuttlefish predation during the shrimp attack, but it is not known whether this is a form of camouflage or a warning signal to predators., (Copyright © 2025. Published by Elsevier B.V.)

The COVID-19 pandemic has required an expeditious advancement of innovative antiviral drugs. In this study, focused compound libraries are synthesized in 96- well plates utilizing modular click chemistry to rapidly discover potent inhibitors targeting the main protease (M pro ) of SARS-CoV-2. Subsequent direct biological screening identifies novel 1,2,3-triazole derivatives as robust M pro inhibitors with high anti-SARS-CoV-2 activity. Notably, C5N17B demonstrates sub-micromolar M pro inhibitory potency (IC 50 = 0.12 µM) and excellent antiviral activity in Calu-3 cells determined in an immunofluorescence-based antiviral assay (EC 50 = 0.078 µM, no cytotoxicity: CC 50 > 100 µM). C5N17B shows superior potency to nirmatrelvir (EC 50 = 1.95 µM) and similar efficacy to ensitrelvir (EC 50 = 0.11 µM). Importantly, this compound displays high antiviral activities against several SARS-CoV-2 variants (Gamma, Delta, and Omicron, EC 50 = 0.13 - 0.26 µM) and HCoV-OC43, indicating its broad-spectrum antiviral activity. It is worthy that C5N17B retains antiviral activity against nirmatrelvir-resistant strains with T21I/E166V and L50F/E166V mutations in M pro (EC 50 = 0.26 and 0.15 µM, respectively). Furthermore, C5N17B displays favorable pharmacokinetic properties. Crystallography studies reveal a unique, non-covalent multi-site binding mode. In conclusion, these findings substantiate the potential of C5N17B as an up-and-coming drug candidate targeting SARS-CoV-2 M pro for clinical therapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Recent advancements have elucidated the multifaceted roles of the Schlafen (SLFN) family, including SLFN5, SLFN11, SLFN12, SLFN13, and SLFN14, which are implicated in immunological responses. However, little is known about the roles of this gene family in relation to malignancy development. The current study aimed to explore the diagnostic and prognostic potential of Schlafen family genes in colorectal adenocarcinoma (COAD) through bioinformatics analysis. Leveraging advanced bioinformatics tools of bulk RNA-sequencing and single-cell sequencing, we conducted in-depth analyses of gene expressions, functional enrichment, and survival patterns of patients with colorectal cancer compared to normal tissue. Among Schlafen family genes, the transcription levels of SLFN5 in COAD tissues were significantly elevated and correlated with poor survival outcomes. Furthermore, SLFN5 regulated the immune response via Janus kinase (JAK)/signal transduction and activator of transcription (STAT)/interferon (IFN)-alpha/beta signaling. These chemokines in inflammation are associated with diabetes and metabolism, suggesting their involvement in altered cellular energetics for COAD progress. In addition, an immune cell deconvolution analysis indicated a correlation between SLFN5 expression and immune-related cell populations, such as regulatory T cells (Tregs). These findings highlighted the potential clinical significance of SLFN5 in COAD and provided insights into its involvement in the tumor microenvironment and immune regulation. Meanwhile, the drug discovery data of SFLN5 with potential targeted small molecules suggested its therapeutic potential for COAD. Collectively, the current research demonstrated that SFLN5 play crucial roles in tumor development and serve as a prospective biomarker for COAD., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The blood supply in the retina ensures photoreceptor function and maintains regular vision. Leber's hereditary optic neuropathy (LHON), caused by the mitochondrial DNA mutations that deteriorate complex I activity, is characterized by progressive vision loss. Although some reports indicated retinal vasculature abnormalities as one of the comorbidities in LHON, the paracrine influence of LHON-affected retinal ganglion cells (RGCs) on vascular endothelial cell physiology remains unclear. To address this, we established an in vitro model of mitochondrial complex I deficiency using induced pluripotent stem cell-derived RGCs (iPSC-RGCs) treated with a mitochondrial complex I inhibitor rotenone (Rot) to recapitulate LHON pathologies. The secretomes from Rot-treated iPSC-RGCs (Rot-iPSC-RGCs) were collected, and their treatment effect on human umbilical vein endothelial cells (HUVECs) was studied. Rot induced LHON-like characteristics in iPSC-RGCs, including decreased mitochondrial complex I activity and membrane potential, and increased mitochondrial reactive oxygen species (ROS) and apoptosis, leading to mitochondrial dysfunction. When HUVECs were exposed to conditioned media (CM) from Rot-iPSC-RGCs, the angiogenesis of HUVECs was suppressed compared to those treated with CM from control iPSC-RGCs (Ctrl-iPSC-RGCs). Angiogenesis-related proteins were altered in the secretomes from Rot-iPSC-RGC-derived CM, particularly angiopoietin, MMP-9, uPA, collagen XVIII, and VEGF were reduced. Notably, GeneMANIA analysis indicated that VEGFA emerged as the pivotal angiogenesis-related protein among the identified proteins secreted by health iPSC-RGCs but reduced in the secretomes from Rot-iPSC-RGCs. Quantitative real-time PCR and western blots confirmed the reduction of VEGFA at both transcription and translation levels, respectively. Our study reveals that Rot-iPSC-RGCs establish a microenvironment to diminish the angiogenic potential of vascular cells nearby, shedding light on the paracrine regulation of LHON-affected RGCs on retinal vasculature., 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 Masson SAS.. All rights reserved.)

WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms 1-5 . Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214. This compound selectively engages a cysteine (C727) located in a region of the helicase domain subject to interdomain movement during DNA unwinding. VVD-133214 binds WRN protein cooperatively with nucleotide and stabilizes compact conformations lacking the dynamic flexibility necessary for proper helicase function, resulting in widespread double-stranded DNA breaks, nuclear swelling and cell death in MSI-high (MSI-H), but not in microsatellite-stable, cells. The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Porcine circovirus type 2 (PCV2) infection is ubiquitous around the world. Diagnosis of the porcine circovirus-associated disease requires clinic-pathological elements together with the quantification of viral loads. Furthermore, given pig farms in regions lacking access to sufficient laboratory equipment, developing diagnostic devices with high accuracy, accessibility, and affordability is a necessity., Objectives: This study aims to investigate two newly developed diagnostic tools that may satisfy these criteria., Methods: We collected 250 specimens, including 170 PCV2-positive and 80 PCV2-negative samples. The standard diagnosis and cycle threshold (Ct) values were determined by quantitative polymerase chain reaction (qPCR). Then, two point-of-care (POC) diagnostic platforms, convective polymerase chain reaction (cPCR, qualitative assay: positive or negative results are shown) and EZtargex (quantitative assay: Ct values are shown), were examined and analyzed., Results: The sensitivity and specificity of cPCR were 88.23% and 100%, respectively; the sensitivity and specificity of EZtargex were 87.65% and 100%, respectively. These assays also showed excellent concordance compared with the qPCR assay (κ = 0.828 for cPCR and κ = 0.820 for EZtargex). The statistical analysis showed a great diagnostic power of the EZtargex assay to discriminate between samples with different levels of positivity., Conclusions: The two point-of-care diagnostic platforms are accurate, rapid, convenient and require little training for PCV2 diagnosis. These POC platforms can discriminate viral loads to predict the clinical status of the animals. The current study provided evidence that these diagnostics were applicable with high sensitivity and specificity in the diagnosis of PCV2 infection in the field., Competing Interests: Schweitzer Biotech Company (SBC) Ltd. is the sponsor of the project. Hsieh WJ, Lin CC, and Ting JM. are employees of the SBC. However, the authors declare that the research was conducted with integrity, following all ethical guidelines. All other authors declare no competing interests., (© 2024 The Korean Society of Veterinary Science.)

