Discriminating factors of body composition characteristics for academic performance in nursing college students: a cross-sectional study.

BACKGROUND: Poor body composition may affect health status, and better body composition is often associated with better academic performance. Nursing students face heavy academic and practical pressures, and the relationship between body composition and academic performance in this group is not fully understood. METHODS: This cross-sectional observational study used de-identified student data from a university of technology in southern Taiwan to analyze the correlation between body composition characteristics and academic performance using regression models. RESULTS: A total of 275 nursing college students were divided into four groups according to academic performance. The group with the lowest academic performance had a lower percentage of body fat (P < 0.05) but a higher percentage of muscle mass (P < 0.05) than the other three groups. Academic performance was positively correlated with percentage of body fat (R = 0.16, P < 0.01) and body age (R = 0.41, P < 0.01), but was negatively correlated with percentage of muscle mass (R = - 0.16, P < 0.01). Percentage of body fat, visceral fat area, and body age were significant discriminators of academic performance (P < 0.05). CONCLUSIONS: The relationship between academic performance and body composition among nursing college students is not straightforward. Contrary to our initial hypothesis, students with higher academic performance tended to have a higher percentage of body fat and a lower percentage of muscle mass. Percentage of body fat, visceral fat area, and body age were significant discriminators of academic performance, indicating that body composition should be considered an important factor in nursing education and practice.

Synthetic protein circuits for programmable control of mammalian cell death.

Natural cell death pathways such as apoptosis and pyroptosis play dual roles: they eliminate harmful cells and modulate the immune system by dampening or stimulating inflammation. Synthetic protein circuits capable of triggering specific death programs in target cells could similarly remove harmful cells while appropriately modulating immune responses. However, cells actively influence their death modes in response to natural signals, making it challenging to control death modes. Here, we introduce naturally inspired "synpoptosis" circuits that proteolytically regulate engineered executioner proteins and mammalian cell death. These circuits direct cell death modes, respond to combinations of protease inputs, and selectively eliminate target cells. Furthermore, synpoptosis circuits can be transmitted intercellularly, offering a foundation for engineering synthetic killer cells that induce desired death programs in target cells without self-destruction. Together, these results lay the groundwork for programmable control of mammalian cell death.

Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs.

The choroid plexus (ChP) of the brain plays a central role in orchestrating the recruitment of peripheral leukocytes into the central nervous system (CNS) through the blood-cerebrospinal fluid (BCSF) barrier in pathological conditions, thus offering a unique niche to diagnose CNS disorders. We explored whether magnetic resonance imaging of the ChP could be optimized for mild traumatic brain injury (mTBI). mTBI induces subtle, yet influential, changes in the brain and is currently severely underdiagnosed. We hypothesized that mTBI induces sufficient alterations in the ChP to cause infiltration of circulating leukocytes through the BCSF barrier and developed macrophage-adhering gadolinium [Gd(III)]-loaded anisotropic micropatches (GLAMs), specifically designed to image infiltrating immune cells. GLAMs are hydrogel-based discoidal microparticles that adhere to macrophages without phagocytosis. We present a fabrication process to prepare GLAMs at scale and demonstrate their loading with Gd(III) at high relaxivities, a key indicator of their effectiveness in enhancing image contrast and clarity in medical imaging. In vitro experiments with primary murine and porcine macrophages demonstrated that GLAMs adhere to macrophages also under shear stress and did not affect macrophage viability or functions. Studies in a porcine mTBI model confirmed that intravenously administered macrophage-adhering GLAMs provide a differential signal in the ChP and lateral ventricles at Gd(III) doses 500- to 1000-fold lower than those used in the current clinical standard Gadavist. Under the same mTBI conditions, Gadavist did not offer a differential signal at clinically used doses. Our results suggest that macrophage-adhering GLAMs could facilitate mTBI diagnosis.

Polymer Micropatches as Natural Killer Cell Engagers for Tumor Therapy.

