The cross-talk between Bax, Bcl2, caspases, and DNA damage in bystander HepG2 cells is regulated by γ-radiation dose and time of conditioned media transfer.

Although radiation-induced bystander effects have been broadly explored in various biological systems, the molecular mechanisms and the consequences of different regulatory factors (dose, time, cell type) on bystander responses are not clearly understood. This study investigates the effects of irradiated cell-conditioned media (ICCM) collected at different times post-irradiation on bystander cancer cells regarding DNA damage and apoptosis induction. Human hepatocellular carcinoma HepG2 cells were exposed to γ-ray doses of 2 Gy, 5 Gy, and 8 Gy. In the early and late stages (1 h, 2 h, and 24 h) after irradiation, the ICCM was collected and transferred to unirradiated cells. Compared to control, bystander cells showed an increased level of H2AX phosphorylation, mitochondrial membrane depolarization, and elevation of intrinsic apoptotic pathway mediators such as p53, Bax, cas9, cas-3, and PARP cleavage. These results were confirmed by phosphatidylserine (PS) externalization and scanning electron microscopic observations, suggesting a rise in bystander HepG2 cell apoptosis. Anti-apoptotic Bcl2-level and viability were lower in bystander cells compared to control. The highest effects were observed in 8 Gy γ radiation-induced bystander cells. Even though the bystander effect was persistent at all time points of the study, ICCM at the early time points (1 or 2 h) had the most significant impact on the apoptosis markers in bystander cells. Nevertheless, 24 h ICCM induced the highest increase in H2AX and p53 phosphorylation and Bax levels. The effects of ICCM of irradiated HepG2 cells were additionally studied in normal liver cells BRL-3A to simulate actual radiotherapy conditions. The outcomes suggest that the expression of the signaling mediators in bystander cells is highly dynamic. A cross-talk between those signaling mediators regulates bystander responses depending on the radiation dose and time of incubation post-irradiation.

The interaction of oxidative stress with MAPK, PI3/AKT, NF-κB, and DNA damage kinases influences the fate of γ-radiation-induced bystander cells.

Oxidative stress is associated with the induction of a plethora of effects on cellular macromolecules and signaling cascades. The onset of oxidative imbalance characterizes irradiated cells. The present study investigates the effects of ionizing radiation on oxidative stress induction in bystander cells and their interactions with critical cell signaling mediators. The effect of irradiated cell-conditioned medium (ICCM) from γ-irradiated hepatocellular carcinoma (HepG2) cells were studied in bystander HepG2 and normal liver (BRL-3A) cells at early (1 h, 2 h) and later (24 h) time points post-irradiation. Although ROS generation and lipid peroxidation showed the highest effects in both bystander cell groups at the early time points, antioxidant enzymes superoxide dismutase and catalase showed the lowest activity. Oxidative stress was persistent up to 24 h, but the highest level was seen in 1 h ICCM treated 8By cells. Although the levels of all pro-survival signaling factors (p-PI3K, p-Akt, p-p38MAPK, p-JNK, and p-NFκB) increased in bystander HepG2 cells, they showed a significant decrease in bystander BRL-3A cells. JAK2-STAT3 activation, however, was reduced only in BRL-3A cells, with no effect in HepG2 cells. However, in both bystander cell groups, activation of DNA damage sensors ATM, ATR, and cell cycle inhibitor p21 increased. Elevated ROS levels down-regulated the activation of PI3K, Akt, JNK, and NF-κB in BRL-3A cells but enhanced the activation of ATM and p21. In contrast, in HepG2 cells, increased ROS level elevated the activation of PI3K, JNK, p38MAPK, NF-κB with no effect on p-ATM or p21. ROS differentially influenced the interactions between the signaling mediators in the bystander cells. p-ATR levels, although increased in both bystander cell groups, showed no association with other factors. ICCM from the same HepG2 cells differently affected signaling factors in two groups of cells, highlighting the critical significance of the study in the field of radiation biology.

Household air pollution, ultrasound measurement, fetal biometric parameters and intrauterine growth restriction.