Previous studies have demonstrated that the size of the prey relative to the cuttlefish is important to the choice between tentacular strike and jump-on tactics. In the present study, we investigated the decision-making in the cuttlefish's tactical switch when preying on the same size prey. A servomotor system controlling the movement of a shrimp was used to elicit the cuttlefish's preying behavior. The success rate of prey capture and the kinematics of visual attack were examined systematically. The results showed that the jump-on behavior appeared mostly after a miss attack by previous tentacular strike on a moving shrimp. Compared with a visual attack with tentacles, the jump-on tactic has over a shorter attacking distance and wider attacking angles. Thus, these two different preying tactics have different operating ranges relative to the prey. More importantly, the cuttlefish can adjust their preying tactics adaptively depending on their prior preying experience., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Non-valvular atrial fibrillation (NVAF) is a common form of cardiac arrhythmia that affects 1-1.5% of adults and roughly 10% of elderly adults with dysphagia. Apixaban is an anticoagulant referred to as a factor Xa inhibitor, which has been shown to reduce the risk of stroke and systemic embolism in cases of NVAF. Our objective in the current study was to formulate an orally disintegrating film to facilitate the administration of apixaban to elderly patients who have difficulty swallowing. Researchers have used a wide variety of cellulose-based or non-cellulose-based polymers in a variety of combinations to achieve specific characteristics related to film formation, disintegration performance, drug content, in vitro drug release, and stability. One of the two formulations in this study was specify that bioequivalence criteria met with respect to Cmax of the reference drug (ELIQUIS®) in terms of pharmacokinetic profile. Further research will be required to assess the applicability of orodispersible films created using colloidal polymers of high and low molecular weights to other drugs with poor solubility in water., Competing Interests: Ta-Chien Lu and Catherine Lee filed patent application for the discovery of pharmaceutical composition and use of Apixaban film products for the treatment and prevention of thrombosis and related disorders on 03 June 2022 (20220387415 A1). The authors declare that they have no competing financial interests or personal relationships that may appear to influence the work reported in this paper., (© 2023 The Authors.)

Aim: This paper explored the differences in perspectives on the core competencies of nurse preceptors among postgraduate-year nurses, clinical nursing preceptors and head nurses., Design: Cross-sectional design with nominal group technique (NGT)., Method: The sample consisted of 32 postgraduate-year nurses, 42 preceptors and 27 head nurses. Two rounds of NGT were used to collect the group opinions., Results: While the rank/level of importance varied, three groups all agreed that teaching traits, clinical nursing profession, communication and collaboration, teaching pedagogy, reaction of contingency and consultation of academic writing were important core competencies for nurse preceptors. The three groups disagreed on critical thinking and reflection, as well as lifelong learning. This study clarifies cognitive differences and expectations among three groups and can assist medical institutes in designing preceptor training courses., (© 2022 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

The complexity of lung adenocarcinoma (LUAD) including many interacting biological processes makes it difficult to find therapeutic biomarkers for treatment. Previous studies demonstrated that PSMG (proteasome assembly chaperone) family members regulate the degradation of abnormal proteins. However, transcript expressions of this gene family in LUAD still need to be more fully investigated. Therefore, we used a holistic bioinformatics approach to explore PSMG genes involved in LUAD patients by integrating several high-throughput databases and tools including The Cancer Genome Atlas (TCGA), and Kaplan-Meier plotter database. These data demonstrated that PSMG3 and PSMG4 were expressed at significantly higher levels in neoplastic cells than in normal lung tissues. Notably, increased expressions of these proteins were correlated with poor prognoses of lung cancer patients, which probably confirmed their fundamental roles in the staging of LUAD tumors. Meanwhile, it was also indicated that there were positive correlations between PSMG family genes and the immune response, metabolism of ubiquinone, cell cycle regulatory pathways, and heat shock protein 90 (HSP90)/phosphatidylinositol 3-kinase (PI3K)/Wnt signaling. Experimental data also confirmed that the knockdown of PSMG4 in LUAD cell lines decreased cell proliferation and influenced expressions of downstream molecules. Collectively, this study revealed that PSMG family members are novel prognostic biomarkers for LUAD progression, which also provide new therapeutic targets of LUAD patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Although adjuvant tamoxifen therapy is beneficial to estrogen receptor-positive (ER + ) breast cancer patients, a significant number of patients still develop metastasis or undergo recurrence. Therefore, identifying novel diagnostic and prognostic biomarkers for these patients is urgently needed. Predictive markers and therapeutic strategies for tamoxifen-resistant ER + breast cancer are not clear, and micro (mi)RNAs have recently become a focal research point in cancer studies owing to their regulation of gene expressions, metabolism, and many other physiological processes. Therefore, systematic investigation is required to understand the modulation of gene expression in tamoxifen-resistant patients. High-throughput technology uses a holistic approach to observe differences among expression profiles of thousands of genes, which provides a comprehensive level to extensively investigate functional genomics and biological processes. Through a bioinformatics analysis, we revealed that glutamine synthetase/glutamate-ammonia ligase ( GLUL ) might play essential roles in the recurrence of tamoxifen-resistant ER + patients. GLUL increases intracellular glutamine usage via glutaminolysis, and further active metabolism-related downstream molecules in cancer cell. However, how GLUL regulates the tumor microenvironment for tamoxifen-resistant ER + breast cancer remains unexplored. Analysis of MetaCore pathway database demonstrated that GLUL is involved in the cell cycle, immune response, interleukin (IL)-4-induced regulators of cell growth, differentiation, and metabolism-related pathways. Experimental data also confirmed that the knockdown of GLUL in breast cancer cell lines decreased cell proliferation and influenced expressions of specific downstream molecules. Through a Connectivity Map (CMap) analysis, we revealed that certain drugs/molecules, including omeprazole, methacholine chloride, ioversol, fulvestrant, difenidol, cycloserine, and MK-801, may serve as potential treatments for tamoxifen-resistant breast cancer patients. These drugs may be tested in combination with current therapies in tamoxifen-resistant breast cancer patients. Collectively, our study demonstrated the crucial roles of GLUL , which provide new targets for the treatment of tamoxifen-resistant breast cancer patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Breast cancer is one of the leading deaths in all kinds of malignancies; therefore, it is important for early detection. At the primary tumor site, tumor cells could take on mesenchymal properties, termed the epithelial-to-mesenchymal transition (EMT). This process is partly regulated by members of the cadherin ( CDH ) family of genes, and it is an essential step in the formation of metastases. There has been a lot of study of the roles of some of the CDH family genes in cancer; however, a holistic approach examining the roles of distinct CDH family genes in the development of breast cancer remains largely unexplored. In the present study, we used a bioinformatics approach to examine expression profiles of CDH family genes using the Oncomine, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), cBioPortal, MetaCore, and Tumor IMmune Estimation Resource (TIMER) platforms. We revealed that CDH1/2/4/11/12/13 messenger (m)RNA levels are overexpressed in breast cancer cells compared to normal cells and were correlated with poor prognoses in breast cancer patients' distant metastasis-free survival. An enrichment analysis showed that high expressions of CDH1/2/4/11/12/13 were significantly correlated with cell adhesion, the extracellular matrix remodeling process, the EMT, WNT/beta-catenin, and interleukin-mediated immune responses. Collectively, CDH1/2/4/11/12/13 are thought to be potential biomarkers for breast cancer progression and metastasis.

