Narcissistic personality disorder in the ICD-11: Severity and trait profiles of grandiosity and vulnerability.

Modern diagnostic and classification frameworks such as the ICD-11 and DSM-5-AMPD have adopted a dimensional approach to diagnosing personality disorder using a dual "severity" and "trait" model. As narcissistic personality has historically struggled to be adequately captured in dominant diagnostic systems, this study investigated the utility of the new ICD-11 framework in capturing diverse narcissistic expressions. Participants were mental health clinicians (N = 180, 67% female, age = 38.9), who completed ratings of ICD-11 personality severity, trait domains and a clinical reflection for two hypothetical case vignettes reflecting either prototypical "grandiose" or "vulnerable" narcissism. The majority of clinicians (82%) endorsed a diagnosis of personality disorder for both grandiose and vulnerable vignettes. Discriminant elements of personality impairment included rigid, unrealistically positive self-view, low empathy and high conflict with others for grandiosity, and incoherent identity, low self-esteem and hypervigilant, avoidant relations with others for vulnerability. Regarding trait profile, grandiose narcissism was predominately dissocial whereas vulnerable narcissism was primarily associated with negative affectivity and detachment. Qualitative responses highlight distinct clinical themes for each presentation. These findings suggest that clinicians using the ICD-11 framework are able to identify common core elements of personality dysfunction in grandiose and vulnerable narcissism while also recognizing their distinctive differences.

Signatures of cysteine oxidation on muscle structural and contractile proteins are associated with physical performance and muscle function in older adults: Study of Muscle, Mobility and Aging (SOMMA).

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (R = 0.48) between a higher oxidation level of eight Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impairs muscle power and strength, walking speed, and cardiopulmonary fitness with aging.

Signatures of Cysteine Oxidation on Muscle Structural and Contractile Proteins Are Associated with Physical Performance and Muscle Function in Older Adults: Study of Muscle, Mobility and Aging (SOMMA).

Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (r = 0.48) between a higher oxidation level of 8 Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impair muscle power and strength, walking speed, and cardiopulmonary fitness with aging.

Rat bronchoalveolar lavage proteome changes following e-cigarette aerosol exposures.

E-cigarette liquids are complex mixtures of chemicals consisting of humectants, such as propylene glycol (PG) and vegetable glycerin (VG), with nicotine or flavorings added. Published literature emphasizes the toxicity of e-cigarette aerosols with flavorings whereas much less attention has been given to the biologic effects of humectants. The purpose of the current study was to provide a comprehensive view of the acute biologic effects of e-cigarette aerosols on rat bronchoalveolar lavage (BAL) using mass spectrometry-based global proteomics. Sprague-Dawley rats were exposed to e-cigarette aerosol for 3 h/day for three consecutive days. Groups included: PG/VG alone, PG/VG + 2.5% nicotine (N), or PG/VG + N + 3.3% vanillin (V). Right lung lobes were lavaged for BAL and supernatants prepared for proteomics. Extracellular BAL S100A9 concentrations and BAL cell staining for citrullinated histone H3 (citH3) were also performed. From global proteomics, ∼2,100 proteins were identified from rat BAL. The greatest change in number of BAL proteins occurred with PG/VG exposures alone compared with controls with biological pathways enriched for acute phase responses, extracellular trap formation, and coagulation. Extracellular BAL S100A9 concentrations and the number of citH3 + BAL cells also increased significantly in PG/VG and PG/VG + 2.5% N. In contrast to PG/VG or PG/VG + N, the addition of vanillin to PG/VG + N increased BAL neutrophilia and downregulated lipid transport proteins. In summary, global proteomics support e-cigarette aerosol exposures to PG/VG alone as having a significant biologic effect on the lung independent of nicotine or flavoring with increased markers of extracellular trap formation.

"It's not you, it's me": identity disturbance as the main contributor to interpersonal problems in pathological narcissism.