Natural killer (NK) cell therapies have emerged as a potential therapeutic approach to various cancers. Their efficacy, however, is limited by their low persistence and anergy. Current approaches to sustain NK cell persistence in vivo include genetic modification, activation via pretreatment, or coadministration of supporting cytokines or antibodies. Such supporting therapies exhibit limited efficacy in vivo, in part due to the reversal of their effect within the immunosuppressive tumor microenvironment and off-target toxicity. Here, we report a material-based approach to address this challenge. Specifically, we describe the use of polymeric micropatches as a platform for sustained, targeted activation of NK cells, an approach referred to as microparticles as cell engagers (MACE). Poly(lactide-co-glycolic) acid (PLGA) micropatches, 4-8 µm in diameter and surface-modified with NK cell receptor targeting antibodies, exhibited strong adhesion to NK cells and induced their activation without the need of coadministered cytokines. The activation induced by MACE was greater than that induced by nanoparticles, attesting to the crucial role of MACE geometry in the activation of NK cells. MACE-bound NK cells remained viable and exhibited trans-endothelial migration and antitumor activity in vitro. MACE-bound NK cells activated T cells, macrophages, and dendritic cells in vitro. Adoptive transfer of NK-MACE also demonstrated superior antitumor efficacy in a mouse melanoma lung metastasis model compared to unmodified NK cells. Overall, MACE offers a simple, scalable, and effective way of activating NK cells and represents an attractive platform to improve the efficacy of NK cell therapy.

Materials for Cell Surface Engineering.

Cell therapies are emerging as a promising new therapeutic modality in medicine, generating effective treatments for previously incurable diseases. Clinical success of cell therapies has energized the field of cellular engineering, spurring further exploration of novel approaches to improve their therapeutic performance. Engineering of cell surfaces using natural and synthetic materials has emerged as a valuable tool in this endeavor. This review summarizes recent advances in the development of technologies for decorating cell surfaces with various materials including nanoparticles, microparticles, and polymeric coatings, focusing on the ways in which surface decorations enhance carrier cells and therapeutic effects. Key benefits of surface-modified cells include protecting the carrier cell, reducing particle clearance, enhancing cell trafficking, masking cell-surface antigens, modulating inflammatory phenotype of carrier cells, and delivering therapeutic agents to target tissues. While most of these technologies are still in the proof-of-concept stage, the promising therapeutic efficacy of these constructs from in vitro and in vivo preclinical studies has laid a strong foundation for eventual clinical translation. Cell surface engineering with materials can imbue a diverse range of advantages for cell therapy, creating opportunities for innovative functionalities, for improved therapeutic efficacy, and transforming the fundamental and translational landscape of cell therapies.

DNA methylation signature aberration as potential biomarkers in treatment-resistant schizophrenia: Constructing a methylation risk score using a machine learning method.

Treatment-resistant schizophrenia (TRS) is defined as a non-response to at least two trials of antipsychotic medication with an adequate dose and duration. We aimed to evaluate the discriminant abilities of DNA methylation probes and methylation risk score between treatment-resistant schizophrenia and non-treatment-resistant schizophrenia. This study recruited 96 schizophrenia patients (TRS and non-TRS) and 56 healthy controls (HC). Participants were divided into a discovery set and a validation set. In the discovery set, we conducted genome-wide methylation analysis (human MethylationEPIC 850K BeadChip) on the subject's blood DNA and discriminated significant methylation signatures, then verified these methylation signatures in the validation set. Based on genome-wide scans of TRS versus non-TRS, thirteen differentially methylated probes were identified at FDR <0.05 and >20% differences in DNA methylation ß-values. Next, we selected six probes within gene coding regions (LOC404266, LOXL2, CERK, CHMP7, and SLC17A9) to conduct verification in the validation set using quantitative methylation-specific PCR (qMSP). These six methylation probes showed satisfactory discrimination between TRS patients and non-TRS patients, with an AUC ranging from 0.83 to 0.92, accuracy ranging from 77.8% to 87.3%, sensitivity ranging from 80% to 90%, and specificity ranging from 65.6% to 85%. This methylation risk score model showed satisfactory discrimination between TRS patients and non-TRS patients, with an accuracy of 88.3%. These findings support that methylation signatures may be used as an indicator of TRS vulnerability and provide a model for the clinical use of methylation to identify TRS.