Nociception is the neural process of encoding noxious stimuli and is typically accompanied by a reflex withdrawal response away from the potentially injurious stimulus. Studies on nociception in cephalopods have so far focused on octopus and squid, with no investigations to our knowledge on cuttlefish. Yet, these are an important species both in scientific and commercial use. Therefore, the present study demonstrated that a standard pain stimulus, acetic acid, induced grooming behaviour directed towards the injection site in cuttlefish and that the injection of lidocaine reduces grooming behaviours in acetic-acid-injected cuttlefish. Wound-directed behaviour demonstrates that the animal is aware of the damage; thus, when subjecting these animals to any painful treatments in the laboratory, researchers should consider alleviating pain by the administration of pain-relieving drugs.

Quantum two-level systems (TLSs) intrinsic to glasses induce decoherence in many modern quantum devices, such as superconducting qubits. Although the low-temperature physics of these TLSs is usually well-explained by a phenomenological standard tunneling model of independent TLSs, the nature of these TLSs, as well as their behavior out of equilibrium and at high energies above 1 K, remain inconclusive. Here we measure the non-equilibrium dielectric loss of TLSs in amorphous silicon using a superconducting resonator, where energies of TLSs are varied in time using a swept electric field. Our results show the existence of two distinct ensembles of TLSs, interacting weakly and strongly with phonons, where the latter also possesses anomalously large electric dipole moment. These results may shed new light on the low temperature characteristics of amorphous solids, and hold implications to experiments and applications in quantum devices using time-varying electric fields., (© 2022. The Author(s).)

Monkeypox virus (MPV) is a smallpox-like virus belonging to the genus Orthopoxvirus of the family Poxviridae. Unlike smallpox with no animal reservoir identified and patients suffering from milder symptoms with less mortality, several animals were confirmed to serve as natural hosts of MPV. The reemergence of a recently reported monkeypox epidemic outbreak in nonendemic countries has raised concerns about a global outburst. Since the underlying mechanism of animal-to-human transmission remains largely unknown, comprehensive analyses to discover principal differences in gene signatures during disease progression have become ever more critical. In this study, two MPV-infected in vitro models, including human immortal epithelial cancer (HeLa) cells and rhesus monkey ( Macaca mulatta ) kidney epithelial (MK2) cells, were chosen as the two subjects to identify alterations in gene expression profiles, together with co-regulated genes and pathways that are affected during monkeypox disease progression. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and MetaCore analyses, we discovered that elevated expression of genes associated with interleukins (ILs), G protein-coupled receptors (GPCRs), heat shock proteins (HSPs), Toll-like receptors (TLRs), and metabolic-related pathways play major roles in disease progression of both monkeypox-infected monkey MK2 and human HeLa cell lines. Interestingly, our analytical results also revealed that a cluster of differentiation 40 (CD40), plasmin, and histamine served as major regulators in the monkeypox-infected monkey MK2 cell line model, while interferons (IFNs), macrophages, and neutrophil-related signaling pathways dominated the monkeypox-infected human HeLa cell line model. Among immune pathways of interest, apart from traditional monkeypox-regulated signaling pathways such as nuclear factor- (NF- κ B), mitogen-activated protein kinases (MAPKs), and tumor necrosis factors (TNFs), we also identified highly significantly expressed genes in both monkey and human models that played pivotal roles during the progression of monkeypox infection, including CXCL1 , TNFAIP3 , BIRC3 , IL6 , CCL2 , ZC3H12A , IL11 , CSF2 , LIF , PTX3 , IER3 , EGR1 , ADORA2A , and DUOX1 , together with several epigenetic regulators, such as histone cluster family gene members, HIST1H3D , HIST1H2BJ , etc. These findings might contribute to specific underlying mechanisms related to the pathophysiology and provide suggestions regarding modes of transmission, post-infectious sequelae, and vaccine development for monkeypox in the future., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Do Thi Minh Xuan et al.)

Internationally, the impact of venous leg ulcers (VLUs) on the quality of life is well recognised; however, in Taiwan, the focus is only on chronic wound management. This cross-sectional correlational study conducted at the cardiovascular and plastic surgery clinics of a regional teaching hospital between August 2019 and June 2020 investigates venous clinical severity, pain, fatigue, depression, sleep quality, quality of life, and related factors among 167 patients with VLUs. The potential predictors of the quality of life in terms of activities were venous clinical severity (P < 0.001), pain (P = 0.004), and fatigue (P < 0.001) after adjusting for covariates. The potential predictors of the quality of life in terms of the psychological domain were marital status (single/divorced) (P = 0.016), marital status (widowed) (P = 0.027), venous clinical severity (P < 0.001), pain (P = 0.001), and fatigue (P = 0.002). The potential predictors of the quality of life with regard to symptoms were venous clinical severity (P < 0.001), pain (P < 0.001), fatigue (P = 0.001), and depression (P = 0.038). These potential predictors can serve as the basis of interventions for patients with VLUs, such as those related to nutrition or training in wound dressing., (© 2021 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival characterized by various genetic changes. The continuous activation of oncogenic pathways leads to the development of drug resistance and limits current therapeutic efficacy. Therefore, a multi-targeting inhibitor may overcome drug resistance observed in AML treatment. Recently, groups of flavonoids, such as flavones and flavonols, have been shown to inhibit a variety of kinase activities, which provides potential opportunities for further anticancer applications., Purpose: In this study, we evaluated the anticancer effects of flavonoid compounds collected from our in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells., Methods: The cytotoxic effect of the compounds was detected by cell viability assays. The kinase inhibitory activity of the selected compound was detected by kinase-based and cell-based assays. The binding conformation and interactions were investigated by molecular docking analysis. Flow cytometry was used to evaluate the cell cycle distribution and cell apoptosis. The protein and gene expression were estimated by western blotting and qPCR, respectively., Results: In this study, an O-methylated flavonol (compound 11) was found to possess remarkable cytotoxic activity against AML cells compared to treatment in other cancer cell lines. The compound was demonstrated to act against multiple kinases, which play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 with IC 50 values of 1 - 2 μM. Compared to our previous flavonoid compounds, which only showed inhibitions against MNKs or FLT3, compound 11 exhibited multiple kinase inhibitory abilities. Moreover, compound 11 showed effectiveness in inhibiting internal tandem duplications of FLT3 (FLT3-ITDs), which accounts for 25% of AML cases. The interactions between compound 11 and targeted kinases were investigated by molecular docking analysis. Mechanically, compound 11 caused dose-dependent accumulation of leukemic cells at the G 0 /G 1 phase and followed by the cells undergoing apoptosis., Conclusion: O-methylated flavonol, compound 11, can target multiple kinases, which may provide potential opportunities for the development of novel therapeutics for drug-resistant AMLs. This work provides a good starting point for further compound optimization., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The propagation of the hepatitis C virus (HCV) is regulated in part by the phosphorylation of its nonstructural protein NS5A that undergoes sequential phosphorylation on several highly conserved serine residues and switches from a hypo- to a hyperphosphorylated state. Previous studies have shown that NS5A sequential phosphorylation requires NS3 encoded on the same NS3-NS4A-NS4B-NS5A polyprotein. Subtle mutations in NS3 without affecting its protease activity could affect NS5A phosphorylation. Given the ATPase domain in the NS3 COOH terminus, we tested whether NS3 participates in NS5A phosphorylation similarly to the nucleoside diphosphate kinase-like activity of the rotavirus NSP2 nucleoside triphosphatase (NTPase). Mutations in the NS3 ATP-binding motifs blunted NS5A hyperphosphorylation and phosphorylation at serines 225, 232, and 235, whereas a mutation in the RNA-binding domain did not. The phosphorylation events were not rescued with wild-type NS3 provided in trans . When provided with an NS3 ATPase-compatible ATP analog, N 6 -benzyl-ATP-γ-S, thiophosphorylated NS5A was detected in the cells expressing the wild-type NS3-NS5B polyprotein. The thiophosphorylation level was lower in the cells expressing NS3-NS5B with a mutation in the NS3 ATP-binding domain. In vitro assays with a synthetic peptide and purified wild-type NS3 followed by dot blotting and mass spectrometry found weak NS5A phosphorylation at serines 222 and 225 that was sensitive to an inhibitor of casein kinase Iα but not helicase. When casein kinase Iα was included in the assay, much stronger phosphorylation was observed at serines 225, 232, and 235. We concluded that NS5A sequential phosphorylation requires the ATP-binding domain of the NS3 helicase and that casein kinase Iα is a potent NS5A kinase. IMPORTANCE For more than 20 years, NS3 was known to participate in NS5A sequential phosphorylation. In the present study, we show for the first time that the ATP-binding domain of NS3 is involved in NS5A phosphorylation. In vitro assays showed that casein kinase Iα is a very potent kinase responsible for NS5A phosphorylation at serines 225, 232, and 235. Our data suggest that ATP binding by NS3 probably results in conformational changes that recruit casein kinase Iα to phosphorylate NS5A, initially at S225 and subsequently at S232 and S235. Our discovery reveals intricate requirements of the structural integrity of NS3 for NS5A hyperphosphorylation and HCV replication.