BACKGROUND: Low birthweight, intrauterine growth restriction (IUGR) and perinatal mortality have been associated with air pollution. However, intervention studies that use ultrasound measurements to assess the effects of household air pollution (HAP) on fetal biometric parameters (FBP) are rare. We investigated the effect of a cookstove intervention on FBP and IUGR in a randomized controlled trial (RCT) cohort of HAP-exposed pregnant Nigerian women. METHODS: We recruited 324 women early in the second trimester of pregnancy. Between 16 and 18 weeks, we randomized them to either continue cooking with firewood/kerosene (control group) or receive a CleanCook stove and ethanol fuel (intervention group). We measured fetal biparietal diameter (BPD), head circumference (HC), femur length (FL), abdominal circumference (AC) and ultrasound-estimated fetal weight (U-EFW) in the second and third trimesters. The women were clinically followed up at six regular time points during their pregnancies. Once during the women's second trimester and once during the third, we made 72-h continuous measurements of their personal exposures to particulate matter having aerodynamic diameter < 2.5 µm (PM2.5). We adopted a modified intent-to-treat approach for the analysis. Differences between the intervention and control groups on impact of HAP on fetal growth trajectories were analyzed using mixed effects regression models. RESULTS: There were no significant differences in fetal growth trajectories between the intervention and control groups. CONCLUSIONS: Larger studies in a setting of low ambient air pollution are required to further investigate the effect of transitioning to a cleaner fuel such as ethanol on intrauterine growth. TRIAL REGISTRATION: ClinicalTrials.gov NCT02394574 ; September 2012.

Randomized Controlled Ethanol Cookstove Intervention and Blood Pressure in Pregnant Nigerian Women.

RATIONALE: Hypertension during pregnancy is a leading cause of maternal mortality. Exposure to household air pollution elevates blood pressure (BP). OBJECTIVES: To investigate the ability of a clean cookstove intervention to lower BP during pregnancy. METHODS: We conducted a randomized controlled trial in Nigeria. Pregnant women cooking with kerosene or firewood were randomly assigned to an ethanol arm (n = 162) or a control arm (n = 162). BP measurements were taken during six antenatal visits. In the primary analysis, we compared ethanol users with control subjects. In subgroup analyses, we compared baseline kerosene users assigned to the intervention with kerosene control subjects and compared baseline firewood users assigned to ethanol with firewood control subjects. MEASUREMENTS AND MAIN RESULTS: The change in diastolic blood pressure (DBP) over time was significantly different between ethanol users and control subjects (P = 0.040); systolic blood pressure (SBP) did not differ (P = 0.86). In subgroup analyses, there was no significant intervention effect for SBP; a significant difference for DBP (P = 0.031) existed among preintervention kerosene users. At the last visit, mean DBP was 2.8 mm Hg higher in control subjects than in ethanol users (3.6 mm Hg greater in control subjects than in ethanol users among preintervention kerosene users), and 6.4% of control subjects were hypertensive (SBP ≥140 and/or DBP ≥90 mm Hg) versus 1.9% of ethanol users (P = 0.051). Among preintervention kerosene users, 8.8% of control subjects were hypertensive compared with 1.8% of ethanol users (P = 0.029). CONCLUSIONS: To our knowledge, this is the first cookstove randomized controlled trial examining prenatal BP. Ethanol cookstoves have potential to reduce DBP and hypertension during pregnancy. Accordingly, clean cooking fuels may reduce adverse health impacts associated with household air pollution. Clinical trial registered with www.clinicaltrials.gov (NCT02394574).

Comparative study of the effectiveness and limitations of current methods for detecting sequence coevolution.

MOTIVATION: With rapid accumulation of sequence data on several species, extracting rational and systematic information from multiple sequence alignments (MSAs) is becoming increasingly important. Currently, there is a plethora of computational methods for investigating coupled evolutionary changes in pairs of positions along the amino acid sequence, and making inferences on structure and function. Yet, the significance of coevolution signals remains to be established. Also, a large number of false positives (FPs) arise from insufficient MSA size, phylogenetic background and indirect couplings. RESULTS: Here, a set of 16 pairs of non-interacting proteins is thoroughly examined to assess the effectiveness and limitations of different methods. The analysis shows that recent computationally expensive methods designed to remove biases from indirect couplings outperform others in detecting tertiary structural contacts as well as eliminating intermolecular FPs; whereas traditional methods such as mutual information benefit from refinements such as shuffling, while being highly efficient. Computations repeated with 2,330 pairs of protein families from the Negatome database corroborated these results. Finally, using a training dataset of 162 families of proteins, we propose a combined method that outperforms existing individual methods. Overall, the study provides simple guidelines towards the choice of suitable methods and strategies based on available MSA size and computing resources. AVAILABILITY AND IMPLEMENTATION: Software is freely available through the Evol component of ProDy API.

