Biology subjects

Jones, T.

Publications and source records attributed to Jones, T..

3 recordsLinked to original sources

bioRxiv2018

Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining

Purpose: Following cytotoxic therapy, 70% of patients with human papillomavirus (HPV) positive oropharyngeal head and neck squamous cell carcinoma (HNSCC) are alive at 5 years compared to 30% of those with similar HPV-negative cancer, which is thought to be due to dysregulation of DNA repair. Loss of transforming growth factor {beta} (TGF{beta}) signaling is a poorly studied consequence of HPV that could contribute to this phenotype.\n\nExperimental Design: Human HNSCC cell lines (n=9), patient-derived xenografts (n=9), tissue microarray (n=194), TCGA expression data and primary tumor specimens (n=10) were used to define the relationship between TGF{beta} competency, response to DNA damage, and type of DNA repair.\n\nResults: Analysis of HNSCC specimens in situ and in vitro showed that HPV associates with loss of TGF{beta} signaling that increases the response to radiation or cisplatin. TGF{beta} suppressed miR-182 that inhibited both BRCA1, necessary for homologous recombination repair, and FOXO3, which is required for ATM kinase activity. TGF{beta} signaling blockade by either HPV or inhibitors released this control, compromised HRR and increased response to PARP inhibition. Antagonizing miR-182 rescued the homologous recombination deficit in HPV+ cells. Loss of TGF{beta} signaling unexpectedly increased error-prone, alternative end-joining repair.\n\nConclusions: HPV-positive HNSCC cells are unresponsive to TGF{beta}. Abrogated TGF{beta} signaling compromises homologous recombination and shifts reliance on alt-EJ repair that provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGF{beta}s role in DNA repair proficiency and further raises the translational potential of TGF{beta} inhibitors in cancer therapy.

cancer biology↗

bioRxiv2018

Spatio-temporally specific transcranial magnetic stimulation to test the locus of perceptual decision making in the human brain

Previous research modeling EEG, fMRI and behavioral data has identified three spatially distributed brain networks that activate in temporal sequence, and are thought to enable perceptual decision-making during face-versus-car categorization. These studies have linked late activation (>300ms post stimulus onset) in the lateral occipital cortex (LOC) to object discrimination processes. We applied paired-pulse transcranial magnetic stimulation (ppTMS) to LOC at different temporal latencies with the specific prediction, based on these studies, that ppTMS beginning at 400ms after stimulus onset would slow reaction time (RT) performance. Thirteen healthy adults performed a two-alternative forced choice task selecting whether a car or face was present on each trial amidst visual noise pre-titrated to approximate 79% accuracy. ppTMS, with pulses separated by 50ms, was applied at one of five stimulus onset asynchronies: -200, 200, 400, 450, or 500ms, and a sixth no-stimulation condition. As predicted, TMS at 400ms resulted in significant slowing of RTs, providing causal evidence in support of LOC contribution to perceptual decision processing. In addition, TMS delivered at -200ms resulted in faster RTs, indicating early stimulation may result in performance enhancement. These findings build upon correlational EEG and fMRI observations and demonstrate the use of TMS in predictive validation of psychophysiological models.

neuroscience↗

bioRxiv2017

Complete assembly of a dengue virus type 3 genome from a recent genotype III clade by metagenomic sequencing of serum

BackgroundMosquito-borne flaviviruses causing diseases such as dengue and Japanese encephalitis are devastating, particularly in the tropics. Although, multiple flaviviruses are known to co-circulate in India, when a patient presents with febrile illness, testing is usually limited to specific pathogens. Unbiased metagenomic sequencing of febrile cases can reveal the presence of multiple pathogens and provide complete genome information. Sequence information, a cornerstone for tracing virus evolution, is relevant for the design of vaccines and therapeutics. In order to assess the usefulness of unbiased metagenomic sequencing for the identification of viruses associated with febrile illness, we sequenced serum from four individuals and plasma from one individual, all hospitalized at a tertiary care centre in South India with severe or prolonged febrile illnesses, together with one healthy control in 2014.\n\nResultsWe identified and assembled a complete dengue virus type 3 (DENV3) sequence from the serum of a case classified as severe dengue. We also found a small number of Japanese encephalitis virus (JEV) sequences in the serum of two adults with febrile illness, including the one who had dengue. Phylogenetic analysis of the dengue sequence indicates that it belongs to a predominantly Asian, DENV3, genotype III clade. It had an estimated divergence time of 13.86 years (95% Highest Posterior Densities 12.94 - 14.83 years) with the closest Indian strain. Amino acid substitutions were present throughout the sequenced genome, including 11 substitutions in the antigenic envelope protein compared to the strain used for the development of the first commercial dengue vaccine. Of these one substitution (E361D) was unique and six were in critical antigenic sites.\n\nConclusionsWe demonstrate that both genome assembly and detection of a low number of viral sequences are possible by unbiased sequencing of clinical material. Complete dengue virus sequence analysis places the sequenced genome in a recent, predominantly Asian clade within genotype III of DENV3. The detection of JEV, an agent not routinely tested in febrile illness in India, warrants further analysis and highlights the need to study co-circulating flaviviruses in parallel.

microbiology↗