Despite numerous studies demonstrating the cognitive ability of cephalopods, there is currently no study showing an emotion-like behavior in this group of animals. To examine whether cuttlefish have different internal states, we developed a behavioral paradigm to assess if prior surprised events are able to alter the choice made by cuttlefish. By presenting unexpected food rewards to cuttlefish before the test, we investigated whether the reaction time of choosing between two shrimps, an intuitive response toward the prey without previous learning, at three different levels of discriminative tests (easy, difficult, and ambiguous), are different compared to the one without an unexpected reward. This behavioral paradigm serves to demonstrate whether cuttlefish are aware of ambiguous situations, and their choice outcome and reaction time are dependent of their internal states. The results show that the response latency was significantly shortened in the difficult and ambiguous tests when choosing from two shrimps that are either moderately different in size or similar sizes, respectively, when cuttlefish have received unexpected rewards before the test. These results were compared with tests during which the cuttlefish did not receive any reward in advance. Furthermore, this shortening of latency did not result in a difference in choice outcome during the difficult and ambiguous tests. Interestingly, even when cuttlefish have obtained the expected food rewards or simply made tentacular strike without prey capture each time before test, these prior experiences were sufficient to shorten the response latency in the difficult and ambiguous tests. However, different from the result of unexpected rewards, food consumption alone or prey capture failure did affect the choice outcome during the simple and difficult tests. Taken together, our findings suggest that pre-test treatments of unexpected and expected rewards or simply unsuccessful visual attack seem to induce cuttlefish to adopt different foraging behaviors. This context dependent decision making suggests that cuttlefish's foraging strategies are influenced by the previously surprised event and their internal states. It also shows a speed-accuracy tradeoff in difficult and ambiguous situations when foraging for prey. This observation may lead to a future investigation of the presence of emotional state in cephalopods., (© 2022. The Author(s).)

Objective: To design and verify a CMOS 256-pixel photovoltaic-powered subretinal prosthetic chip with key advances over the state-of-the-art. The three key advances are: 1) automatic adaptation to changing background illuminance levels; 2) increase of injection charges with reduced crosstalk leakage charges, enhanced charge balance, and low process variations; 3) stable stimulation voltage to keep the safety of water window., Methods: The novel auto-adaptive pixel circuit is designed to realize the Michealis - Menten equation (MME) so that the automatic adaptation to changing background illuminance can be achieved. Both improved biphasic constant current stimulator (CCS) via bi-directional shared electrodes (BDSEs) with optimized stimulation pattern and improved constant current generator/ring oscillator are designed to achieve the above second advance on injection charges. The closed-loop charge pump is designed to achieve the third advance., Results: The measured dynamic range of image illuminance is increased to 54.7 dB. The maximum stimulation charge is 8.89nC. The measured stimulation current mismatch is 1.7% and the measured residual charge is 0.150 nC. The measured variations of stimulation frequencies are from 26 Hz to 29.7 Hz. The results of ex vivo tests have shown that the proposed subretinal chip can evoke spiking responses of RGCs. The function of adaptation process to background illuminance has also been verified., Conclusion and Significance: Through both electrical measurement and ex vivo tests, the functions of designed subretinal chip have been validated successfully. It is shown that the proposed subretinal chip is a promising solution for subretinal prostheses.

The complexity of breast cancer includes many interacting biological processes that make it difficult to find appropriate therapeutic treatments. Therefore, identifying potential diagnostic and prognostic biomarkers is urgently needed. Previous studies demonstrated that 26S proteasome delta subunit, non-ATPase (PSMD) family members significantly contribute to the degradation of damaged, misfolded, abnormal, and foreign proteins. However, transcriptional expressions of PSMD family genes in breast cancer still remain largely unexplored. Consequently, we used a holistic bioinformatics approach to explore PSMD genes involved in breast cancer patients by integrating several high-throughput databases, including The Cancer Genome Atlas (TCGA), cBioPortal, Oncomine, and Kaplan-Meier plotter. These data demonstrated that PSMD1, PSMD2, PSMD3, PSMD7, PSMD10, PSMD12, and PSMD14 were expressed at significantly higher levels in breast cancer tissue compared to normal tissues. Notably, the increased expressions of PSMD family genes were correlated with poor prognoses of breast cancer patients, which suggests their roles in tumorigenesis. Meanwhile, network and pathway analyses also indicated that PSMD family genes were positively correlated with ubiquinone metabolism, immune system, and cell-cycle regulatory pathways. Collectively, this study revealed that PSMD family members are potential prognostic biomarkers for breast cancer progression and possible promising clinical therapeutic targets.

The complexity of breast cancer includes many interacting biological processes, and proteasome alpha (PSMA) subunits are reported to be involved in many cancerous diseases, although the transcriptomic expression of this gene family in breast cancer still needs to be more thoroughly investigated. Consequently, we used a holistic bioinformatics approach to study the PSMA genes involved in breast cancer by integrating several well-established high-throughput databases and tools, such as cBioPortal, Oncomine, and the Kaplan-Meier plotter. Additionally, correlations of breast cancer patient survival and PSMA messenger RNA expressions were also studied. The results demonstrated that breast cancer tissues had higher expression levels of PSMA genes compared to normal breast tissues. Furthermore, PSMA2 , PSMA3 , PSMA4 , PSMA6 , and PSMA7 showed high expression levels, which were correlated with poor survival of breast cancer patients. In contrast, PSMA5 and PSMA8 had high expression levels, which were associated with good prognoses. We also found that PSMA family genes were positively correlated with the cell cycle, ubiquinone metabolism, oxidative stress, and immune response signaling, including antigen presentation by major histocompatibility class, interferon-gamma, and the cluster of differentiation signaling. Collectively, these findings suggest that PSMA genes have the potential to serve as novel biomarkers and therapeutic targets for breast cancer. Nevertheless, the bioinformatic results from the present study would be strengthened with experimental validation in the future by prospective studies on the underlying biological mechanisms of PSMA genes and breast cancer.

