Periodontitis and periodontopathic bacteria as risk factors for rheumatoid arthritis: A review of the last 10 years.

Rheumatoid arthritis (RA) is characterized by chronic inflammatory destruction of joint tissue and is caused by an abnormal autoimmune response triggered by interactions between genetics, environmental factors, and epigenetic and posttranslational modifications. RA has been suggested to be interrelated with periodontitis, a serious form or stage of chronic inflammatory periodontal disease associated with periodontopathic bacterial infections, genetic predisposition, environmental factors, and epigenetic influences. Over the last decade, a number of animal and clinical studies have been conducted to assess whether or not periodontitis and associated periodontopathic bacteria constitute risk factors for RA. The present review introduces recent accumulating evidence to support the associations of periodontitis and periodontopathic bacteria with the risk of RA or the outcome of RA pharmacological treatment with disease-modifying antirheumatic drugs. In addition, the results from intervention studies have suggested an improvement in RA clinical parameters after nonsurgical periodontal treatment. Furthermore, the potential causal mechanisms underlying the link between periodontitis and periodontopathic bacteria and RA are summarized.

Genital self-amputation-its psychological urge.

Genital self-mutilation (GSM) is a rare phenomenon that can occur in patients with severe mental health illness. This case report highlights a rare case of self-inflicted bilateral testicular amputation and partial penile amputation in a patient who is a transwoman with a psychiatric history. The patient initially presented to urology in extremis with bilateral testicular amputation. The patient was resuscitated but required emergency surgery in the form of bilateral inguinal approach to ligate the cord and control haemostasis. The testes were not re-implanted as the patient refused and, after psychiatric discussion, was deemed to have capacity. She then re-presented within a week with self-inflicted partial amputation of penis. On both admissions, the patient had psychiatric evaluation but she was sectioned under the mental health act the second time. This case demonstrates how one can control haemostasis in the emergency scenarios of GSM and emphasizes the importance of psychiatric illness and evaluation in patients presenting with GSM.

The role of foreign body response in peri-implantitis: What is the evidence?

Historically, there has been broad consensus that osseointegration represents a homeostasis between a titanium dental implant and the surrounding bone, and that the crestal bone loss characteristic of peri-implantitis is a plaque-induced inflammatory process. However, this notion has been challenged over the past decade by proponents of a theory that considers osseointegration an inflammatory process characterized by a foreign body reaction and peri-implant bone loss as an exacerbation of this inflammatory response. A key difference in these two schools of thought is the perception of the relative importance of dental plaque in the pathogenesis of crestal bone loss around implants, with obvious implications for treatment. This review investigates the evidence for a persistent foreign body reaction at osseointegrated dental implants and its possible role in crestal bone loss characteristic of peri-implantitis. Further, the role of implant-related material release within the surrounding tissue, particularly titanium particles and corrosion by-products, in the establishment and progression in peri-implantitis is explored. While it is acknowledged that these issues require further investigation, the available evidence suggests that osseointegration is a state of homeostasis between the titanium implant and surrounding tissues, with little evidence that a persistent foreign body reaction is responsible for peri-implant bone loss after osseointegration is established. Further, there is a lack of evidence for a unidirectional causative role of corrosion by-products and titanium particles as possible non-plaque related factors in the etiology of peri-implantitis.

Associations between inflammation-related LL-37 with subgingival microbial dysbiosis in rheumatoid arthritis patients.

OBJECTIVE: This study investigated the subgingival microbial profile of rheumatoid arthritis (RA) patients and its associations with disease parameters and the inflammation-related antimicrobial peptide, LL-37. METHODS: RA and non-RA (NRA) patients were assessed for periodontal status and divided into periodontitis (CP), gingivitis (G), and healthy (H) groups. Subgingival plaque 16s rRNA gene sequencing data was processed and analyzed using the CLC Genomic Workbench (Qiagen). Bacterial diversity and co-occurrence patterns were examined. Differential abundance between groups was also investigated. Associations between bacterial genera with disease parameters and LL-37 levels were explored qualitatively using canonical correlation analysis. RESULTS: Subgingival microbial community clustered in CP status. Co-occurrence network in NRA-H was dominated by health-associated genera, while the rest of the networks' key genera were both health- and disease-associated. RA-CP displayed highly inter-generic networks with a statistically significant increase in periodontal disease-associated genera (p<0.05). In NRA-H, disease parameters and LL-37 were correlated positively with disease-associated genera while negatively with health-associated genera. However, in the remaining groups, mixed positive and negative correlations were noted with genera. CONCLUSION: RA patients demonstrated subgingival microbial dysbiosis where the bacteria networks were dominated by health- and disease-associated genera. Mixed correlations with disease parameters and LL-37 levels were noted. CLINICAL RELEVANCE: The subgingival microbial dysbiosis in RA may predispose these patients to developing periodontal inflammation with an associated detrimental effect on host immune responses. Routine periodontal assessment may allow initiation of treatment strategies to minimize the effects of gingival inflammation on the existing heightened immune response present in RA patients.