αvß6 integrin is required for TGFß1-mediated matrix metalloproteinase2 expression.

Transforming growth factor (TGF) ß1 activity depends on a complex signalling cascade that controls expression of several genes. Among others, TGFß1 regulates expression of matrix metalloproteinases (MMPs) through activation of Smads. In the present study, we demonstrate for the first time that the αvß6 integrin interacts with TGFß receptor II (TßRII) through the ß6 cytoplasmic domain and promotes Smad3 activation in prostate cancer (PrCa) cells. Another related αv integrin, αvß5, as well as the αvß6/3 integrin, which contains a chimeric form of ß6 with a ß3 cytoplasmic domain, do not associate with TßRII and fail to show similar responses. We provide evidence that αvß6 is required for up-regulation of MMP2 by TGFß1 through a Smad3-mediated transcriptional programme in PrCa cells. The functional relevance of these results is underscored by the finding that αvß6 modulates cell migration in an MMP2-dependent manner on an αvß6-specific ligand, latency-associated peptide (LAP)-TGFß. Overall, these mechanistic studies establish that expression of a single integrin, αvß6, is sufficient to promote activation of Smad3, regulation of MMP2 levels and consequent catalytic activity, as well as cell migration. Our study describes a new TGFß1-αvß6-MMP2 signalling pathway that, given TGFß1 pro-metastatic activity, may have profound implications for PrCa therapy.

Dynamics and allosteric potential of the AMPA receptor N-terminal domain.

Glutamate-gated ion channels (ionotropic glutamate receptors, iGluRs) sense the extracellular milieu via an extensive extracellular portion, comprised of two clamshell-shaped segments. The distal, N-terminal domain (NTD) has allosteric potential in NMDA-type iGluRs, which has not been ascribed to the analogous domain in AMPA receptors (AMPARs). In this study, we present new structural data uncovering dynamic properties of the GluA2 and GluA3 AMPAR NTDs. GluA3 features a zipped-open dimer interface with unconstrained lower clamshell lobes, reminiscent of metabotropic GluRs (mGluRs). The resulting labile interface supports interprotomer rotations, which can be transmitted to downstream receptor segments. Normal mode analysis reveals two dominant mechanisms of AMPAR NTD motion: intraprotomer clamshell motions and interprotomer counter-rotations, as well as accessible interconversion between AMPAR and mGluR conformations. In addition, we detect electron density for a potential ligand in the GluA2 interlobe cleft, which may trigger lobe motions. Together, these data support a dynamic role for the AMPAR NTDs, which widens the allosteric landscape of the receptor and could provide a novel target for ligand development.

Evol and ProDy for bridging protein sequence evolution and structural dynamics.

UNLABELLED: Correlations between sequence evolution and structural dynamics are of utmost importance in understanding the molecular mechanisms of function and their evolution. We have integrated Evol, a new package for fast and efficient comparative analysis of evolutionary patterns and conformational dynamics, into ProDy, a computational toolbox designed for inferring protein dynamics from experimental and theoretical data. Using information-theoretic approaches, Evol coanalyzes conservation and coevolution profiles extracted from multiple sequence alignments of protein families with their inferred dynamics. AVAILABILITY AND IMPLEMENTATION: ProDy and Evol are open-source and freely available under MIT License from http://prody.csb.pitt.edu/.

Chronic inhalation of biomass smoke is associated with DNA damage in airway cells: involvement of particulate pollutants and benzene.