To evaluate the potential benefit of HyperArc (HA) fractionated stereotactic radiotherapy (FSRT) for the benign brain lesion. Sixteen patients with a single deep-seated, centrally located benign brain lesion treated by CyberKnife (CK, G4 cone-based model) were enrolled. Treatment plans for HA with two different optimization algorithms (SRS NTO and ALDO) and coplanar RapidArc (RA) were generated for each patient to meet the corresponding treatment plan criteria. These four FSRT treatment plans were divided into two groups-the homogeneous delivery group (HA-SRS NTO and coplanar RA) and the inhomogeneous delivery group (HA-ALDO and cone-based CK)-to compare for dosimetric outcomes. For homogeneous delivery, the brain V5, V12, and V24 and the mean brainstem dose were significantly lower with the HA-SRS NTO plans than with the coplanar RA plans. The conformity index, high and intermediate dose spillage, and gradient radius were significantly better with the HA-SRS NTO plans than with the coplanar RA plans. For inhomogeneous delivery, the HA-ALDO exhibited superior PTV coverage levels to the cone-based CK plans. Almost all the doses delivered to organs at risk and dose distribution metrics were significantly better with the HA-ALDO plans than with the cone-based CK plans. Good dosimetric distribution makes HA an attractive FSRT technique for the treatment of benign brain lesions., (© 2021. The Author(s).)

Brugada electrocardiogram (ECG) pattern describes a characteristic right bundle branch block (RBBB) appearance with persistent ST-segment elevation in precordial leads V1 to V3, often associated with Brugada syndrome, a genetic sodium channelopathy, in the absence of ischemic or structural heart disease. Known triggers such as fever, electrolyte abnormalities, medications, or recreational drugs may elicit such an ECG pattern without a clear clinical significance yet creating a dilemma for clinicians providing care in the urgent setting. We present a case of reversible Brugada electrocardiogram pattern (BEP) after recreational use of delta-8-tetrahydrocannabinol (THC) and explore the need for further research on the safety of such an over-the-counter supplement., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Jo et al.)

Background: Pathogenic coronaviruses include Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2. These viruses have induced outbreaks worldwide, and there are currently no effective medications against them. Therefore, there is an urgent need to develop potential drugs against coronaviruses., Methods: High-throughput technology is widely used to explore differences in messenger (m)RNA and micro (mi)RNA expression profiles, especially to investigate protein-protein interactions and search for new therapeutic compounds. We integrated miRNA and mRNA expression profiles in MERS-CoV-infected cells and compared them to mock-infected controls from public databases., Results: Through the bioinformatics analysis, there were 251 upregulated genes and eight highly differentiated miRNAs that overlapped in the two datasets. External validation verified that these genes had high expression in MERS-CoV-infected cells, including RC3H1, NF-κB, CD69, TNFAIP3, LEAP-2, DUSP10, CREB5, CXCL2, etc. We revealed that immune, olfactory or sensory system-related, and signal-transduction networks were discovered from upregulated mRNAs in MERS-CoV-infected cells. In total, 115 genes were predicted to be related to miRNAs, with the intersection of upregulated mRNAs and miRNA-targeting prediction genes such as TCF4, NR3C1, and POU2F2. Through the Connectivity Map (CMap) platform, we suggested potential compounds to use against MERS-CoV infection, including diethylcarbamazine, harpagoside, bumetanide, enalapril, and valproic acid., Conclusions: The present study illustrates the crucial roles of miRNA-mRNA interacting networks in MERS-CoV-infected cells. The genes we identified are potential targets for treating MERS-CoV infection; however, these could possibly be extended to other coronavirus infections., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Background: Research has shown that nursing interventions are able to affect short-term outcomes in patients with injury. However, evidence based on a comprehensive nurse-led intervention may be beneficial for trauma care., Purpose: This study was designed to assess the effect of a nursing intervention on the illness perceptions and quality of life of patients with injury., Methods: A two-group experimental design and a follow-up period of 12 months were used. Ninety-four patients were randomly assigned to either the experimental group or the control group. A nurse-led cognitive behavioral therapy intervention was used to improve outcomes., Results: The illness perception variables of "personal control" and "treatment control" were found to be significantly improved in the experimental group at 3 months after discharge, whereas "emotional perception" was significantly improved at 6 months after discharge. The intervention was also shown to improve "social quality of life" at 6 and 12 months after injury., Conclusions: This study adds new knowledge related to nursing interventions for patients with injury in terms of the intervention achieving longer-term effects than the interventions examined in previous studies. The results highlight the importance of providing interprofessional collaborative care. However, the intervention protocol should be tested further in future studies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc.)

Breast cancer (BRCA) is one of the most complex diseases and involves several biological processes. Members of the L-antigen (LAGE) family participate in the development of various cancers, but their expressions and prognostic values in breast cancer remain to be clarified. High-throughput methods for exploring disease progression mechanisms might play a pivotal role in the improvement of novel therapeutics. Therefore, gene expression profiles and clinical data of LAGE family members were acquired from the cBioportal database, followed by verification using the Oncomine and The Cancer Genome Atlas (TCGA) databases. In addition, the Kaplan-Meier method was applied to explore correlations between expressions of LAGE family members and prognoses of breast cancer patients. MetaCore, GlueGo, and GluePedia were used to comprehensively study the transcript expression signatures of LAGEs and their co-expressed genes together with LAGE-related signal transduction pathways in BRCA. The result indicated that higher LAGE3 messenger (m)RNA expressions were observed in BRCA tissues than in normal tissues, and they were also associated with the stage of BRCA patients. Kaplan-Meier plots showed that overexpression of LAGE1, LAGE2A, LAGE2B, and LAGE3 were highly correlated to poor survival in most types of breast cancer. Significant associations of LAGE family genes were correlated with the cell cycle, focal adhesion, and extracellular matrix (ECM) receptor interactions as indicated by functional enrichment analyses. Collectively, LAGE family members' gene expression levels were related to adverse clinicopathological factors and prognoses of BRCA patients; therefore, LAGEs have the potential to serve as prognosticators of BRCA patients.

Background: The availability of a reliable tumor target for advanced colorectal cancer (CRC) therapeutic approaches is critical since current treatments are limited. Epidermal growth factor-like domain 6 (EGFL6) has been reported to be associated with cancer development. Here, we focused on the role of EGFL6 in CRC progression and its clinical relevance. In addition, an anti-EGFL6 antibody was generated by phage display technology to investigate its potential therapeutic efficacy in CRC., Results: EGFL6 expression significantly increased in the colon tissues from CRC patients and mice showing spontaneous tumorigenesis, but not in normal tissue. Under hypoxic condition, EGFL6 expression was enhanced at both protein and transcript levels. Moreover, EGFL6 could promote cancer cell migration invasion, and proliferation of CRC cells via up-regulation of the ERK/ AKT pathway. EGFL6 also regulated cell migration, invasion, proliferation, and self-renewal through EGFR/αvβ3 integrin receptors. Treatment with the anti-EGFL6 antibody EGFL6-E5-IgG showed tumor-inhibition and anti-metastasis abilities in the xenograft and syngeneic mouse models, respectively. Moreover, EGFL6-E5-IgG treatment had no adverse effect on angiogenesis and wound healing CONCLUSIONS: We demonstrated that EGFL6 plays a role in CRC tumorigenesis and tumor progression, indicating that EGFL6 is a potential therapeutic target worth further investigation.