Multi-context genetic modeling of transcriptional regulation resolves novel disease loci.

A majority of the variants identified in genome-wide association studies fall in non-coding regions of the genome, indicating their mechanism of impact is mediated via gene expression. Leveraging this hypothesis, transcriptome-wide association studies (TWAS) have assisted in both the interpretation and discovery of additional genes associated with complex traits. However, existing methods for conducting TWAS do not take full advantage of the intra-individual correlation inherently present in multi-context expression studies and do not properly adjust for multiple testing across contexts. We introduce CONTENT-a computationally efficient method with proper cross-context false discovery correction that leverages correlation structure across contexts to improve power and generate context-specific and context-shared components of expression. We apply CONTENT to bulk multi-tissue and single-cell RNA-seq data sets and show that CONTENT leads to a 42% (bulk) and 110% (single cell) increase in the number of genetically predicted genes relative to previous approaches. We find the context-specific component of expression comprises 30% of heritability in tissue-level bulk data and 75% in single-cell data, consistent with cell-type heterogeneity in bulk tissue. In the context of TWAS, CONTENT increases the number of locus-phenotype associations discovered by over 51% relative to previous methods across 22 complex traits.

A Pilot Study to Assess Opportunistic Use of CT-Scan for Osteoporosis Screening in Chronic Pancreatitis.

Objectives: CT scans are commonly performed in patients with chronic pancreatitis (CP). Osteopathy and fractures are recognized in CP but no osteoporosis screening guidelines are recommended. "Opportunistic" CT scan-derived bone density thresholds are assessed for identifying osteoporosis in CP. Methods: Retrospective pilot cohort study. CP subjects who had CT scans and dual-energy x-ray absorptiometry (DXA) within 1 year were included. CT-derived bone density was measured at the L1 level. Pearson's correlation was performed between age and CT-derived bone density in Hounsfield unit (HU). Univariate analysis using HU to identify osteoporosis was performed at various thresholds of bone density. The discriminatory ability of the model was evaluated with the area under the receiver operating characteristic (ROC) curve (AUC). Several HU thresholds were tested. Results: Twenty-seven CP subjects were included, of whom 11 had normal bone density, 12 osteopenia, and four osteoporosis on DXA. The mean age was 59.9 years (SD 13.0). There was a negative correlation of age with HU (r = -0.519, p = 0.006). CT-derived bone density predicted DXA-based osteoporosis in the univariable analysis (Odds Ratio (OR) = 0.97 95% Confidence Interval (CI) 0.94-1.00, p = 0.03). HU thresholds were tested. A threshold of 106 HU maximized the accuracy (AUC of 0.870). Conclusions: CT scan may be repurposed for "opportunistic" screening to rule out osteoporosis in CP. A larger study is warranted to confirm these results.

Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon-stimulated genes (ISGs) in monocytes, reduction of naïve CD4+ T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic GZMH+ CD8+ T cells. Cell type-specific expression features predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell type-specific cis-expression quantitative trait loci and to link SLE-associated variants to cell type-specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE.

Synthetic mammalian signaling circuits for robust cell population control.