This study examined whether indoor air pollution from biomass fuel burning induces DNA damage in airway cells. For this, sputum cells were collected from 56 premenopausal rural women who cooked with biomass (wood, dung, crop residues) and 49 age-matched controls who cooked with cleaner liquefied petroleum gas. The levels of particulate matters with diameters of less than 10 and 2.5 µm (PM(10) and PM(2.5)) in indoor air were measured using a real-time aerosol monitor. Benzene exposure was monitored by measuring trans,trans-muconic acid (t,t-MA) in urine by HPLC-UV. DNA damage was examined by alkaline comet assay in sputum cells. Generation of reactive oxygen species (ROS) and level of superoxide dismutase (SOD) in sputum cells were measured by flow cytometry and spectrophotometry, respectively. Compared with controls, biomass users had 4 times higher tail percentage DNA, 37% more comet tail length and 5 times more Olive tail moment (p < 0.001) in inflammatory and epithelial cells in sputum, suggesting extensive DNA damage. In addition, women who cooked with biomass had 6 times higher levels of urinary t,t-MA and 2-fold higher levels of ROS generation concomitant with 28% depletion of SOD. Indoor air of biomass-using households had 2-4 times more PM(10) and PM(2.5) than that of controls. After controlling potential confounders, positive association was found between DNA damage parameters, particulate pollution, urinary t,t-MA and ROS. Thus, long-term exposure to biomass smoke induces DNA damage in airway cells and the effect was probably mediated, at least in part, by oxidative stress generated by inhaled particulate matter and benzene.

Characteristics and outcomes of gallbladder cancer patients at the Tata Medical Center, Kolkata 2017-2019.

BACKGROUND: The north and north-eastern regions of India have among the highest incidence of gallbladder cancer (GBC) in the world. We report the clinicopathological charateristics and outcome of GBC patients in India. METHODS: Electronic medical records of patients diagnosed with GBC at Tata Medical Center, Kolkata between 2017 and 2019 were analyzed. RESULTS: There were 698 cases of confirmed GBC with a median age of 58 (IQR: 50-65) years and female:male ratio of 1.96. At presentation, 91% (496/544) had stage III/IV disease and 30% (189/640) had incidental GBC. The 2-year overall survival (OS) was 100% (95% CI: 100-100); 61% (95% CI: 45-83); 30% (95% CI: 21-43); and 9% (95% CI: 6-13) for stages I-IV, respectively (p = <0.0001).   For all patients, the 2-year OS in patients who had a radical cholecystectomy followed by adjuvant therapy (N = 36) was 50% (95% CI: 39-64), compared to 29% (95% CI: 22-38) for those who had a simple cholecystectomy and/or chemotherapy (N = 265) and 9% (95% CI: 6-14) in patients who were palliated (N = 107) (p = <0.0001). CONCLUSION: The combined surgical/chemotherapy approach for patients with stage II GBC showed the best outcomes. Early detection of GBC remains problematic with the majority of patients presenting with stage III-IV and who have a median survival of 9.1 months. Our data suggests that the tumor is chemoresponsive and multi-center collaborative clinical trials to identify alternative therapies are urgently required.

Systemic inflammatory changes and increased oxidative stress in rural Indian women cooking with biomass fuels.

The study was undertaken to investigate whether regular cooking with biomass aggravates systemic inflammation and oxidative stress that might result in increase in the risk of developing cardiovascular disease (CVD) in rural Indian women compared to cooking with a cleaner fuel like liquefied petroleum gas (LPG). A total of 635 women (median age 36 years) who cooked with biomass and 452 age-matched control women who cooked with LPG were enrolled. Serum interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α) and interleukin-8 (IL-8) were measured by ELISA. Generation of reactive oxygen species (ROS) by leukocytes was measured by flow cytometry, and erythrocytic superoxide dismutase (SOD) was measured by spectrophotometry. Hypertension was diagnosed following the Seventh Report of the Joint Committee. Tachycardia was determined as pulse rate >100 beats per minute. Particulate matter of diameter less than 10 and 2.5 µm (PM10 and PM2.5, respectively) in cooking areas was measured using real-time aerosol monitor. Compared with control, biomass users had more particulate pollution in indoor air, their serum contained significantly elevated levels of IL-6, IL-8, TNF-α and CRP, and ROS generation was increased by 37% while SOD was depleted by 41.5%, greater prevalence of hypertension and tachycardia compared to their LPG-using neighbors. PM10 and PM2.5 levels were positively associated with markers of inflammation, oxidative stress and hypertension. Inflammatory markers correlated with raised blood pressure. Cooking with biomass exacerbates systemic inflammation, oxidative stress, hypertension and tachycardia in poor women cooking with biomass fuel and hence, predisposes them to increased risk of CVD development compared to the controls. Systemic inflammation and oxidative stress may be the mechanistic factors involved in the development of CVD.

