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The ubiquity of digital devices and the Internet, along with continuing technological innovation, makes it difficult not to rely on them in some capacity, whether for work or play, in our daily lives. This dependence on their usage could impact life satisfaction. Furthermore, the recognition and perception of this dependence could have implications for life satisfaction as well, whether positive or negative. We thus sought to explore how perceptions of dependence and dependent behaviour on digital devices and the Internet affected life satisfaction. We also examined whether one had a greater effect than the other. We conducted three online nationally representative surveys with 7991, 7703, and 8356 Singaporeans, and performed a hierarchical linear regression analysis on the data. The results show significant but weak positive relationships between dependence on digital devices, the importance of the Internet, and life satisfaction. A greater consistent effect on life satisfaction was also observed from the perceptions of dependence compared with dependent behavior. The implications are discussed, with implications for governmental policy strategy for reducing the potential harms of dependence on digital devices and the Internet.

The dynamics of charge separation, where the underlying mechanisms are a complex interplay of many contributing factors, govern the properties and performance of solar cells. Here, the authors investigate the role of vibrational motion in the charge dynamics of donor-acceptor networks using a non-perturbative simulation tool.

Abstract Inference and analysis of gene regulatory networks (GRNs) require software that integrates multi-omic data from various sources. The Network Zoo (netZoo; netzoo.github.io) is a collection of open-source methods to infer GRNs, conduct differential network analyses, estimate community structure, and explore the transitions between biological states. The netZoo builds on our ongoing development of network methods, harmonizing the implementations in various computing languages and between methods to allow better integration of these tools into analytical pipelines. We demonstrate the utility using multi-omic data from the Cancer Cell Line Encyclopedia. We will continue to expand the netZoo to incorporate additional methods.

Quantum systems are inherently open and susceptible to environmental noise, which can have both detrimental and beneficial effects on their dynamics. This phenomenon has been observed in biomolecular systems, where noise enables novel functionalities, making the simulation of their dynamics a crucial target for digital and analog quantum simulation. Nevertheless, the computational capabilities of current quantum devices are often limited due to their inherent noise. In this work, we present a novel approach that capitalizes on the intrinsic noise of quantum devices to reduce the computational resources required for simulating open quantum systems. Our approach combines quantum noise characterization methods with quantum error mitigation techniques, enabling us to manipulate and control the intrinsic noise in a quantum circuit. Specifically, we selectively enhance or reduce decoherence rates in the quantum circuit to achieve the desired simulation of open-system dynamics. We provide a detailed description of our methods and report on the results of noise characterization and quantum error mitigation experiments conducted on both real and emulated IBM Quantum computers. Additionally, we estimate the experimental resource requirements for our techniques. Our approach holds the potential to unlock new simulation techniques in noisy intermediate-scale quantum devices, harnessing their intrinsic noise to enhance quantum computations.

Abstract The tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an APC mutation. We set out to identify mechanisms underlying APC mutation-negative (APC mut– ) CRCs. We analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between APC mut– and APC mutation-positive (APC mut+) microsatellite stable CRCs. Transcriptionally, APC mut– CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist RNF43, increased expression of the WNT agonist RSPO3, activating mutation of BRAF, or increased methylation and decreased expression of AXIN2. APC mut– CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3. APC mut– CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways.

Fecaliths or fecomucoliths can form in rectal stumps after a Hartmann procedure or in a coloneovaginal conduit. They can cause significant distress to the patient by causing symptoms such as discharge and odor. We describe a novel and effective method of endoscopic obliteration and removal where other techniques such as removal during examination under anesthesia or serial enemas have failed. By using a combination of hydrodissection with a saline injector gun and biopsy forceps and a polypectomy snare to break down the fecomucolith or fecalith, this troublesome problem can be resolved endoscopically. Successful removal of the fecalith/fecomucolith and resolution of the symptoms for the patients were achieved. No complications are reported. We describe an effective and novel method for endoscopic removal of fecaliths and fecomucoliths.