BACKGROUND: Core impairments in self and other functioning typify individuals with personality disorder. While interpersonal dysfunction is a known element of narcissistic disorders, empirical research investigating intrapersonal elements is lacking. The aim of this study was to investigate the internal representations of individuals with grandiose and vulnerable features, as manifested through their attachment styles, and the specific role of identity disturbance in explaining the relationship between pathological narcissism and maladaptive interpersonal functioning. METHODS: A sample of 270 university students completed the Brief Pathological Narcissism Inventory (B-PNI), the Severity Indices of Personality Problems (SIPP), the Relationship Questionnaire (RQ), and the Inventory of Interpersonal Problems (IIP-32). RESULTS: Both vulnerable and grandiose narcissism were positively associated with both fearful and preoccupied attachment, and negatively associated with secure attachment, whilst grandiose narcissism was also positively associated with dismissive attachment. Furthermore, unstable representations of self, poor self-reflective functioning, and low sense of purpose fully mediated the relationship between interpersonal problems and grandiose narcissism while partially mediating the relationship between interpersonal problems and vulnerable narcissism. CONCLUSIONS: Overall, our findings suggest that for individuals presenting with narcissistic features, capacity for adaptive interpersonal functioning is grounded by deficits in identity integration. Implications of these findings are discussed.

Safety of age-dosed, single low-dose primaquine in children with glucose-6-phosphate dehydrogenase deficiency who are infected with Plasmodium falciparum in Uganda and the Democratic Republic of the Congo: a randomised, double-blind, placebo-controlled, non-inferiority trial.

BACKGROUND: WHO recommends gametocytocidal, single low-dose primaquine for blocking the transmission of Plasmodium falciparum; however, safety concerns have hampered the implementation of this strategy in sub-Saharan Africa. We aimed to investigate the safety of age-dosed, single low-dose primaquine in children from Uganda and the Democratic Republic of the Congo. METHODS: We conducted this randomised, double-blind, placebo-controlled, non-inferiority trial at the Mbale Regional Referral Hospital, Mbale, Uganda, and the Kinshasa Mahidol Oxford Research Unit, Kinshasa, Democratic Republic of the Congo. Children aged between 6 months and 11 years with acute uncomplicated P falciparum infection and haemoglobin concentrations of at least 6 g/dL were enrolled. Patients were excluded if they had a comorbid illness requiring inpatient treatment, were taking haemolysing drugs for glucose-6-phosphate dehydrogenase (G6PD) deficiency, were allergic to the study drugs, or were enrolled in another clinical trial. G6PD status was defined by genotyping for the G6PD c.202T allele, the cause of the G6PD-deficient A- variant. Participants were randomly assigned (1:1) to receive single low-dose primaquine combined with either artemether-lumefantrine or dihydroartemisinin-piperaquine, dosed by bodyweight. Randomisation was stratified by age and G6PD status. The primary endpoint was the development of profound (haemoglobin <4 g/dL) or severe (haemoglobin <5 g/dL) anaemia with severity features, within 21 days of treatment. Analysis was by intention to treat. The sample size assumed an incidence of 1·5% in the placebo group and a 3% non-inferiority margin. The trial is registered at ISRCTN, 11594437, and is closed to new participants. FINDINGS: Participants were recruited at the Mbale Regional Referral Hospital between Dec 18, 2017, and Oct 7, 2019, and at the Kinshasa Mahidol Oxford Research Unit between July 17, 2017, and Oct 5, 2019. 4620 patients were assessed for eligibility. 3483 participants were excluded, most owing to negative rapid diagnostic test or negative malaria slide (n=2982). 1137 children with a median age of 5 years were enrolled and randomly assigned (286 to the artemether-lumefantrine plus single low-dose primaquine group, 286 to the artemether-lumefantrine plus placebo group, 283 to the dihydroartemisinin-piperaquine plus single low-dose primaquine group, and 282 to the dihydroartemisinin-piperaquine plus placebo group). Genotyping of G6PD identified 239 G6PD-c.202T hemizygous males and 45 G6PD-c.202T homozygous females (defining the G6PD-deficient group), 119 heterozygous females, 418 G6PD-c.202C normal males and 299 G6PD-c.202C normal females (defining the non-G6PD-deficient group), and 17 children of unknown status. 67 patients were lost to follow-up and four patients withdrew during the study-these numbers were similar between groups. No participants developed profound anaemia and three developed severe anaemia: from the G6PD-deficient group, none (0%) of 133 patients who received placebo and one (0·66%) of 151 patients who received primaquine (difference -0·66%, 95% CI -1·96 to 0·63; p=0·35); and from the non-G6PD-deficient group, one (0·23%) of 430 patients who received placebo and one (0·25%) of 407 patients who received primaquine (-0·014%, -0·68 to 0·65; p=0·97). INTERPRETATION: Gametocytocidal, age-dosed, single low-dose primaquine was well tolerated in children from Uganda and the Democratic Republic of the Congo who were infected with P falciparum, and the safety profile of this treatment was similar to that of the placebo. These data support the wider implementation of single low-dose primaquine in Africa. FUNDING: UK Government Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust Joint Global Health Trials Scheme.