Abstract: Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 induces severe infection, and it is responsible for a worldwide disease outbreak starting in late 2019. Currently, there are no effective medications against coronavirus. In the present study, we utilized a holistic bioinformatics approach to study gene signatures of SARS-CoV- and SARS-CoV-2-infected Calu-3 lung adenocarcinoma cells. Through the Gene Ontology platform, we determined that several cytokine genes were up-regulated after SARS-CoV-2 infection, including TNF, IL6, CSF2, IFNL1, IL-17C, CXCL10, and CXCL11. Differentially regulated pathways were detected by the Kyoto Encyclopedia of Genes and Genomes, gene ontology, and Hallmark platform, including chemokines, cytokines, cytokine receptors, cytokine metabolism, inflammation, immune responses, and cellular responses to the virus. A Venn diagram was utilized to illustrate common overlapping genes from SARS-CoV- and SARS-CoV-2-infected datasets. An Ingenuity pathway analysis discovered an enrichment of tumor necrosis factor- (TNF-) and interleukin (IL)-17-related signaling in a gene set enrichment analysis. Downstream networks were predicted by the Database for Annotation, Visualization, and Integrated Discovery platform also revealed that TNF and TNF receptor 2 signaling elicited leukocyte recruitment, activation, and survival of host cells after coronavirus infection. Our discovery provides essential evidence for transcript regulation and downstream signaling of SARS-CoV and SARS-CoV-2 infection., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Decision-making, when humans and other animals choose between two options, is not always based on the absolute values of the options but can also depend on their relative values. The present study examines whether decision-making by cuttlefish is dependent on relative values learned from previous experience. Cuttlefish preferred a larger quantity when making a choice between one or two shrimps (1 versus 2) during a two-alternative forced choice. However, after cuttlefish were primed under conditions where they were given a small reward for choosing one shrimp in a no shrimp versus one shrimp test (0 versus 1) six times in a row, they chose one shrimp significantly more frequently in the 1 versus 2 test. This reversed preference for a smaller quantity was not due to satiation at the time of decision-making, as cuttlefish fed a small shrimp six times without any choice test prior to the experiment still preferred two shrimps significantly more often in a subsequent 1 versus 2 test. This suggests that the preference of one shrimp in the quantity comparison test occurs via a process of learned valuation. Foraging preference in cuttlefish thus depends on the relative value of previous prey choices., Competing Interests: We have no competing interests to declare., (© 2020 The Authors.)

Background: Barriers related to comprehensive posttrauma care and health outcome monitoring exist. The insights and perspectives of health professionals on this issue may help integrate care experiences to provide continuous care to patients with traumatic injury., Purpose: The purpose of this study was to explore the perspectives of health professionals with regard to comprehensive care to improve the outcomes of patients with traumatic injury., Methods: Data were collected at two teaching hospitals in Taiwan. In total, 28 health professionals across various disciplines were interviewed in five focus groups., Results: Six themes were delineated, including "wound care is a primary concern for patients," "ineffective health education during the hospital stay," "patients and families worry about postinjury conditions," "current continuity of care is not effective," "lack of standards for discharge planning," and "incorporation of interdisciplinary care to improve patient outcomes.", Conclusions: The experiences of health professionals are useful to the establishment of a foundation for trauma case management and interdisciplinary care for hospitals.

Introduction: Breast cancer is a common malignancy worldwide. Smartphones have gradually become indispensable to our modern lives and have already changed lifestyles of human beings. To our best knowledge, no study has investigated the relationship between smartphone use and breast cancer. This case-control study purposely investigated the relationship between smartphone use and breast cancer risk., Materials and Methods: This was a case-control study comprising 894 healthy controls and 211 patients with breast cancer. All participants were asked to respond to standard questionnaires to collect information on sleep quality, smartphone addiction, and smartphone use., Results: Participants with smartphone addiction had a significantly higher 1.43-fold risk of breast cancer. Individuals with the habitual behavior of smartphone use >4.5 minutes before bedtime had a significantly increased 5.27-fold risk of breast cancer compared to those who used a smartphone for ≤4.5 minutes before bedtime. Additionally, a closer distance between the smartphone and the breasts when using the smartphone exhibited a significantly increased 1.59-fold risk. Participants who carried their smartphone near their chest or waist-abdomen area had significantly increased 5.03-fold and 4.06-fold risks of breast cancer, respectively, compared to those who carried the smartphone below the waist. Moreover, there was a synergistic effect of smartphone addiction and smartphone use of >4.5 minutes before bedtime which increased the breast cancer risk., Conclusion: Excessive smartphone use significantly increased the risk of breast cancer, particularly for participants with smartphone addiction, a close distance between the breasts and smartphone, and the habit of smartphone use before bedtime., Competing Interests: The authors report no conflicts of interest with regard to this work., (© 2020 Shih et al.)

Replication of the genotype 2 hepatitis C virus (HCV) requires hyperphosphorylation of the nonstructural protein NS5A. It has been known that NS5A hyperphosphorylation results from the phosphorylation of a cluster of highly conserved serine residues (S2201, S2208, S2211, and S2214) in a sequential manner. It has also been known that NS5A hyperphosphorylation requires an NS3 protease encoded on one single NS3-5A polyprotein. It was unknown whether NS3 protease participates in this sequential phosphorylation process. Using an inventory of antibodies specific to S2201, S2208, S2211, and S2214 phosphorylation, we found that protease-dead S1169A mutation abrogated NS5A hyperphosphorylation and phosphorylation at all serine residues measured, consistent with the role of NS3 in NS5A sequential phosphorylation. These effects were not rescued by a wild-type NS3 protease provided in trans by another molecule. Mutations (T1661R, T1661Y, or T1661D) that prohibited proper cleavage at the NS3-4A junction also abolished NS5A hyperphosphorylation and phosphorylation at all serine residues, whereas mutations at the other cleavage sites, NS4A-4B (C1715S) or NS4B-5A (C1976F), did not. In fact, any combinatory mutations that prohibited NS3-4A cleavage (T1661Y/C1715S or T1661Y/C1976F) abrogated NS5A hyperphosphorylation and phosphorylation at all serine residues. In the C1715S/C1976F double mutant, which resulted in an NS4A-NS4B-NS5A fusion polyprotein, a hyperphosphorylated band was observed and was phosphorylated at all serine residues. We conclude that NS3-mediated autocleavage at the NS3-4A junction is critical to NS5A hyperphosphorylation at S2201, S2208, S2211, and S2214 and that NS5A hyperphosphorylation could occur in an NS4A-NS4B-NS5A polyprotein. IMPORTANCE For ca. 20 years, the HCV protease NS3 has been implicated in NS5A hyperphosphorylation. We now show that it is the NS3-mediated cis cleavage at the NS3-4A junction that permits NS5A phosphorylation at serines 2201, 2208, 2211, and 2214, leading to hyperphosphorylation, which is a necessary condition for genotype 2 HCV replication. We further show that NS5A may already be phosphorylated at these serine residues right after NS3-4A cleavage and before NS5A is released from the NS4A-5A polyprotein. Our data suggest that the dual-functional NS3, a protease and an ATP-binding RNA helicase, could have a direct or indirect role in NS5A hyperphosphorylation., (Copyright © 2020 American Society for Microbiology.)