In multicellular organisms, cells actively sense and control their own population density. Synthetic mammalian quorum-sensing circuits could provide insight into principles of population control and extend cell therapies. However, a key challenge is reducing their inherent sensitivity to "cheater" mutations that evade control. Here, we repurposed the plant hormone auxin to enable orthogonal mammalian cell-cell communication and quorum sensing. We designed a paradoxical population control circuit, termed "Paradaux," in which auxin stimulates and inhibits net cell growth at different concentrations. This circuit limited population size over extended timescales of up to 42 days of continuous culture. By contrast, when operating in a non-paradoxical regime, population control became more susceptible to mutational escape. These results establish auxin as a versatile "private" communication system and demonstrate that paradoxical circuit architectures can provide robust population control.

DNA methylation signature of psychological resilience in young adults: Constructing a methylation risk score using a machine learning method.

Resilience is a process associated with the ability to recover from stress and adversity. We aimed to explore the resilience-associated DNA methylation signatures and evaluate the abilities of methylation risk scores to discriminate low resilience (LR) individuals. The study recruited 78 young adults and used Connor-Davidson Resilience Scale (CD-RISC) to divide them into low and high resilience groups. We randomly allocated all participants of two groups to the discovery and validation sets. We used the blood DNA of the subjects to conduct a genome-wide methylation scan and identify the significant methylation differences of CpG Sites in the discovery set. Moreover, the classification accuracy of the DNA methylation probes was confirmed in the validation set by real-time quantitative methylation-specific polymerase chain reaction. In the genome-wide methylation profiling between LR and HR individuals, seventeen significantly differentially methylated probes were detected. In the validation set, nine DNA methylation signatures within gene coding regions were selected for verification. Finally, three methylation probes [cg18565204 (AARS), cg17682313 (FBXW7), and cg07167608 (LINC01107)] were included in the final model of the methylation risk score for LR versus HR. These methylation risk score models of low resilience demonstrated satisfactory discrimination by logistic regression and support vector machine, with an AUC of 0.81 and 0.93, accuracy of 72.3% and 87.1%, sensitivity of 75%, and 87.5%, and specificity of 70% and 80%. Our findings suggest that methylation signatures can be utilized to identify individuals with LR and establish risk score models that may contribute to the field of psychology.

Solitary Cystic Psoas Muscle Metastasis From Rectosigmoid Adenocarcinoma.

The most common subtype of colon cancer is colorectal adenocarcinoma. Compared with other subtypes, such as signet-ring and mucinous, colorectal adenocarcinoma has been found to have lower rates of metastasis. Approximately 20% of colorectal cancer cases present with metastatic disease on initial evaluation. The most common locations for metastasis are the liver, lung, peritoneum, bone, and extra-regional lymph nodes. Metastatic disease to the skeletal muscle, however, is considerably rare. We present a clinical case of a 52-year-old female found to have a cystic iliopsoas muscle metastasis from rectosigmoid adenocarcinoma, initially classified as an infected fluid collection.

A Comparison of the Wound Healing Efficacy of Trolamine Emulsion, Manuka Gel, and Polymyxin-Bacitracin Ointment.

OBJECTIVE: To compare the efficacy of three topical agents commonly used in cutaneous wound healing. METHODS: Wound healing was studied in 29 participants, and each participant served as his or her own control. In each participant, three similarly sized and located seborrheic keratoses were removed by curettage. Resultant wounds were treated with either trolamine emulsion, manuka honey gel, or polymyxin-bacitracin ointment until the wounds were fully healed. RESULTS: Wounds treated with trolamine emulsion healed significantly faster than wounds treated with either manuka honey or polymyxin-bacitracin (15 vs 19 days; P < .001). CONCLUSIONS: Trolamine emulsion may be preferred in clinical practice to accelerate the healing time of clean, shallow wounds.

dCas9-targeted locus-specific protein isolation method identifies histone gene regulators.