Abstract We investigated whether a unique immune response was instigated with the development of oral tongue squamous cell carcinomas (OTSCC), with/without nodal involvement, with/without recurrent metastatic disease, or within tumor involved nodes. One hundred and ten formalin‐fixed paraffin‐embedded samples were collected from a retrospective cohort of 67 OTSCC patients and 10 non‐cancerous tongue samples. Targets including CD4, CD8, FOXP3, PD‐L1, and PD‐1 were analyzed by immunohistochemistry. The Nanostring PanCancer Immune Profiling Panel was used for gene expression profiling. Data were externally validated in the The Cancer Genome Atlas (TCGA) head and neck (HNSCC), melanoma and lung squamous cell carcinoma (LSCC) cohorts. A 24‐immune gene signature was identified that discriminated more aggressive OTSCC cases, and although not prognostic in HNSCC was associated with survival in other TCGA cohorts (improved survival for melanoma, P

Summary: Reestablishing cerebral connectivity is a critical part of restoring neuronal network integrity and brain function after trauma, stroke, and neurodegenerative diseases. Creating transplantable axon tracts in the laboratory is an unexplored strategy for overcoming the common barriers limiting axon regeneration in vivo, including growth-inhibiting factors and the limited outgrowth capacity of mature neurons in the brain. We describe the generation, phenotype, and connectivity of constrained three-dimensional human axon tracts derived from brain organoids. These centimeter-long constructs are encased in an agarose shell that permits physical manipulation and are composed of discrete cellular regions spanned by axon tracts, mirroring the separation of cerebral gray and white matter. Features of cerebral cortex also are emulated, as evidenced by the presence of neurons with different cortical layer phenotypes. This engineered neural tissue represents a first step toward potentially reconstructing brain circuits by physically replacing neuronal populations and long-range axon tracts in the brain. : Biological Sciences; Neuroscience; Tissue Engineering Subject Areas: Biological Sciences, Neuroscience, Tissue Engineering

Assessment of instrumental activities of daily living (IADL) is essential for the diagnosis and staging of dementia. However, current IADL assessments are subjective and cannot be administered remotely. We proposed a smart-home design, called IADLSys, for remote monitoring of IADL. IADLSys consists of three major components: (1) wireless physical tags (pTAG) attached to objects of interest, (2) a pendant–sensor to monitor physical activities and detect interaction with pTAGs, and (3) an interactive tablet as a gateway to transfer data to a secured cloud. Four studies, including an exploratory clinical study with five older adults with clinically confirmed cognitive impairment, who used IADLSys for 24 h/7 days, were performed to confirm IADLSys feasibility, acceptability, adherence, and validity of detecting IADLs of interest and physical activity. Exploratory tests in two cases with severe and mild cognitive impairment, respectively, revealed that a case with severe cognitive impairment either overestimated or underestimated the frequency of performed IADLs, whereas self-reporting and objective IADL were comparable for the case with mild cognitive impairment. This feasibility and acceptability study may pave the way to implement the smart-home concept to remotely monitor IADL, which in turn may assist in providing personalized support to people with cognitive impairment, while tracking the decline in both physical and cognitive function.