Activation of protein kinase B (PKB/Akt) and risk of lung cancer among rural women in India who cook with biomass fuel.

The impact of indoor air pollution (IAP) from biomass fuel burning on the risk of carcinogenesis in the airways has been investigated in 187 pre-menopausal women (median age 34years) from eastern India who cooked exclusively with biomass and 155 age-matched control women from same locality who cooked with cleaner fuel liquefied petroleum gas. Compared with control, Papanicolau-stained sputum samples showed 3-times higher prevalence of metaplasia and 7-times higher prevalence of dysplasia in airway epithelial cell (AEC) of biomass users. Immunocytochemistry showed up-regulation of phosphorylated Akt (p-Akt(ser473) and p-Akt(thr308)) proteins in AEC of biomass users, especially in metaplastic and dysplastic cells. Compared with LPG users, biomass-using women showed marked rise in reactive oxygen species (ROS) generation and depletion of antioxidant enzyme, superoxide dismutase (SOD) indicating oxidative stress. There were 2-5 times more particulate pollutants (PM(10) and PM(2.5)), 72% more nitrogen dioxide and 4-times more particulate-laden benzo(a)pyrene, but no change in sulfur dioxide in indoor air of biomass-using households, and high performance liquid chromatography estimated 6-fold rise in the concentration of benzene metabolite trans,trans-muconic acid (t,t-MA) in urine of biomass users. Metaplasia and dysplasia, p-Akt expression and ROS generation were positively associated with PM and t,t-MA levels. It appears that cumulative exposure to biomass smoke increases the risk of lung carcinogenesis via oxidative stress-mediated activation of Akt signal transduction pathway.

Prevalence of hypertension and pre-hypertension in rural women: a report from the villages of West Bengal, a state in the eastern part of India.

OBJECTIVE: To find out the prevalence of hypertension, pre-hypertension and tachycardia among the women in rural areas of West Bengal, identify co-factors associated with the prevalence and contribute to the body of evidence for future health programs to identify at-risk groups. DESIGN: A population-based cross-sectional study was conducted. SETTING: The study was conducted in remote villages. PARTICIPANTS: 1186 women participants, aged 18 years or more were included. MAIN OUTCOME MEASURES: They were interviewed using standard structured questionnaire. Blood pressure and tachycardia was monitored using digital sphygmomanometer. For each participant, we made two blood pressure measurements with an interval of 48 hours. Data was analysed statistically using SPSS software. RESULTS: Overall prevalence of hypertension in the study subjects was 24.7% and that of pre-hypertension and tachycardia was 40.8% and 6.4%, respectively. Both hypertension and pre-hypertension were seen to increase with age. Other identified significant factors were use of biomass fuel for cooking, absence of separate kitchen, higher body mass index (BMI), education and average family income. CONCLUSION: This study suggests quite high prevalence of hypertension as well as pre-hypertension among the women of rural areas. The findings are significant from the women health perspectives. Early detection of pre-hypertensive and hypertensive subjects will help to formulate intervention strategies to allay the spread of cardiovascular diseases.

CD Spectroscopy to Study DNA-Protein Interactions.

Circular dichroism (CD) spectroscopy is a simple and convenient method to investigate the secondary structure and interactions of biomolecules. Recent advancements in CD spectroscopy have enabled the study of DNA-protein interactions and conformational dynamics of DNA in different microenvironments in detail for a better understanding of transcriptional regulation in vivo. The area around a potential transcription zone needs to be unwound for transcription to occur. This is a complex process requiring the coordination of histone modifications, binding of the transcription factor to DNA, and other chromatin remodeling activities. Using CD spectroscopy, it is possible to study conformational changes in the promoter region caused by regulatory proteins, such as ATP-dependent chromatin remodelers, to promote transcription. The conformational changes occurring in the protein can also be monitored. In addition, queries regarding the affinity of the protein towards its target DNA and sequence specificity can be addressed by incorporating mutations in the target DNA. In short, the unique understanding of this sensitive and inexpensive method can predict changes in chromatin dynamics, thereby improving the understanding of transcriptional regulation.

PLK-1 Interacting Checkpoint Helicase, PICH, Mediates Cellular Oxidative Stress Response.

