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P-TEFb goes viral

Zaborowska J, Isa NF, Murphy S

Inside Cell, 2016 04;1(2):106-116.
PMID: 27398404

Positive transcription elongation factor b (P-TEFb), which comprises cyclin-dependent kinase 9 (CDK9) kinase and cyclin T subunits, is an essential kinase complex in human cells. Phosphorylation of the negative elongation factors by P-TEFb is required for productive elongation of transcription of protein-coding genes by RNA polymerase II (pol II). In addition, P-TEFb-mediated phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of pol II mediates the recruitment of transcription and RNA processing factors during the transcription cycle. CDK9 also phosphorylates p53, a tumor suppressor that plays a central role in cellular responses to a range of stress factors. Many viral factors affect transcription by recruiting or modulating the activity of CDK9. In this review, we will focus on how the function of CDK9 is regulated by viral gene products. The central role of CDK9 in viral life cycles suggests that drugs targeting the interaction between viral products and P-TEFb could be effective anti-viral agents.
P-TEFb goes viral

Zaborowska J, Isa NF, Murphy S

Bioessays, 2016 07;38 Suppl 1:S75-85.
PMID: 27417125 DOI: 10.1002/bies.201670912

Positive transcription elongation factor b (P-TEFb), which comprises cyclin-dependent kinase 9 (CDK9) kinase and cyclin T subunits, is an essential kinase complex in human cells. Phosphorylation of the negative elongation factors by P-TEFb is required for productive elongation of transcription of protein-coding genes by RNA polymerase II (pol II). In addition, P-TEFb-mediated phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of pol II mediates the recruitment of transcription and RNA processing factors during the transcription cycle. CDK9 also phosphorylates p53, a tumor suppressor that plays a central role in cellular responses to a range of stress factors. Many viral factors affect transcription by recruiting or modulating the activity of CDK9. In this review, we will focus on how the function of CDK9 is regulated by viral gene products. The central role of CDK9 in viral life cycles suggests that drugs targeting the interaction between viral products and P-TEFb could be effective anti-viral agents.
Sex differences in PTSD symptoms: A differential item functioning approach

Murphy S, Elklit A, Chen YY, Ghazali SR, Shevlin M

Psychol Trauma, 2019 Mar;11(3):319-327.
PMID: 29723027 DOI: 10.1037/tra0000355

OBJECTIVE: Evidence has suggested there are sex differences in posttraumatic stress disorder (PTSD) symptom expression; however, few studies have assessed whether these differences are due to measurement invariance. This study aimed to examine sex differences in PTSD symptoms based on the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) using differential item functioning (DIF).
METHOD: Confirmatory factor analysis was conducted on the DSM-5 model of PTSD, followed by a multiple indicators multiple causes (MIMIC) model to examine possible DIF using the PTSD Checklist for DSM-5. Data were analyzed from a Malaysian adolescent sample (n = 481) of which 61.7% were female, with a mean age of 17.03 years.
RESULTS: The results indicated the presence of DIF for 2 of 20 PTSD criteria. Females scored significantly higher on emotional cue reactivity (B4), and males reported significantly higher rates of reckless or self-destructive behavior (E2) while statistically controlling for the latent variables in the model. However, the magnitude of these item-level differences was small.
CONCLUSION: These findings indicate that despite the presence of DIF for 2 DSM-5 symptoms, this does not provide firm support for nonequivalence across sex. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
Fulltext Gender-based market constraints to informal fish retailing: Evidence from analysis of variance and linear regression

Murphy S, Arora D, Kruijssen F, McDougall C, Kantor P

PLoS One, 2020;15(3):e0229286.
PMID: 32231375 DOI: 10.1371/journal.pone.0229286

Over the last decade, Egypt's aquaculture sector has expanded rapidly, which has contributed substantially to per capita fish supply, and the growth of domestic fish markets and employment across the aquaculture value chain. Despite the growing importance of aquaculture sector in Egyptian labour force, only a few studies have explored the livelihoods of Egypt's women and men fish retailers. Even fewer studies have examined gender-based market constraints experienced by these informal fish retailers. This study uses sex-disaggregated data collected in 2013 in three governorates of Lower Egypt to examine the economic and social constraints to scale of enterprises between women (n = 162) and men informal fish retailers (n = 183). Specifically, we employ linear regression method to determine the correlates of enterprise performance. We found that both women and men retailers in the informal fish market earn low profits and face livelihood insecurities. However, women's enterprise performance is significantly lower than that of men even after controlling for individual socio-economic and retailing characteristics. Specifically, the burden of unpaid household work and lack of support therein impedes women's ability to generate higher revenues. These findings strengthen the argument for investing in understanding how gender norms and attitudes affect livelihood options and outcomes. This leads to recommendations on gender-responsive interventions that engage with both men and women and enhance the bargaining power and collective voice of fish retailers.
Fulltext HSV-1 ICP22 Is a Selective Viral Repressor of Cellular RNA Polymerase II-Mediated Transcription Elongation