The emerging role of small extracellular vesicles in saliva and gingival crevicular fluid as diagnostics for periodontitis.

Periodontitis is a highly prevalent multifactorial chronic inflammatory disease associated with a destructive host immune-inflammatory response to microbial dysbiosis. Current clinical diagnosis is reliant on measuring past periodontal tissue loss, with a lack of molecular biomarkers to accurately diagnose periodontitis activity in 'real-time'. Thus, discovery of new classes of diagnostic biomarkers is of critical importance in periodontology. Small extracellular vesicles (<200 nm in diameter; sEVs) from oral biofluids (saliva and gingival crevicular fluid-GCF) are lipid-encapsulated bilayered vesicles and have recently emerged as a potential source of biomarkers for periodontal disease (gingivitis and periodontitis), due to the cargo of protein, genetic material and lipids derived from their parent cells. There is limited information on the isolation and characterisation methods of saliva/GCF-sEVs or the characterisation of sEVs cargo as biomarkers for periodontitis. In this review, we detail the composition of sEVs and summarise their isolation and characterisation from saliva and GCF. The potential role of saliva and GCF-derived sEVs in periodontitis diagnosis is also explored. It is proposed that sEVs cargo, including protein, microRNA, message RNA and DNA methylation, are potential biomarkers for periodontitis with good diagnostic power (area under the curve-AUC > 0.9).

Periodontal and Dental Pulp Cell-Derived Small Extracellular Vesicles: A Review of the Current Status.

Extracellular vesicles (EVs) are membrane-bound lipid particles that are secreted by all cell types and function as cell-to-cell communicators through their cargos of protein, nucleic acid, lipids, and metabolites, which are derived from their parent cells. There is limited information on the isolation and the emerging therapeutic role of periodontal and dental pulp cell-derived small EVs (sEVs, <200 nm, or exosome). In this review, we discuss the biogenesis of three EV subtypes (sEVs, microvesicles and apoptotic bodies) and the emerging role of sEVs from periodontal ligament (stem) cells, gingival fibroblasts (or gingival mesenchymal stem cells) and dental pulp cells, and their therapeutic potential in vitro and in vivo. A review of the relevant methodology found that precipitation-based kits and ultracentrifugation are the two most common methods to isolate periodontal (dental pulp) cell sEVs. Periodontal (and pulp) cell sEVs range in size, from 40 nm to 2 µm, due to a lack of standardized isolation protocols. Nevertheless, our review found that these EVs possess anti-inflammatory, osteo/odontogenic, angiogenic and immunomodulatory functions in vitro and in vivo, via reported EV cargos of EV-miRNAs, EV-circRNAs, EV-mRNAs and EV-lncRNAs. This review highlights the considerable therapeutic potential of periodontal and dental pulp cell-derived sEVs in various regenerative applications.

Antibodies against citrullinated proteins in relation to periodontitis with or without rheumatoid arthritis: a cross-sectional study.

BACKGROUND: Previous studies have reported conflicting findings between serum anti-citrullinated protein antibodies (ACPA) levels in rheumatoid arthritis (RA) participants with and without periodontitis (Pd). This study aimed to analyse possible correlations between serum ACPA levels and clinical parameters in Pd and RA participants. METHODS: Full mouth periodontal examination (probing pocket depth, clinical attachment levels, gingival bleeding index, visual plaque index) was conducted and serum samples obtained from 80 participants comprising RA, Pd, both RA and Pd (RAPd) and healthy individuals (HC). Erythrocyte sedimentation rates (ESR) and periodontal inflamed surface area (PISA) were obtained. Serum samples were analysed for ACPA quantification using enzyme-linked immunosorbent assay (ELISA). RESULTS: Median levels (IU/mL) of ACPA (interquartile range, IQR) in RAPd, RA, Pd and HC groups were 118.58(274.51), 102.02(252.89), 78.48(132.6) and 51.67(91.31) respectively. ACPA levels were significantly higher in RAPd and RA as compared to HC group (p < 0.05). However, ACPA levels of any of the groups were not correlated with any clinical periodontal and RA parameters within the respective groups. CONCLUSIONS: At individual level, the amount of serum ACPA seem to have an increasing trend with the diseased condition in the order of RAPd > RA > Pd > HC. However, lack of any significant correlation between the serum ACPA levels with the clinical Pd and RA parameters warrants further studies to investigate the causal link between RA and Pd for such a trend. Further studies involving more inflammatory biomarkers might be useful to establish the causal link between Pd in the development and progression of RA or vice versa.