Cells respond to oxidative stress by elevating the levels of antioxidants, signaling, and transcriptional regulation, often implemented by chromatin remodeling proteins. The study presented here shows that the expression of PICH, a Rad54-like helicase belonging to the ATP-dependent chromatin remodeling protein family, is upregulated during oxidative stress in HeLa cells. We also show that PICH regulates the expression of Nrf2, a transcription factor regulating antioxidant response in both the absence and presence of oxidative stress. The overexpression of PICH in PICH-depleted cells restored Nrf2 as well as antioxidant gene expression. In turn, Nrf2 regulated the expression of PICH in the presence of oxidative stress. ChIP experiments showed that PICH is present on the Nrf2 as well as antioxidant gene promoters, suggesting that the protein might be regulating the expression of these genes directly by binding to the DNA sequences. In addition, Nrf2 and histone acetylation (H3K27ac) also played a role in activating transcription in the presence of oxidative stress. Both Nrf2 and H3K27ac were found to be present on PICH and antioxidant promoters. Their occupancy was dependent on the PICH expression as fold enrichment was found to be decreased in PICH-depleted cells. PICH ablation led to the reduced expression of Nrf2 and impaired antioxidant response, leading to increased ROS content and thus showing PICH is essential for the cell to respond to oxidative stress.

Impact of prenatal maternal psychological distress on fetal biometric parameters in household air pollution-exposed Nigerian women.

RATIONALE: Studies identify prenatal household air pollution (HAP) exposure and maternal psychological distress (PMPD) as independent factors contributing to gestational ill-health and adverse birth outcomes. OBJECTIVE: We investigated the impact of PMPD on fetal biometric parameters (FBP) in HAP-exposed pregnant Nigerian women. METHODS: The randomized controlled trial (RCT; ClinicalTrials.gov NCT02394574) investigated effects of HAP exposure in pregnant Nigerian women (n = 324), who customarily cooked with polluting fuels (firewood or kerosene). Half of the women (intervention group) were given CleanCook ethanol stoves to use for 156 days during the study. Once a month, all women were administered an abridged version of the SF-12v2TM health-related quality of life questionnaire to assess psychological distress. Using mixed effects linear regression models, adjusted for relevant covariates, we analyzed associations between the women's exposure to PM2·5 (particulate matter with an aerodynamic diameter<2·5 microns) from HAP, their PMPD scores, and FBP (ultrasound estimated fetal weight [UEFW], head circumference [HC], abdominal circumference [AC], femur length [FL], biparietal diameter [BPD], estimated gestational age [GA] and intrauterine growth restriction [IUGR]), and birth anthropometric measures (birth weight [BW] and birth length [BL]). RESULTS: PMPD negatively impacted UEFW, HC, FL, BPD and BL (p<0·05). Controls (kerosene/firewood users) experienced significantly higher PMPD compared with ethanol-stove users (p<0·05). The mediation analysis revealed that the proportion of the outcome (fetal biometrics, birth anthropometrics, IUGR and GA), which can be explained via PMPD by groups (intervention vs. control) after adjusting for confounding variables was 6·2% (0·062). No significant correlation was observed between levels of PM2.5 exposure and PMPD scores. CONCLUSIONS: PMPD was an independent mediator of adverse fetal biometric parameters in pregnant women, who were exposed to HAP from burning of firewood/kerosene. Formulating preventative measures to alleviate maternal distress during pregnancy and reducing exposure to HAP is important from public health perspectives.

Fun30 and Rtt109 Mediate Epigenetic Regulation of the DNA Damage Response Pathway in C. albicans.

Fun30, an ATP-dependent chromatin remodeler from S. cerevisiae, is known to mediate both regulation of gene expression as well as DNA damage response/repair. The Fun30 from C. albicans has not yet been elucidated. We show that C. albicans Fun30 is functionally homologous to both S. cerevisiae Fun30 and human SMARCAD1. Further, C. albicans Fun30 can mediate double-strand break end resection as well as regulate gene expression. This protein regulates transcription of RTT109, TEL1, MEC1, and SNF2-genes that encode for proteins involved in DNA damage response and repair pathways. The regulation mediated by C. albicans Fun30 is dependent on its ATPase activity. The expression of FUN30, in turn, is regulated by histone H3K56 acetylation catalyzed by Rtt109 and encoded by RTT109. The RTT109Hz/FUN30Hz mutant strain shows sensitivity to oxidative stress and resistance to MMS as compared to the wild-type strain. Quantitative PCR showed that the sensitivity to oxidative stress results from downregulation of MEC1, RAD9, MRC1, and RAD5 expression; ChIP experiments showed that Fun30 but not H3K56ac regulates the expression of these genes in response to oxidative stress. In contrast, upon treatment with MMS, the expression of RAD9 is upregulated, which is modulated by both Fun30 and H3K56 acetylation. Thus, Fun30 and H3K56 acetylation mediate the response to genotoxic agents in C. albicans by regulating the expression of DNA damage response and repair pathway genes.