Targeted antibodies and methoxy-PEGylated nanocarriers have gradually become a mainstream of cancer therapy. To increase the anti-cancer effects of targeted antibodies combined with mPEGylated liposomes (mPEG-liposomes), we describe a bispecific antibody in which an anti-methoxy-polyethylene glycol scFv (αmPEG scFv) was fused to the C-terminus of an anti-HER2 (αHER2) antibody to generate a HER2 × mPEG BsAb that retained the original efficacy of a targeted antibody while actively attracting mPEG-liposomes to accumulate at tumor sites. HER2 ×mPEG BsAb can simultaneously bind to HER2-high expressing MCF7/HER2 tumor cells and mPEG molecules on mPEG-liposomal doxorubicin (Lipo-Dox). Pre-incubation of HER2 × mPEG BsAb with cells increased the endocytosis of Lipo-DiD and enhanced the cytotoxicity of Lipo-Dox to MCF7/HER2 tumor cells. Furthermore, pre-treatment of HER2 × mPEG BsAb enhanced the tumor accumulation and retention of Lipo-DiR 2.2-fold in HER2-high expressing MCF7/HER2 tumors as compared to HER2-low expressing MCF7/neo1 tumors. Importantly, HER2 × mPEG BsAb plus Lipo-Dox significantly suppressed tumor growth as compared to control BsAb plus Lipo-Dox in MCF7/HER2 tumor-bearing mice. These results indicate that HER2 × mPEG BsAb can enhance tumor accumulation of mPEG-liposomes to improve the therapeutic efficacy of combination treatment. Anti-mPEG scFv can be fused to any kind of targeted antibody to generate BsAbs to actively attract mPEG-drugs and improve anti-cancer efficacy. STATEMENT OF SIGNIFICANCE: Antibody targeted therapy and PEGylated drugs have gradually become the mainstream of cancer therapy. To enhance the anti-cancer effects of targeted antibodies combined with PEGylated drugs is very important. To this aim, we fused an anti-PEG scFv to the C-terminal of HER2 targeted antibodies to generate a HER2×mPEG bispecific antibody (BsAb) to retain the original efficacy of targeted antibody whilst actively attract mPEG-liposomal drugs to accumulate at tumor sites. The present study demonstrates pre-treatment of HER2×mPEG BsAb can enhance tumor accumulation of mPEG-liposomal drugs to improve the therapeutic efficacy of combination treatment. Anti-mPEG scFv can be fused to any kind of targeted antibody to generate BsAbs to actively attract mPEG-drugs and improve anti-cancer efficacy., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest or personal 764 relationships that could have appeared to influence the work re- 765 ported in this paper., (Copyright © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: To evaluate dosimetric differences of salvage irradiations using two commercially available volumetric modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) techniques: RapidArc (RA) and HyperArc (HA), for recurrent nasopharyngeal carcinoma (NPC) after initial radiation therapy., Methods: Ten patients with recurrent NPC status previously treated with radiation therapy were considered suitable candidates for salvage SBRT using VMAT approach. Two separate treatment plans were created with HA and RA techniques for each case, with dosimetric outcomes compared with respect to tumor target coverage and organs-at-risk (OARs) sparing. Furthermore, the cumulative radiobiological effects to the relevant OARs from the original radiotherapy to the respective salvage SBRT plans were analyzed in terms of biologically effective dose (BED)., Results: Treatment with HA exhibited similar target dose coverage as with RA, while delivering a higher mean dose to the targets. Using RA technique, the mean maximal doses to optic apparatus and the mean brain dose were reduced by 1 to 1.5 Gy, comparing to HA technique. The conformity index, gradient radius, and intermediate dose spillage in HA plans were significantly better than those in RA. With HA technique, the volume of brain receiving 12 Gy or more was reduced by 44%, comparing to RA technique. The cumulative BEDs to spinal cord and optic apparatus with RA technique were 1 to 2 Gy 3 less than those with HA. HA technique significantly reduced the volume within body that received more than 100 Gy., Conclusions: With better dose distribution than RA while maintaining sufficient target dose coverage, HA represents an attractive salvage SBRT technique for recurrent NPC.

The cluster of differentiation 34 (CD34) family, which includes CD34, podocalyxin-like protein 1 (PODXL), and PODXL2, are type-I transmembrane sialomucins and markers of hematopoietic stem cells (HSCs) and vascular-associated tissues. CD34 family proteins are expressed by endothelial cells and hematopoietic precursors. PODXL is well known to be associated with invadopodia formation and to promote the epithelial-mesenchymal transition, tumor migration and invasion. PODXL expression was correlated with poor survival of cancer patients. However, the role of PODXL2 in cancer has been less fully explored. To reveal the novel role of PODXL2 in breast cancer, the present study evaluated PODXL2 levels in relation to clinical outcomes of cancer patients by performing a bioinformatics analysis using the Oncomine database, Kaplan-Meier plots, and the CCLE database. Empirical validation of bioinformatics predictions was conducted utilizing the short hairpin (sh)-RNA silencing method for PODXL2 in the BT474 invasive ductal breast carcinoma cell line. The bioinformatics analysis revealed that PODXL2 overexpression was correlated with poor survival of breast cancer patients, suggesting an oncogenic role of PODXL2 in breast carcinoma. In a validation experiment, knockdown of PODXL2 in BT474 cells slightly influenced cell proliferation, suppressed migration, and inhibited expressions of downstream molecules, including Ras-related C3 botulinum toxin substrate 1 (Rac1), phosphorylated (p)-Akt (S473), and p-paxillin (Y31) proteins. In addition, knockdown of PODXL2 reduced expression levels of cancer stem cell (CSC) markers, including Oct-4 and Nanog, and the breast CSC marker aldehyde dehydrogenase 1 (ALDH1). Collectively, our present study demonstrated that PODXL2 plays a crucial role in cancer development and could serve as a potential prognostic biomarker in breast cancer patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Visual attack for prey capture in cuttlefish involves three well characterized sequential stages: attention, positioning, and seizure. This visually guided behavior requires accurate sensorimotor integration of information on the target's direction and tentacular strike control. While the behavior of cuttlefish visual attack on a stationary prey has been described qualitatively, the kinematics of visual attack on a moving target has not been analyzed quantitatively. A servomotor system controlling the movement of a shrimp prey and a high resolution imaging system recording the behavior of the cuttlefish predator, together with the newly developed DeepLabCut image processing system, were used to examine the tactics used by cuttlefish during a visual attack on moving prey. The results showed that cuttlefish visually tracked a moving prey target using mainly body movement, and that they maintained a similar speed to that of the moving prey right before making their tentacular strike. When cuttlefish shot out their tentacles for prey capture, they were able to either predict the target location based on the prey's speed and compensate for the inherent sensorimotor delay or adjust the trajectory of their tentacular strike according to the prey's direction of movement in order to account for any changes in prey position. These observations suggest that cuttlefish use the various visual tactics available to them flexibly in order to capture moving prey, and that they are able to extract direction and speed information from moving prey in order to allow an accurate visual attack., (Copyright © 2020 Wu, Hung, Lin and Chiao.)