OBJECTIVES/GOALS: The objective of this study is to examine the associated changes in the EHR use patterns after the widespread implementation of telehealth in the ambulatory care setting after the COVID pandemic. METHODS/STUDY POPULATION: The study sample will be all attending ambulatory care physicians at UCSF Health. Signal measures captured by Epic Systems are markers of EHR use pattern that characterize EHR use at the individual provider level in terms of time spent performing certain activities, time spent at particular times of the day, and the number of EHR tools being used. We will use the Single Interrupted Time Series framework to analyze the changes in Signal measures that occur after the widespread implementation of telehealth with pre-telehealth time period defined as Jan 2018 – Feb 2020 and post-telehealth time period defined as March 2020 – present. RESULTS/ANTICIPATED RESULTS: The outcomes of this study will reveal how the increased use of telehealth following the COVID pandemic has changed the way providers utilize various functions within EHR (e.g. time in EHR at particular time of day, documentation, medication and non-medication orders, chart review, etc). These results can, in turn, inform us potential impacts of increased telehealth use on physician burnout given that a number of markers of EHR use pattern (i.e. Signal measures) in previous studies have been associated with burnout. In addition, a stratified version of Interrupted Time Series by specialty and clinical work volume may inform us how different subgroups of providers exhibit varying EHR use patterns in response to the increased use of telehealth. DISCUSSION/SIGNIFICANCE: The use of telehealth will likely remain a strong presence in health care delivery in the post-COVID era. This study can serve as a baseline study on the influence of telehealth on EHR use. Future studies may focus on potential targeted interventions to best support the usage of telehealth.

Recombinant adeno-associated virus (rAAV), produced from a nonpathogenic parvovirus, has become an increasing popular vector for gene therapy applications in human clinical trials. However, transduction and transgene expression of rAAVs can differ across in vitro and ex vivo cellular transduction strategies. This study compared 11 rAAV serotypes, carrying one reporter transgene cassette containing a cytomegalovirus immediate-early enhancer (eCMV) and chicken beta actin (CBA) promoter driving the expression of an enhanced green-fluorescent protein (eGFP) gene, which was transduced into four different cell types: human iPSC, iPSC-derived RPE, iPSC-derived cortical, and dissociated embryonic day 18 rat cortical neurons. Each cell type was exposed to three multiplicity of infections (MOI: 1E4, 1E5, and 1E6 vg/cell). After 24, 48, 72, and 96 h posttransduction, GFP-expressing cells were examined and compared across dosage, time, and cell type. Retinal pigmented epithelium showed highest AAV-eGFP expression and iPSC cortical the lowest. At an MOI of 1E6 vg/cell, all serotypes show measurable levels of AAV-eGFP expression; moreover, AAV7m8 and AAV6 perform best across MOI and cell type. We conclude that serotype tropism is not only capsid dependent but also cell type plays a significant role in transgene expression dynamics.

ABSTRACT IMPACT: This study will provide the essential characterization of intrinsic neural activity in human brain organoids, both at the single cell and network levels, to harness for translational purposes. OBJECTIVES/GOALS: Brain organoids are 3D, stem cell-derived neural tissues that recapitulate neurodevelopment. However, to levy their full translational potential, a deeper understanding of their intrinsic neural activity is essential. Here, we present our preliminary analysis of maturing neural activity in human forebrain organoids. METHODS/STUDY POPULATION: Forebrain organoids were generated from human iPSC lines derived from healthy volunteers. Linear microelectrode probes were employed to record spontaneous electrical activity from day 77, 100, and 130 organoids. Single unit recordings were collected during hour-long recordings, involving baseline recordings followed by glutamatergic blockade. Subsequently, tetrodotoxin, was used to abolish action potential firing. Single units were identified via spike sorting, and the spatiotemporal evolution of baseline neural properties and network dynamics was characterized. RESULTS/ANTICIPATED RESULTS: Nine organoids were recorded successfully (n=3 per timepoint). A significant difference in number of units was seen across age groups (F (2,6) = 6.4178, p = 0.0323). Post hoc comparisons by the Tukey HSD test showed significantly more units in day 130 (51.67 ±14.15) than day 77 (16.33 ±14.98) organoids. Mean firing rates were significantly different in organoids based on age, with drug condition also trending toward significance (F (6,12) = 9.97; p = 0.0028 and p = 0.08 respectively). Post hoc comparisons showed a higher baseline firing rate in day 130 (0.99Hz ±0.30) organoids than their day 77 counterparts at baseline (0.31Hz ±0.066) and glutamate blockade (0.31Hz ±0.045). Preliminary network analysis showed no modularity or small-world features; however, these features are expected to emerge as organoids mature. DISCUSSION/SIGNIFICANCE OF FINDINGS: Initial analysis of brain organoid activity demonstrates changes in single unit properties as they mature. Additional work in this area, as well as further network analyses, will confer better sense of how to rationally utilize brain organoids for translational purposes.