Salivary Outer Membrane Vesicles and DNA Methylation of Small Extracellular Vesicles as Biomarkers for Periodontal Status: A Pilot Study.

Periodontitis is an inflammatory disease, associated with a microbial dysbiosis. Early detection using salivary small extracellular vesicles (sEVs) biomarkers may facilitate timely prevention. sEVs derived from different species (i.e., humans, bacteria) are expected to circulate in saliva. This pilot study recruited 22 participants (seven periodontal healthy, seven gingivitis and eight periodontitis) and salivary sEVs were isolated using the size-exclusion chromatography (SEC) method. The healthy, gingivitis and periodontitis groups were compared in terms of salivary sEVs in the CD9+ sEV subpopulation, Gram-negative bacteria-enriched lipopolysaccharide (LPS+) outer membrane vesicles (OMVs) and global DNA methylation pattern of 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and N6-Methyladenosine (m6dA). It was found that LPS+ OMVs, global 5mC methylation and four periodontal pathogens (T. denticola, E. corrodens, P. gingivalis and F. nucleatum) that secreted OMVs were significantly increased in periodontitis sEVs compared to those from healthy groups. These differences were more pronounced in sEVs than the whole saliva and were more superior in distinguishing periodontitis than gingivitis, in comparison to healthy patients. Of note, global 5mC hypermethylation in salivary sEVs can distinguish periodontitis patients from both healthy controls and gingivitis patients with high sensitivity and specificity (AUC = 1). The research findings suggest that assessing global sEV methylation may be a useful biomarker for periodontitis.

The autotaxin-lysophosphatidic acid pathway mediates mesenchymal cell recruitment and fibrotic contraction in lung transplant fibrosis.

BACKGROUND: Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality in lung transplant recipients. CLAD is characterized by respiratory failure owing to the accumulation of fibrotic cells in small airways and alveoli, inducing tissue contraction and architectural destruction. However, the source of the fibroblastic cells and the mechanism(s) underlying the accumulation and activation remain unexplained. Mesenchymal stromal cells (MSCs) are multipotent progenitors that are normally located in the lung tissue but can be isolated from the alveolar space in lung transplant recipients, where they have a profibrotic phenotype. Our objective was to identify the mediator(s) inducing migration and contractile differentiation of lung tissue MSCs. METHODS: Bronchoalveolar lavage (BAL) (7 healthy controls and 21 lung transplant recipients), CCL2, HGF, TGFB, EGF, and PDGF-BB and autotaxin were measured by enzyme-linked immunosorbent assay. BAL (7 healthy controls and 31 lung transplant recipients) lysophosphatidic acid (LPA) (16:0, 18:0, 18:1, 22:4) was measured by liquid chromatography with tandem mass spectrometry. The effect of inhibition of candidate mediators on BAL-mediated chemoattraction of MSCs and contraction of MSC-spiked collagen gel assays was assessed. BAL cells from a lung transplant recipient with CLAD were analyzed by single-cell RNA sequencing. RESULTS: We first demonstrate that BAL fluid from lung transplant recipients and particularly those with CLAD is potently chemoattractive to human lung tissue‒derived MSCs and induces a contractile phenotype. After excluding several candidate mediators, we show that LPA blockade completely abrogated transplant recipient BAL‒mediated chemoattraction of MSCs and contraction of MSC-spiked collagen gels. Furthermore, LPA levels were enriched in transplant recipient BAL, and LPA replicated the observed in vitro profibrotic effects of transplant recipient BAL. Finally, we identify BAL monocyte‒derived macrophages with autotaxin (ENPP2) and fibrotic transcriptional signature. CONCLUSIONS: Autotaxin-expressing alveolar macrophages are present in CLAD BAL. These cells potentially provide a local source of autotaxin/LPA that drives MSC recruitment and tissue contraction in CLAD. These cells are analogous to an aberrant macrophage population recently identified in idiopathic pulmonary fibrosis, suggesting an overlap in pathogenesis between CLAD and other forms of lung fibrosis.