Objectives: Venous diseases in the lower extremities long lacked an objective diagnostic tool prior to the advent of the triggered angiography non-contrast-enhanced (TRANCE) technique., Methods: An observational study with retrospective data analysis., Materials: Between April 2017 and June 2019, 66 patients were evaluated for venous diseases through TRANCE-magnetic resonance imaging (MRI) and were grouped according to whether they had occlusive venous (OV) disease, a static venous ulcer (SU), or symptomatic varicose veins (VV). The clinical appliance of TRANCE-MRI was analysed by groups., Results: In total, 63 patients completed the study. TRANCE-MRI could identify venous thrombosis, including that of the abdominal and pelvic vessels, and it enabled the timely treatment of underlying diseases in patients with OV disease. TRANCE-MRI was statistically compared with the duplex scan, the gold standard to exclude deep vein thrombosis (DVT) in the legs, with regard to their abilities to detect venous thrombosis by using Cohen's kappa coefficient at a compatible value of 0.711. It could provide the occlusion degree of the peripheral artery for treating an SU. Finally, TRANCE-MRI can be used to outline all collateral veins and occult thrombi before treating symptomatic or recurrent VV to ensure a perfect surgical plan and to avoid complications., Conclusions: TRANCE-MRI is an innovative tool in the treatment of versatile venous pathology in the lower extremities and is widely used for vascular diseases in our institution.

Although a previous study suggested that erythropoietin-producing hepatoma (EPH) receptors play important roles in tumor progression and the overexpression of EPHs in cancer patients is related to poor prognoses, high-throughput gene expression profiling of EPH family members in different types and subtypes of cancers has so far not been conducted. We herein carried out a series of bioinformatic analyses on expressive profiles of every EPH member across 21 different types of clinical cancers versus matched normal tissues gathered from the Oncomine platform. We validated these results by protein expression study of all EPHs family members by The Human Protein Atlas repository. Our results uncovered the overexpression of most EPH subunits in numerous cancer types, especially the dramatic overexpression of six EPHs members, namely EPHA1, EPHA2, EPHA3, EPHA4 and EPHB1, EPHB2, EPHB3, EPHB4 in bladder, colorectal, esophageal, gastric, and prostate cancers. Furthermore, EPHB2 was specifically highly expressed in cervical cancer, EPHA3 in liver cancer, and EPHB1 in uterine cancer. Collectively, expressive profiles of these EPHs were confirmed and correlated with different cancer subtypes as potential biomarkers. This study provides useful information for further studies on cancer development and clinical treatments., Competing Interests: None., (IJCEP Copyright © 2020.)

An improved design of CMOS 256-pixel photovoltaic-powered implantable chip for subretinal prostheses is presented. In the proposed subretinal chip, a high-efficiency fully-integrated 4× charge pump is designed and integrated with on-chip photovoltaic (PV) cells and a 256-pixel array with active pixel sensors (APS) for image light sensing, biphasic constant current stimulators, and electrodes. Thus the PV voltage generated by infrared (IR) light can be boosted to above 1V so that the charge injection is increased. The proposed chip adopts the 32-phase divisional power supply scheme (DPSS) to reduce the required supply current and thus the required area of the PV cells. The proposed chip is designed and fabricated in 180-nm CMOS image sensor (CIS) technology and post-processed with biocompatible IrOx electrodes and silicone packaging. From the electrical measurement results, the measured stimulation frequency is 28.3 Hz under the equivalent electrode impedance load. The measured maximum output stimulation current is 7.1 μA and the amount of injected charges per pixel is 7.36 nC under image light intensity of 3200 lux and IR light intensity of 100 mW/cm 2 . The function of the proposed chip has been further validated successfully with the ex vivo experimental results by recording the electrophysiological responses of retinal ganglion cells (RGCs) of retinas from retinal degeneration (rd1) mice with a multi-electrode array (MEA). The measured average threshold injected charge is about 3.97 nC which is consistent with that obtained from the patch clamp recording on retinas from wild type (C57BL/6) mice with a single electrode pair.

A wireless photovoltaic retinal prosthesis is currently being studied with the aim of providing prosthetic vision to patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD). The major challenge of a photovoltaic device is its limited power efficiency. Our retinal prosthetic design implements a unique divisional power supply scheme (DPSS) system that provides the electrical power generated by all of the solar cells to only a subset of electrodes at any moment in time. The aim of the present study was to systematically characterize the spatiotemporal integration performance of the system under various DPSS conditions using human subjects and a psychophysical approach. A 16x16 pixels LED array controlled by Arduino was used to simulate the output signal of the DPSS design, and human performance under different visual stimulations at various update frequencies was then used to assess the spatiotemporal capability of retinal prostheses. The results showed that the contrast polarity of the image, image brightness, and division number influenced the lower limit of the update frequency of the DPSS system, while, on the other hand, visual angle, ambient light level, and stimulation order did not affect performance significantly. Pattern recognition by visual persistence with spatiotemporal integration of multiple frames of sparse dots is a feasible approach in retinal prosthesis design. These findings provide an insight into how to optimize a photovoltaic retinal prosthesis using a DPSS design with an appropriate update frequency for reliable pattern recognition. This will help the development of a wireless device able to restore vision to RP and AMD patients in the future., Competing Interests: The authors have declared that no competing interests exist.

Increased activity of amino acid transporters has been observed in a wide variety of cancers. However, whether amino acid metabolism is related to estrogen receptor-positive (ER + ) breast cancer has been less well studied. We identified the rate-limiting enzyme involved in amino acid metabolism associated with ER + breast cancer by integrating numerous bioinformatics tools and laboratory studies. The bioinformatics analysis revealed that highly expressed genes in ER + breast cancer patients were correlated with breast cancer-related pathways, including ESR1 and PI3K signaling. The metabolic signaling and the amino acid metabolism were significantly regulated in breast neoplasms. We used the ER + breast cancer cell line MCF-7 and breast cancer tissue from National Cheng Kung University Hospital to validate our findings in bioinformatics. In estradiol-treated MCF-7 cells, genes associated with anabolic metabolism of serine and methionine and genes associated with catabolic metabolism of tyrosine, phenylalanine and arginine were upregulated. Furthermore, the expression levels of ARG2, PSAT1, PSPH, TH, PAH, and MAT1A mRNA were increased in breast cancer patients relative to controls. The aforementioned genes were also found to be highly correlated with distant metastasis-free survival in breast cancer patients. High expression levels of ARG2, CBS, PHGDH, AHCY, HAL, TDO2, SHMT2, MAT1A, MAT2A, GLDC, GLS2, BCAT2, GLUD1, PAH and MTR contributed to poor prognoses, whereas high mRNA expression levels of HECA, CTH, PRODH, TAT, and MAT2B were correlated with good prognoses. FDA-approved drugs, including piperlongumine, ellipticine, etidronic acid, harmine, and meclozine, may have novel therapeutic effects in ER + patients based on connectivity map (CMap) analyses. Collectively, our present study demonstrated that amino acid metabolism genes play crucial roles in tumor development and may serve as prospective drug targets or biomarkers for ER + breast cancer., Competing Interests: None., (AJCR Copyright © 2020.)

Background: Solitary fibrous tumor (SFT) is a rare soft tissue tumor originally reported in the pleura. Although it has been reported in various extra-pleural sites, the occurrence of SFT in the scrotum is extremely rare. Herein, we present a 48-year-old man who had scrotal SFT. There are very few reported cases of genitourinary SFTs, this is only the fifth report of SFT of the scrotum in the English medical literature., Case Presentation: In this study, we report on a 48-year-old man who presented with a 5 × 8 cm scrotal mass between his testes. Physical examination revealed a 4.7 × 8.5 cm lobulated tumor mass located between his testicles. Surgical excision of the tumor with scrotal approach was done and pathology reported a SFT. The patient was alive without tumor recurrence or distant metastasis during ongoing follow-up for 9 months post-operatively.., Conclusion: Scrotal SFTs are very rare and only five cases have been reported in English literature to date. Treatment often involves surgical resection, and a definite diagnosis is made with the help of immunohistochemistry. The current general consensus for the management of SFTs is long-term follow-up after surgical excision of the tumor.