Eukaryotic gene regulation is a complex process, often coordinated by the action of tens to hundreds of proteins. Although previous biochemical studies have identified many components of the basal machinery and various ancillary factors involved in gene regulation, numerous gene-specific regulators remain undiscovered. To comprehensively survey the proteome directing gene expression at a specific genomic locus of interest, we developed an in vitro nuclease-deficient Cas9 (dCas9)-targeted chromatin-based purification strategy, called "CLASP" (Cas9 locus-associated proteome), to identify and functionally test associated gene-regulatory factors. Our CLASP method, coupled to mass spectrometry and functional screens, can be efficiently adapted for isolating associated regulatory factors in an unbiased manner targeting multiple genomic loci across different cell types. Here, we applied our method to isolate the Drosophila melanogaster histone cluster in S2 cells to identify several factors including Vig and Vig2, two proteins that bind and regulate core histone H2A and H3 mRNA via interaction with their 3' UTRs.

PHLPP1 mediates melanoma metastasis suppression through repressing AKT2 activation.

PI3K/AKT pathway activation is thought to be a driving force in metastatic melanomas. Members of the pleckstrin homology (PH) domain leucine-rich repeat protein Ser/Thr specific phosphatase family (PHLPP1 and PHLPP2) can regulate AKT activation. By dephosphorylating specific serine residues in the hydrophobic motif, PHLPP1 and PHLPP2 restrain AKT signalings, thereby regulating cell proliferation and survival. We here show that PHLPP1 expression was significantly downregulated or lost and correlated with metastatic potential in melanoma. Forcing expression of either PHLPP1 or PHLPP2 in melanoma cells inhibited cell proliferation, migration, and colony formation in soft agar; but PHLPP1 had the most profound inhibitory effect on metastasis. Moreover, expression of PH mutant forms of PHLPP1 continued to inhibit metastasis, whereas a phosphatase-dead C-terminal mutant did not. The introduction of activated PHLPP1-specific targets AKT2 or AKT3 also promoted melanoma metastasis, while the non-PHLPP1 target AKT1 did not. AKT2 and AKT3 could even rescue the PHLPP1-mediated inhibition of metastasis. An AKT inhibitor blocked the activity of AKT2 and inhibited AKT2-mediated tumor growth and metastasis in a preclinical mouse model. Our data demonstrate that PHLPP1 functions as a metastasis suppressor through its phosphatase activity, and suggest that PHLPP1 represents a novel diagnostic and therapeutic marker for metastatic melanoma.

A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration.

Deficits in Schwann cell-mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice. HDAC3 antagonizes the myelinogenic neuregulin-PI3K-AKT signaling axis. Moreover, genome-wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann cell-specific deletion of either Hdac3 or Tead4 in mice resulted in an elevation of myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.

Optimization and Standardization of the Immunodeficient Mouse Model for Assessing Fat Grafting Outcomes.

BACKGROUND: Animal models are often used to assess interventions that might improve fat grafting outcomes; however, there is great variability in the models. The authors sought to determine the predictive value of the immunocompromised mouse model for fat grafting so that experiments could be standardized and optimized. METHODS: Human lipoaspirate injections at different volumes and time points were assessed in a nude mouse model and compared with control injections of nonviable fat. Volume retention and explant histologic score were compared. In a separate study, interanimal reproducibility was determined by implanting a highly consistent hydrogel and measuring variability in volume retention. RESULTS: Injection volume significantly affects adipose resorption kinetics at 6 and 12 weeks. Masson trichrome staining revealed that macrophages were unable to infiltrate large (1 ml) grafts, and oil cysts were not absorbed by 18 weeks, which interfered with interpretation of volume retention data. Nonviable tissue was resorbed when grafts were 0.3 ml, and quantification of graft histologic viability correlated well with graft retention at all study time points. Interanimal variability was measured to be 8.44 percent of the mean retention volume for small graft volumes. CONCLUSIONS: Human fat graft retention in the immunodeficient mouse correlates with graft viability in small, 0.3-ml-volume grafts. However, centralized oil cysts in nonviable 1.0-ml grafts were not resorbed by 18 weeks and thus volume measurements were confounded and not significantly different from viable samples. In addition, tissue injury scores increased in initially healthy fat grafts at 18 weeks, possibly because of a delayed immune reaction.