Impact of periodontitis on quality of life among subjects with rheumatoid arthritis: a cross sectional study.

BACKGROUND: This study aimed to assess the impact of periodontitis (PD) on the health related quality of life (HRQoL) and oral health related QoL (OHRQoL) of subjects with rheumatoid arthritis (RA) and PD. METHODS: Subjects from dental and RA clinics were screened. Complete periodontal examinations were performed. Subjects were divided into 4 groups: RA-PD, RA, PD and healthy controls (HC). Questionnaires on characteristics and Malaysian versions of Oral Health Impact Profile (OHIP-14(M)) and Health Assessment Questionnaire (HAQ-DI)) were answered. RESULTS: A total of 187 subjects were included (29 RA-PD, 58 RA, 43 PD and 57 HC). OHIP-14(M) severity score was highest in the PD group (17.23 ± 10.36) but only significantly higher than the HC group (p < 0.05). The HAQ-DI scores of the RA group was significantly higher than the PD and HC groups (p < 0.05). The interaction between the effects of PD and RA on the OHRQoL and HRQoL was statistically significant (p < 0.05). CONCLUSION: PD and RA subjects both suffer impacts on their OHRQoL and HRQoL respectively. The interaction effect of both diseases significantly conferred impacts on their OHRQoL and HRQoL as measured by the OHIP-14(M) and HAQ-DI.

Phosphoregulation of HORMA domain protein HIM-3 promotes asymmetric synaptonemal complex disassembly in meiotic prophase in Caenorhabditis elegans.

In the two cell divisions of meiosis, diploid genomes are reduced into complementary haploid sets through the discrete, two-step removal of chromosome cohesion, a task carried out in most eukaryotes by protecting cohesion at the centromere until the second division. In eukaryotes without defined centromeres, however, alternative strategies have been innovated. The best-understood of these is found in the nematode Caenorhabditis elegans: after the single off-center crossover divides the chromosome into two segments, or arms, several chromosome-associated proteins or post-translational modifications become specifically partitioned to either the shorter or longer arm, where they promote the correct timing of cohesion loss through as-yet unknown mechanisms. Here, we investigate the meiotic axis HORMA-domain protein HIM-3 and show that it becomes phosphorylated at its C-terminus, within the conserved "closure motif" region bound by the related HORMA-domain proteins HTP-1 and HTP-2. Binding of HTP-2 is abrogated by phosphorylation of the closure motif in in vitro assays, strongly suggesting that in vivo phosphorylation of HIM-3 likely modulates the hierarchical structure of the chromosome axis. Phosphorylation of HIM-3 only occurs on synapsed chromosomes, and similarly to other previously-described phosphorylated proteins of the synaptonemal complex, becomes restricted to the short arm after designation of crossover sites. Regulation of HIM-3 phosphorylation status is required for timely disassembly of synaptonemal complex central elements from the long arm, and is also required for proper timing of HTP-1 and HTP-2 dissociation from the short arm. Phosphorylation of HIM-3 thus plays a role in establishing the identity of short and long arms, thereby contributing to the robustness of the two-step chromosome segregation.

A cross-sectional study of immune seroconversion to SARS-CoV-2 in front-line maternity health professionals

COVID-19, the respiratory disease caused by the SARS-CoV-2, is thought to cause a milder illness in pregnancy with a greater proportion of asymptomatic carriers. This has important implications for the risk of patient-to-staff, staff-to-staff and staff-to patient transmission among health professionals in maternity. The aim of this study was to investigate the prevalence of previously undiagnosed SARS-CoV-2 infection in health professionals from two tertiary-level maternity units in London, UK and to determine associations between HCW characteristics, reported symptoms and serological evidence of prior SARS-CoV-2 infection. 200 anaesthetists, midwives and obstetricians with no previously confirmed diagnosis of COVID-19 were tested for immune seroconversion using laboratory IgG assays. Comprehensive symptom and medical histories were also collected. 5/40 (12.5%; 95% CI: 4.2-26.8) anaesthetists, 7/52 (13.5%; 95% CI: 5.6-25.8%) obstetricians and 17/108 (15.7%; 95% CI: 9.5-24.0%) midwives were seropositive, with an overall total of 29/200 (14.5%; 95% CI: 9.9-20.1%) of maternity healthcare workers testing positive for IgG antibodies against SARS-CoV-2. Of those who had seroconverted, 10/29 (35.5%) were completely asymptomatic. Fever or cough were only present in 6/29 (20.7%) and (10/29 (34.5%) respectively. Anosmia was the most common symptom occurring in 15/29 (51.7%) seropositive participants and was the only symptom that was predictive of positive seroconversion (OR 18; 95% CI 6 - 55). 58.6% of those who were seropositive had not self-isolated at any point and continued to provide patient care in the hospital setting. This study was the largest study of baseline immune seroconversion in maternity healthcare workers conducted to date and reveals that 1 in 6 were seropositive, of whom 1 in 3 were asymptomatic. This has significant implications for the risk of occupational transmission of SARS-CoV-2 for both staff and patients in maternity and regular testing of staff, including asymptomatic staff should be considered to reduce transmission risk.

