Project description:Therapies mobilizing host immunity against cancer cells have profoundly improved prognosis of cancer patients. However, efficacy of immunotherapies depends on local immune conditions. The "cold" tumor, which is characterized by lacking inflamed T cells, is insensitive to immunotherapy. Current strategies of improving the "cold" tumor microenvironment are far from satisfying. Nanoparticle-based therapies provide novel inspiration in firing up the tumor microenvironment. In this review, we presented progress and limitations of conventional immunotherapies. Then, we enumerate advantages of nanoparticle-based therapies in remodeling the "cold" tumor microenvironment. Finally, we discuss the prospect of nanoparticle-based therapies in clinical application.
Project description:Accurate genome duplication requires a tightly regulated DNA replication program that relies on the fine regulation of origin firing. While the molecular steps involved in origin firing have been determined predominantly in budding yeast, the complexity of this process in human cells has yet to be fully elucidated. Here, we describe a straightforward proteomics approach to systematically analyze protein recruitment to the chromatin during induced origin firing in human cells. Using a specific inhibitor against CHK1 kinase, we induced a synchronized wave of dormant origin firing (DOF) and assessed the S phase chromatin proteome at different time points. We provide time-resolved loading dynamics of 3269 proteins, including the core replication machinery and origin firing factors. This dataset accurately represents known temporal dynamics of proteins on the chromatin during the activation of replication forks and the subsequent DNA damage due to the hyperactivation of excessive replication forks. Finally, we used our dataset to identify the condensin II subunit NCAPH2 as a novel factor required for efficient origin firing and replication. Overall, we provide a comprehensive resource to interrogate the protein recruitment dynamics of replication origin firing events in human cells.
Project description:ObjectiveTo report the interim results from the training of providers inevidence-based psychotherapies (EBPs) and use of mobile applications.Design and settingThe Partnerships in Research to Implement and Disseminate Sustainable and Scalable Evidence (PRIDE) study is a cluster-randomised hybrid effectiveness-implementation trial comparing three delivery pathways for integrating comprehensive mental healthcare into primary care in Mozambique. Innovations include the use of EBPs and scaling-up of task-shifted mental health services using mobile applications.Main outcome measuresWe examined EBP training attendance, certification, knowledge and intentions to deliver each component. We collected qualitative data through rapid ethnography and focus groups. We tracked the use of the mobile applications to investigate early reach of a valid screening tool (Electronic Mental Wellness Tool) and the roll out of the EBPs PARTICIPANTS: Psychiatric technicians and primary care providers trained in the EBPs.ResultsPRIDE has trained 110 EBP providers, supervisors and trainers and will train 279 community health workers in upcoming months. The trainings improved knowledge about the EBPs and trainees indicated strong intentions to deliver the EBP core components. Trained providers began using the mobile applications and appear to identify cases and provide appropriate treatment.ConclusionsThe future of EBPs requires implementation within existing systems of care with fidelity to their core evidence-based components. To sustainably address the vast mental health treatment gap globally, EBP implementation demands: expanding the mental health workforce by training existing human resources; sequential use of EBPs to comprehensively treat mental disorders and their comorbid presentations and leveraging digital screening and treatment applications.
Project description:There is growing interest in using genetic variants to augment the reference genome into a graph genome, with alternative sequences, to improve read alignment accuracy and reduce allelic bias. While adding a variant has the positive effect of removing an undesirable alignment score penalty, it also increases both the ambiguity of the reference genome and the cost of storing and querying the genome index. We introduce methods and a software tool called FORGe for modeling these effects and prioritizing variants accordingly. We show that FORGe enables a range of advantageous and measurable trade-offs between accuracy and computational overhead.
Project description:Autism-spectrum disorders (ASD) are complex genetic disorders collectively characterized by impaired social interactions and language as well as repetitive and restrictive behaviors. Of the hundreds of genes implicated in ASD, those encoding proteins acting at neuronal synapses have been most characterized by candidate gene studies. However, recent unbiased genome-wide analyses have turned up a multitude of novel candidate genes encoding nuclear factors implicated in chromatin remodeling, histone demethylation, histone variants, and the recognition of DNA methylation. Furthermore, the chromatin landscape of the human genome has been shown to influence the location of de novo mutations observed in ASD as well as the landscape of DNA methylation underlying neurodevelopmental and synaptic processes. Understanding the interactions of nuclear chromatin proteins and DNA with signal transduction pathways and environmental influences in the developing brain will be critical to understanding the relevance of these ASD candidate genes and continued uncovering of the "roots" of autism etiology.