Targeting SRC Coactivators Blocks the Tumor-Initiating Capacity of Cancer Stem-like Cells.

Tumor-initiating cells (TIC) represent cancer stem-like cell (CSC) subpopulations within tumors that are thought to give rise to recurrent cancer after therapy. Identifying key regulators of TIC/CSC maintenance is essential for the development of therapeutics designed to limit recurrence. The steroid receptor coactivator 3 (SRC-3) is overexpressed in a wide range of cancers, driving tumor initiation, cell proliferation, and metastasis. Here we report that SRC-3 supports the TIC/CSC state and induces an epithelial-to-mesenchymal transition (EMT) by driving expression of the master EMT regulators and stem cell markers. We also show that inhibition of SRC-3 and SRC-1 with SI-2, a second-generation SRC-3/SRC-1 small-molecule inhibitor, targets the CSC/TIC population both in vitro and in vivo Collectively, these results identify SRC coactivators as regulators of stem-like capacity in cancer cells and that these coactivators can serve as potential therapeutic targets to prevent the recurrence of cancer. Cancer Res; 77(16); 4293-304. ©2017 AACR.

Development of a Novel Anti-HIF-1α Screening System Coupled with Biochemical and Biological Validation for Rapidly Selecting Potent Anti-Cancer Compounds.

Breast cancer (BCa) is the most diagnosed cancer and the second leading cause of cancer death in the American women. Adaptation to the hypoxic environment seen in solid tumors is critical for tumor cell survival and growth. The activation of hypoxia inducible factor-1 alpha (HIF-1α), an important master transcriptional factor that is induced and stabilized by intratumoral hypoxia, stimulates a group of HIF-1α-regulated genes including vascular endothelial growth factor (VEGF), leading tumor cells towards malignant progression. Therefore, a promising therapeutic approach to cancer treatment is to target HIF-1α. The goal of this project was to develop and validate a screening system coupled with secondary screen/validation process that has the capability to screen large numbers of potential anti-cancer small-molecule compounds based on their anti-HIF-1α activities. Breast cancer MDA-231 cells were used as the model to select potent anti-HIF-1α compounds by their abilities to inhibit transactivation of a VEGF promoter fused to a luciferase reporter gene under hypoxia. Positive compounds were then validated by a series of assays that confirm compounds' anti-HIF-1α activities including measurement of HIF-1α downstream VEGF gene expression and angiogenic ability of BCa cells. Results of our pilot screening demonstrate that this prototype screening coupled with validation system can effectively select highly potent anti-HIF-1α agents from the compound library, suggesting that this prototype screen system has the potential to be developed into a high-throughput screen (HTS) coupled with automated validation process for the screening and identification of novel and effective anti-cancer drugs based on anti-HIF-1α mechanism.

pH dependent transfer of nano-pores into membrane of cancer cells to induce apoptosis.

Proper balance of ions in intracellular and extracellular space is the key for normal cell functioning. Changes in the conductance of membranes for ions will lead to cell death. One of the main differences between normal and cancerous cells is the low extracellular pHe and the reverse pH gradient: intracellular pHi is higher than extracellular pHe. We report here pH-selective transfer of nano-pores to cancer cells for the dis-regulation of balance of monovalent cations to induce cell death at mildly acidic pHe as it is in most solid tumors. Our approach is based on the pH-sensitive fusion of cellular membrane with the liposomes containing gramicidin A forming cation-conductive ß-helix in the membrane. Fusion is promoted only at low extracellular pH by the pH (Low) Insertion Peptide (pHLIP®) attached to the liposomes. Gramicidin channels inserted into the cancer cells open flux of protons into the cytoplasm and disrupt balance of other monovalent cations, which induces cell apoptosis.