Periodontitis and rheumatoid arthritis: An update 2012-2017.

Rheumatoid arthritis and chronic periodontitis are both chronic inflammatory diseases characterized by an exacerbated inflammatory reaction that leads to destruction of bone and other connective tissue. Owing to these similarities, the relationship between these two diseases has been investigated for over two decades. In the 2013 proceedings from a workshop jointly held by the European Federation of Periodontology and American Academy of Periodontology in 2012 it was concluded that there was at least minimal evidence of an association between periodontitis and rheumatoid arthritis. In this review, we consider publications in the field over the past 5 years and determine whether the evidence for this relationship has increased.

Lung transplant in a recipient with tracheal bronchus.

We describe the intraoperative surgical management of tracheal bronchus encountered in a lung transplant recipient.

Salivary Small Extracellular Vesicles Associated miRNAs in Periodontal Status-A Pilot Study.

This pilot study aims to investigate whether salivary small extracellular vesicle (sEV)-associated microRNAs could act as potential biomarkers for periodontal disease status. Twenty-nine participants (10 who were healthy, nine with gingivitis, 10 with stage III/IV periodontitis) were recruited and unstimulated whole saliva samples were collected. Salivary sEVs were isolated using the size-exclusion chromatography (SEC) method and characterised by morphology, EV-protein and size distribution using transmission electron microscopy (TEM), Western Blot and Nanoparticle Tracking Analysis (NTA), respectively. Ten mature microRNAs (miRNAs) in salivary sEVs and saliva were evaluated using RT-qPCR. The discriminatory power of miRNAs as biomarkers in gingivitis and periodontitis versus healthy controls was evaluated by Receiver Operating Characteristics (ROC) curves. Salivary sEVs were comparable to sEVs morphology, mode, size distribution and particle concentration in healthy, gingivitis and periodontitis patients. Compared to miRNAs in whole saliva, three significantly increased miRNAs (hsa-miR-140-5p, hsa-miR-146a-5p and hsa-miR-628-5p) were only detected in sEVs in periodontitis when compared to that of healthy controls, with a good discriminatory power (area under the curve (AUC) = 0.96) for periodontitis diagnosis. Our study demonstrated that salivary sEVs are a non-invasive source of miRNAs for periodontitis diagnosis. Three miRNAs that are selectively enriched in sEVs, but not whole saliva, could be potential biomarkers for periodontal disease status.

Intestine-to-Germline Transmission of Epigenetic Information Intergenerationally Ensures Systemic Stress Resistance in C. elegans.

Changes in epigenetic states affect organismal homeostasis, including stress resistance. However, the mechanisms coordinating epigenetic states and systemic stress resistance remain largely unknown. Here, we identify the intestine-to-germline communication of epigenetic states, which intergenerationally enhances stress resistance in C. elegans. The alterations in epigenetic states by deficiency of the histone H3K4me3 modifier ASH-2 in the intestine or germline increase organismal stress resistance, which is abrogated by knockdown of the H3K4 demethylase RBR-2. Remarkably, the increase in stress resistance induced by ASH-2 deficiency in the intestine is abrogated by RBR-2 knockdown in the germline, suggesting the intestine-to-germline transmission of epigenetic information. This communication from intestine to germline in the parental generation increases stress resistance in the next generation. Moreover, the intertissue communication is mediated partly by transcriptional regulation of F08F1.3. These results reveal that intertissue communication of epigenetic information provides mechanisms for intergenerational regulation of systemic stress resistance.

Mapping the evidence of hepatoprotective properties of Moringa oleifera from sub-Saharan African countries: a systematic review protocol.