Isa NF, Bensaude O, Aziz NC, Murphy S

Vaccines (Basel), 2021 Sep 22;9(10).
PMID: 34696162 DOI: 10.3390/vaccines9101054

The Herpes Simplex Virus (HSV-1) immediate-early protein ICP22 interacts with cellular proteins to inhibit host cell gene expression and promote viral gene expression. ICP22 inhibits phosphorylation of Ser2 of the RNA polymerase II (pol II) carboxyl-terminal domain (CTD) and productive elongation of pol II. Here we show that ICP22 affects elongation of pol II through both the early-elongation checkpoint and the poly(A)-associated elongation checkpoint of a protein-coding gene model. Coimmunoprecipitation assays using tagged ICP22 expressed in human cells and pulldown assays with recombinant ICP22 in vitro coupled with mass spectrometry identify transcription elongation factors, including P-TEFb, additional CTD kinases and the FACT complex as interacting cellular factors. Using a photoreactive amino acid incorporated into ICP22, we found that L191, Y230 and C225 crosslink to both subunits of the FACT complex in cells. Our findings indicate that ICP22 interacts with critical elongation regulators to inhibit transcription elongation of cellular genes, which may be vital for HSV-1 pathogenesis. We also show that the HSV viral activator, VP16, has a region of structural similarity to the ICP22 region that interacts with elongation factors, suggesting a model where VP16 competes with ICP22 to deliver elongation factors to viral genes.
Profile of reticulated platelets in the early, subacute and late phases after transient ischemic attack or ischemic stroke

Lim ST, Tobin WO, Murphy S, Kinsella JA, Smith DR, Lim SY, et al.

Platelets, 2022 Jan 02;33(1):89-97.
PMID: 33347340 DOI: 10.1080/09537104.2020.1850670

Information regarding the profile of reticulated platelets (RP) in ischemic cerebrovascular disease (CVD) patients is limited. Data from two prospective, observational, case-control studies were combined to compare the %RP using whole blood flow cytometry in patients ≤ 4 weeks of TIA/stroke onset (baseline, N = 210), and 14 ±7 days (14d, N = 182) and ≥ 90 days (90d, N = 145) after starting or changing antiplatelet therapy with healthy controls (N = 34). There were no differences in median %RP between the overall CVD patient population at baseline or 14d vs. controls (P ≥ 0.2). However, the median %RP was significantly higher in CVD patients overall at 90d (P = .036), and in the subgroup of patients with "lacunar" TIA/ischemic stroke at baseline (P = .04) and at 90d (P = .01), but not at 14d (P = .06) vs. controls. There were no significant differences in the median %RP between other TIA/stroke subgroups and controls (P ≥ 0.05). Elevated circulating reticulated platelets, as a marker of increased platelet production/turnover, may occur following an ischemic event in a well-phenotyped TIA/ischemic stroke population overall, but may precede symptom onset at least in the subgroup with small vessel occlusion. These data improve our understanding of the profile of reticulated platelets in CVD patients.
Alternative models of DSM-5 PTSD: Examining diagnostic implications

Murphy S, Hansen M, Elklit A, Yong Chen Y, Raudzah Ghazali S, Shevlin M

Psychiatry Res, 2018 04;262:378-383.
PMID: 28917443 DOI: 10.1016/j.psychres.2017.09.011

The factor structure of DSM-5 posttraumatic stress disorder (PTSD) has been extensively debated with evidence supporting the recently proposed seven-factor Hybrid model. However, despite myriad studies examining PTSD symptom structure few have assessed the diagnostic implications of these proposed models. This study aimed to generate PTSD prevalence estimates derived from the 7 alternative factor models and assess whether pre-established risk factors associated with PTSD (e.g., transportation accidents and sexual victimisation) produce consistent risk estimates. Seven alternative models were estimated within a confirmatory factor analytic framework using the PTSD Checklist for DSM-5 (PCL-5). Data were analysed from a Malaysian adolescent community sample (n = 481) of which 61.7% were female, with a mean age of 17.03 years. The results indicated that all models provided satisfactory model fit with statistical superiority for the Externalising Behaviours and seven-factor Hybrid models. The PTSD prevalence estimates varied substantially ranging from 21.8% for the DSM-5 model to 10.0% for the Hybrid model. Estimates of risk associated with PTSD were inconsistent across the alternative models, with substantial variation emerging for sexual victimisation. These findings have important implications for research and practice and highlight that more research attention is needed to examine the diagnostic implications emerging from the alternative models of PTSD.
Fulltext CDK9 inhibitors define elongation checkpoints at both ends of RNA polymerase II-transcribed genes

Laitem C, Zaborowska J, Isa NF, Kufs J, Dienstbier M, Murphy S

Nat Struct Mol Biol, 2015 May;22(5):396-403.
PMID: 25849141 DOI: 10.1038/nsmb.3000

Transcription through early-elongation checkpoints requires phosphorylation of negative transcription elongation factors (NTEFs) by the cyclin-dependent kinase (CDK) 9. Using CDK9 inhibitors and global run-on sequencing (GRO-seq), we have mapped CDK9 inhibitor-sensitive checkpoints genome wide in human cells. Our data indicate that early-elongation checkpoints are a general feature of RNA polymerase (pol) II-transcribed human genes and occur independently of polymerase stalling. Pol II that has negotiated the early-elongation checkpoint can elongate in the presence of inhibitors but, remarkably, terminates transcription prematurely close to the terminal polyadenylation (poly(A)) site. Our analysis has revealed an unexpected poly(A)-associated elongation checkpoint, which has major implications for the regulation of gene expression. Interestingly, the pattern of modification of the C-terminal domain of pol II terminated at this new checkpoint largely mirrors the pattern normally found downstream of the poly(A) site, thus suggesting common mechanisms of termination.