Project description:BackgroundThere is a well-documented lack of rapid, low-cost tuberculosis (TB) drug resistance diagnostics in low-income settings across the globe. It is these areas that are plagued with a disproportionately high disease burden and in greatest need of these diagnostics.MethodsIn this study, we compared the performance of Light Forge, a microfluidic high-resolution melting analysis (HRMA) prototype for rapid low-cost detection of TB drug resistance with a commercial HRMA device, a predictive "nearest-neighbor" thermodynamic model, DNA sequencing, and phenotypic drug susceptibility testing (DST). The initial development and assessment of the Light Forge assay was performed with 7 phenotypically drug resistant strains of Mycobacterium tuberculosis (M.tb) that had their rpoB gene subsequently sequenced to confirm resistance to Rifampin. These isolates of M.tb were then compared against a drug-susceptible standard, H37Rv. Seven strains of M.tb were isolated from clinical specimens and individually analyzed to characterize the unique melting profile of each strain.ResultsLight Forge was able to detect drug-resistance linked mutations with 100% concordance to the sequencing, phenotypic DST and the "nearest neighbor" thermodynamic model. Researchers were then blinded to the resistance profile of the seven M.tb strains. In this experiment, Light Forge correctly classified 7 out of 9 strains as either drug resistant or drug susceptible.ConclusionsLight Forge represents a promising prototype for a fast, low-cost diagnostic alternative for detection of drug resistant strains of TB in resource constrained settings.
Project description:Nonrapid eye movement sleep is characterized by high-amplitude and low-frequency electroencephalography signals. These signals are thought to be produced by the synchronized activity of cortical neurons, demonstrating the alternating bursting (up) and resting (down) states. Here, such an activity is referred to as up-down oscillation (UDO). Previously, we discussed the importance of the Ca2+-dependent hyperpolarization pathway in the generation of UDO by simulating neuronal activity based on the Hodgkin-Huxley-type model. We herein focus on intracellular Na+ dynamics. The Na+-centered model indicates that the activation of voltage-gated Na+ channels leads to intracellular Na+ accumulation, which in turn activates Na+-dependent K+ (KNa) channels or Na+/K+ ATPases, resulting in the down state. Activation kinetics of voltage-gated Na+ channels are important in shaping the UDO firing. Therefore, our model demonstrates that voltage-gated Na+ and KNa channels or Na+/K+ ATPases are candidate pathways for UDO induction.
Project description:The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pro-inflammatory immune receptor potentiating acute lung injury (ALI). However, the mechanism of TREM-1-triggered inflammation response remains poorly understood. Here, we showed that TREM-1 blocking attenuated NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome activation and glycolysis in LPS-induced ALI mice. Then, we observed that TREM-1 activation enhanced glucose consumption, induced glycolysis, and inhibited oxidative phosphorylation in macrophages. Specifically, inhibition of glycolysis with 2-deoxyglucose diminished NLRP3 inflammasome activation of macrophages triggered by TREM-1. Hypoxia-inducible factor-1α (HIF-1α) is a critical transcriptional regulator of glycolysis. We further found that TREM-1 activation facilitated HIF-1α accumulation and translocation to the nucleus via the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Inhibiting mTOR or HIF-1α also suppressed TREM-1-induced metabolic reprogramming and NLRP3/caspase-1 activation. Overall, the mTOR/HIF-1α/glycolysis pathway is a novel mechanism underlying TREM-1-governed NLRP3 inflammasome activation. Therapeutic targeting of the mTOR/HIF-1α/glycolysis pathway in TREM-1-activated macrophages could be beneficial for treating or preventing inflammatory diseases, such as ALI.
Project description:Accurate genome duplication requires a tightly regulated DNA replication program, which relies on the fine regulation of origin firing. While the molecular steps involved in origin firing have been determined predominantly in budding yeast, the complexity of this process in human cells has yet to be fully elucidated. Here, we describe a straightforward proteomics approach to systematically analyse protein recruitment to the chromatin during induced origin firing in human cells. Using a specific inhibitor against CHK1 kinase, we induced a synchronised wave of dormant origin firing (DOF) and assessed the S phase chromatin proteome at different time points. We provide time-resolved loading dynamics of 3,269 proteins, including the core replication machinery and origin firing factors. This dataset accurately represents known temporal dynamics of proteins on the chromatin during the activation of replication forks and the subsequent DNA damage due to the hyperactivation of excessive replication forks. Finally, we used our dataset to identify the condensin II subunit NCAPH2 as a novel factor required for efficient origin firing and replication. Overall, we provide a comprehensive resource to interrogate the protein recruitment dynamics of replication origin firing events in human cells.
Project description:Accurate genome duplication requires a tightly regulated DNA replication program, which relies on the fine regulation of origin firing. While the molecular steps involved in origin firing have been determined predominantly in budding yeast, the complexity of this process in human cells has yet to be fully elucidated. Here, we describe a straightforward proteomics approach to systematically analyse protein recruitment to the chromatin during induced origin firing in human cells. Using a specific inhibitor against CHK1 kinase, we induced a synchronised wave of dormant origin firing (DOF) and assessed the S phase chromatin proteome at different time points. We provide time-resolved loading dynamics of 3,269 proteins, including the core replication machinery and origin firing factors. This dataset accurately represents known temporal dynamics of proteins on the chromatin during the activation of replication forks and the subsequent DNA damage due to the hyperactivation of excessive replication forks. Finally, we used our dataset to identify the condensin II subunit NCAPH2 as a novel factor required for efficient origin firing and replication. Overall, we provide a comprehensive resource to interrogate the protein recruitment dynamics of replication origin firing events in human cells.