BACKGROUND: One of the most challenging health problems is liver disease, which can be caused by medications, toxic substances, and excessive consumption of alcohol. Liver problems can be also caused by infections, autoimmune disorders, and food. This study aims to establish evidence of the use of Moringa oleifera in sub-Saharan African countries to manage liver damage conditions in animals. METHODS: In vivo studies will include those in which the activity of the serum levels of hepatic enzymes alanine transaminase (ALT) or serum glutamate-pyruvate transaminase (SGPT), aspartate transaminase (AST) or serum glutamic oxaloacetic transaminase (SGOT), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and malondialdehyde (MDA) were measured after administering substances that induced liver injury as a primary outcome. The secondary outcome will include studies that measure the serum levels of hepatic enzymes (ALT, AST, GGT and ALP, SOD, CAT, and GR), free radical formation represented by MDA after administering the sub-Saharan Moringa oleifera, and decreases in their levels indicating the improvement of their activity. Search engines will include MEDLINE, CINAHL, PubMed, Google Scholar, SABINET, EBSCO, and WHO/African Index Medicus. The screened results will be grouped according to any noteworthy grouping variable, such as study characteristics. Data will be analyzed using Stata statistical software (Stata Corp V.14, TX, USA). Study data will be quantitatively synthesized by first assessing heterogeneity to examine whether the estimates from included studies could be pooled. Heterogeneity will be assessed by the chi-squared test on Cochran's Q statistic, which will be quantified by I 2 values. DISCUSSION: Results from this protocol will give new insights into the Moringa oleifera plant for developing effective hepatoprotective drugs against liver damage. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084698 .

DNA polymerase-γ hypothesis in nucleoside reverse transcriptase-induced mitochondrial toxicity revisited: A potentially protective role for citrus fruit-derived naringenin?

Nucleoside reverse transcriptase inhibitors (NRTIs) form the backbone in combination antiretroviral therapy (cARVs). They halt chain elongation of the viral cDNA by acting as false substrates in counterfeit incorporation mechanism to viral RNA-dependent DNA polymerase. In the process genomic DNA polymerase as well as mitochondrial DNA (mtDNA) polymerase-γ (which has a much higher affinity for these drugs at therapeutic doses) are also impaired. This leads to mitochondrial toxicity that manifests clinically as mitochondrial myopathy, peripheral neuropathy, hyperlactatemia or lactic acidosis and lipoatrophy. This has led to the revision of clinical guidelines by World Health Organization to remove stavudine from first-line listing in the treatment of HIV infections. Recent reports have implicated oxidative stress besides mtDNA polymerase-γ hypothesis in NRTI-induced metabolic complications. Reduced plasma antioxidant concentrations have been reported in HIV positive patients on cARVs but clinical intervention with antioxidant supplements have not been successful either due to low efficacy or poor experimental designs. Citrus fruit-derived naringenin has previously been demonstrated to possess antioxidant and free radical scavenging properties which could prevent mitochondrial toxicity associated with these drugs. This review revisits the controversy surrounding mtDNA polymerase-γ hypothesis and evaluates the potential benefits of naringenin as a potent anti-oxidant and free radical scavenger which as a nutritional supplement or therapeutic adjunct could mitigate the development of mitochondrial toxicity associated with these drugs.

The meiotic phosphatase GSP-2/PP1 promotes germline immortality and small RNA-mediated genome silencing.

Germ cell immortality, or transgenerational maintenance of the germ line, could be promoted by mechanisms that could occur in either mitotic or meiotic germ cells. Here we report for the first time that the GSP-2 PP1/Glc7 phosphatase promotes germ cell immortality. Small RNA-induced genome silencing is known to promote germ cell immortality, and we identified a separation-of-function allele of C. elegans gsp-2 that is compromised for germ cell immortality and is also defective for small RNA-induced genome silencing and meiotic but not mitotic chromosome segregation. Previous work has shown that GSP-2 is recruited to meiotic chromosomes by LAB-1, which also promoted germ cell immortality. At the generation of sterility, gsp-2 and lab-1 mutant adults displayed germline degeneration, univalents, histone methylation and histone phosphorylation defects in oocytes, phenotypes that mirror those observed in sterile small RNA-mediated genome silencing mutants. Our data suggest that a meiosis-specific function of GSP-2 ties small RNA-mediated silencing of the epigenome to germ cell immortality. We also show that transgenerational epigenomic silencing at hemizygous genetic elements requires the GSP-2 phosphatase, suggesting a functional link to small RNAs. Given that LAB-1 localizes to the interface between homologous chromosomes during pachytene, we hypothesize that small localized discontinuities at this interface could promote genomic silencing in a manner that depends on small RNAs and the GSP-2 phosphatase.