Understanding of charge transfer dynamics is essential to the design of high-performance organic semiconductors for optoelectronic applications. Here, the authors show that excitons, polaron pairs and a long-lived vibrational mode are strongly coupled to each other up to 1 picosecond in polythiophene.

Oxidative damage and mitochondrial dysfunction are implicated in aging and age-related neurodegenerative diseases, including Huntington’s disease (HD). Many naturally occurring antioxidants have been tested for their ability to correct for deleterious effects of reactive oxygen species, but often they lack specificity, are tissue variable, and have marginal efficacy in human clinical trials. To increase specificity and efficacy, we have designed a synthetic antioxidant, XJB-5-131, to target mitochondria. We demonstrate in a mouse model of HD that XJB-5-131 has remarkably beneficial effects. XJB-5-131 reduces oxidative damage to mitochondrial DNA, maintains mitochondrial DNA copy number, suppresses motor decline and weight loss, enhances neuronal survival, and improves mitochondrial function. The findings poise XJB-5-131 as a promising therapeutic compound.

Spatial abilities allow animals to retain and cognitively manipulate information about their spatial environment and are dependent upon neural structures that mature during adolescence. Exposure to stress in adolescence is thought to disrupt neural maturation, possibly compromising cognitive processes later in life. We examined whether exposure to chronic unpredictable stress in adolescence affects spatial ability in late adulthood. We evaluated spatial learning, reference and working memory, as well as long-term retention of visuospatial cues using a radial arm water maze. We found that stress in adolescence decreased the rate of improvement in spatial learning in adulthood. However, we found no overall performance impairments in adult reference memory, working memory, or retention caused by adolescent-stress. Together, these findings suggest that adolescent-stress may alter the strategy used to solve spatial challenges, resulting in performance that is more consistent but is not refined by incorporating available spatial information. Interestingly, we also found that adolescent-stressed rats showed a shorter latency to begin the water maze task when re-exposed to the maze after an overnight delay compared with control rats. This suggests that adolescent exposure to reoccurring stressors may prepare animals for subsequent reoccurring challenges. Overall, our results show that stress in adolescence does not affect all cognitive processes, but may affect cognition in a context-dependent manner.

While the role of Transforming Growth Factor β (TGF-β) as an intrinsic pathway has been well established in driving de novo differentiation of Th17 cells, no study has directly assessed the capacity of TGF-β signaling initiated within dendritic cells (DCs) to regulate Th17 differentiation. The central finding of this study is the demonstration that Th17 cell fate during autoimmune inflammation is shaped by TGF-β extrinsic pathway via DCs. First, we provide evidence that TGF-β limits at the site of inflammation the differentiation of highly mature DCs as a means of restricting Th17 cell differentiation and controlling autoimmunity. Second, we demonstrate that TGF-β controls DC differentiation in the inflammatory site but not in the priming site. Third, we show that TGF-β controls DC numbers at a precursor level but not at a mature stage. While it is undisputable that TGF-β intrinsic pathway drives Th17 differentiation, our data provide the first evidence that TGF-β can restrict Th17 differentiation via DC suppression but such a control occurs in the site of inflammation, not at the site of priming. Such a demarcation of the role of TGF-β in DC lineage is unprecedented and holds serious implications vis-à-vis future DC-based therapeutic targets.