Cellular response after crush injury in adult zebrafish spinal cord.

Zebrafish proves to be an excellent model system to study spinal cord regeneration because it can repair its disengaged axons and replace lost cells after injury, allowing the animal to make functional recovery. We have characterized injury response following crush injury, which is comparable to the mammalian mode of injury. Infiltrations of blood cells during early phases involve macrophages that are important in debris clearance and probably in suppression of inflammatory response. Unlike mammals where secondary injury mechanisms lead to apoptotic death of both neurons and glia, here we observe a beneficial role of apoptotic cell death. Injury-induced proliferation, presence of radial glia cells, and their role as progenitor all contribute to cellular replacement and successful neurogenesis after injury in adult zebrafish. Together with cell replacement phenomenon, there is creation of a permissive environment that includes the absence or clearance of myelin debris, presence of Schwann cells, and absence of inflammatory response.

External modulators and redox homeostasis: Scenario in radiation-induced bystander cells.

Redox homeostasis is imperative to maintain normal physiologic and metabolic functions. Radiotherapy disturbs this balance and induces genomic instability in diseased cells. However, radiation-induced effects propagate beyond the targeted cells, affecting the adjacent non-targeted cells (bystander effects). The cellular impact of radiation, thus, encompasses both targeted and non-targeted effects. Use of external modulators along with radiation can increase radio-therapeutic efficiency. The modulators' classification as protectors or sensitizers depends on interactions with damaged DNA molecules. Thus, it is necessary to realize the functions of various radio-sensitizers or radio-protectors in both irradiated and bystander cells. This review focuses on some modulators of radiation-induced bystander effects (RIBE) and their action mechanisms. Knowledge about the underlying signaling cross-talk may promote selective sensitization of radiation-targeted cells and protection of bystander cells.

Impact of prenatal and postnatal household air pollution exposure on lung function of 2-year old Nigerian children by oscillometry.

RATIONALE: Lung function is adversely affected by exposure to household air pollution (HAP). Studies investigating the impact of prenatal and postnatal HAP exposure on early childhood lung development are limited, especially from Sub-Saharan Africa. OBJECTIVE: We used oscillometry to investigate the impact on lung function of prenatal and postnatal HAP exposure of children born to Nigerian women who participated in a randomized controlled cookstove intervention trial. METHODS: We performed oscillometric measurements (R: airway resistance; X: airway reactance; Fres: resonant frequency; AX: reactance area) in 223 children starting at age of 2 years (ethanol stove, n = 113; firewood/kerosene, n = 110). Personal exposure monitoring assessed mothers' prenatal exposure to particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5). Postnatal HAP exposure was measured by determining household PM2.5 levels. We employed linear regression analysis to examine the association of prenatal and postnatal HAP exposures with children's lung function. Models were adjusted for age, gender, weight, height, group (intervention or control), birthweight and gestational age. RESULTS: Mean age of the children was 2.9 years (standard deviation = 0.3); 120 were boys (53.8%) and 103 were girls (46.2%). Higher postnatal PM2.5 exposures were significantly associated with higher airway reactance at 5 Hz (X5 Hz; p = 0.04) in adjusted models. There were no significant associations between prenatal or postnatal PM2.5 exposure levels and other oscillometry parameters in adjusted regression analysis. CONCLUSIONS: This is the first study to use oscillometry to explore the relationship between HAP exposure and lung function in children as young as 2 years. The findings provide some evidence that increased postnatal HAP exposure may result in poorer lung function in children, although larger studies are needed to confirm observed results. This study indicates that oscillometry is a low-cost and effective method to determine lung function in early childhood.