In a network of interacting quantum systems, achieving fast coherent energy transfer is a challenging task. While quantum systems are susceptible to a wide range of environmental factors, in many physical settings their interactions with quantized vibrations, or phonons, of a supporting structure are the most prevalent. This leads to noise and decoherence in the network, ultimately impacting the energy-transfer process. In this work, we introduce a novel type of coherent energy-transfer mechanism for quantum systems, where phonon interactions are able to actually enhance the energy transfer. Here, a shared phonon interacts with the systems and dynamically adjusts their resonances, providing remarkable directionality combined with quantum speed-up. We call this mechanism phonon-induced dynamic resonance energy transfer and show that it enables long-range coherent energy transport even in highly disordered systems.

We show that the influence of the shared phonon bath considered in Hossein-Nejad and Scholes (2010 New J. Phys. 12 065045) on the exciton transfer in a two-molecule system can be reproduced by that of an independent bath model.

We introduce a scheme for generating entanglement between two quantum dots using a plasmonic waveguide made from an array of metal nanoparticles. We show that the scheme is robust to loss, enabling it to work over long distance plasmonic nanoparticle arrays, as well as in the presence of other imperfections such as the detuning of the energy levels of the quantum dots. The scheme represents an alternative strategy to the previously introduced dissipative driven schemes for generating entanglement in plasmonic systems. Here, the entanglement is generated by using dipole-induced interference effects and detection-based postselection. Thus, contrary to the widely held view that loss is major problem for quantum plasmonic systems, we provide a robust-to-loss entanglement generation scheme that could be used as a versatile building block for quantum state engineering and control at the nanoscale.

We recently discovered that coxsackievirus B3 (CVB3) is a potent oncolytic virus against KRAS mutant lung adenocarcinoma. Nevertheless, the evident toxicity restricts the use of wild-type (WT)-CVB3 for cancer therapy. The current study aims to engineer the CVB3 to decrease its toxicity and to extend our previous research to determine its safety and efficacy in treating TP53/RB1 mutant small-cell lung cancer (SCLC). A microRNA-modified CVB3 (miR-CVB3) was generated via inserting multiple copies of tumor-suppressive miR-145/miR-143 target sequences into the viral genome. In vitro experiments revealed that miR-CVB3 retained the ability to infect and lyse KRAS mutant lung adenocarcinoma and TP53/RB1-mutant SCLC cells, but with a markedly reduced cytotoxicity toward cardiomyocytes. In vivo study using a TP53/RB1-mutant SCLC xenograft model demonstrated that a single dose of miR-CVB3 via systemic administration resulted in a significant tumor regression. Most strikingly, mice treated with miR-CVB3 exhibited greatly attenuated cardiotoxicities and decreased viral titers compared to WT-CVB3-treated mice. Collectively, we generated a recombinant CVB3 that is powerful in destroying both KRAS mutant lung adenocarcinoma and TP53/RB1-mutant SCLC, with a negligible toxicity toward normal tissues. Future investigation is needed to address the issue of genome instability of miR-CVB3, which was observed in ~40% of mice after a prolonged treatment. Keywords: coxsackievirus B3, oncolytic virus, lung adenocarcinoma, KRAS mutation, small-cell lung cancer, TP53/RB1 mutation, miRNA-145, miRNA-143, cardiotoxicity, virotherapy

A man in his 60s presented to the clinic due to night sweats and weight loss following pneumonia. He was found to have hyponatraemia due to a syndrome of inappropriate antidiuretic hormone (SIADH). CT of the thorax was concerning for pulmonary nodules. He was ultimately diagnosed with pulmonary coccidioidomycosis (CM) and started on fluconazole 400 mg daily with improvement in symptoms. Due to the report of headaches, head MRI was conducted which suggested central nervous system (CNS) involvement. Cerebrospinal fluid analysis was consistent with CNS CM and head magnetic resonance angiography confirmed the presence of CNS vasculitis. Fluconazole dose was increased to 800 mg daily which the patient continued to tolerate and showed improvement. This report depicts a case of SIADH associated with CNS CM with vasculitis and demonstrates the importance of high clinical suspicion for SIADH secondary to CNS CM in the setting of hyponatraemia and headache. [ABSTRACT FROM AUTHOR]