Defining the S-Glutathionylation Proteome by Biochemical and Mass Spectrometric Approaches.

Protein S-glutathionylation (SSG) is a reversible post-translational modification (PTM) featuring the conjugation of glutathione to a protein cysteine thiol. SSG can alter protein structure, activity, subcellular localization, and interaction with small molecules and other proteins. Thus, it plays a critical role in redox signaling and regulation in various physiological activities and pathological events. In this review, we summarize current biochemical and analytical approaches for characterizing SSG at both the proteome level and at individual protein levels. To illustrate the mechanism underlying SSG-mediated redox regulation, we highlight recent examples of functional and structural consequences of SSG modifications. Finally, we discuss the analytical challenges in characterizing SSG and the thiol PTM landscape, future directions for understanding of the role of SSG in redox signaling and regulation and its interplay with other PTMs, and the potential role of computational approaches to accelerate functional discovery.

A deep redox proteome profiling workflow and its application to skeletal muscle of a Duchenne Muscular Dystrophy model.

Perturbation to the redox state accompanies many diseases and its effects are viewed through oxidation of biomolecules, including proteins, lipids, and nucleic acids. The thiol groups of protein cysteine residues undergo an array of redox post-translational modifications (PTMs) that are important for regulation of protein and pathway function. To better understand what proteins are redox regulated following a perturbation, it is important to be able to comprehensively profile protein thiol oxidation at the proteome level. Herein, we report a deep redox proteome profiling workflow and demonstrate its application in measuring the changes in thiol oxidation along with global protein expression in skeletal muscle from mdx mice, a model of Duchenne Muscular Dystrophy (DMD). In-depth coverage of the thiol proteome was achieved with >18,000 Cys sites from 5,608 proteins in muscle being quantified. Compared to the control group, mdx mice exhibit markedly increased thiol oxidation, where a ∼2% shift in the median oxidation occupancy was observed. Pathway analysis for the redox data revealed that coagulation system and immune-related pathways were among the most susceptible to increased thiol oxidation in mdx mice, whereas protein abundance changes were more enriched in pathways associated with bioenergetics. This study illustrates the importance of deep redox profiling in gaining greater insight into oxidative stress regulation and pathways/processes that are perturbed in an oxidizing environment.

Regulation of hyperoxia-induced neonatal lung injury via post-translational cysteine redox modifications.

Preterm infants and patients with lung disease often have excess fluid in the lungs and are frequently treated with oxygen, however long-term exposure to hyperoxia results in irreversible lung injury. Although the adverse effects of hyperoxia are mediated by reactive oxygen species, the full extent of the impact of hyperoxia on redox-dependent regulation in the lung is unclear. In this study, neonatal mice overexpressing the beta-subunit of the epithelial sodium channel (ß-ENaC) encoded by Scnn1b and their wild type (WT; C57Bl6) littermates were utilized to study the pathogenesis of high fraction inspired oxygen (FiO2)-induced lung injury. Results showed that O2-induced lung injury in transgenic Scnn1b mice is attenuated following chronic O2 exposure. To test the hypothesis that reversible cysteine-redox-modifications of proteins play an important role in O2-induced lung injury, we performed proteome-wide profiling of protein S-glutathionylation (SSG) in both WT and Scnn1b overexpressing mice maintained at 21% O2 (normoxia) or FiO2 85% (hyperoxia) from birth to 11-15 days postnatal. Over 7700 unique Cys sites with SSG modifications were identified and quantified, covering more than 3000 proteins in the lung. In both mouse models, hyperoxia resulted in a significant alteration of the SSG levels of Cys sites belonging to a diverse range of proteins. In addition, substantial SSG changes were observed in the Scnn1b overexpressing mice exposed to hyperoxia, suggesting that ENaC plays a critically important role in cellular regulation. Hyperoxia-induced SSG changes were further supported by the results observed for thiol total oxidation, the overall level of reversible oxidation on protein cysteine residues. Differential analyses reveal that Scnn1b overexpression may protect against hyperoxia-induced lung injury via modulation of specific processes such as cell adhesion, blood coagulation, and proteolysis. This study provides a landscape view of protein oxidation in the lung and highlights the importance of redox regulation in O2-induced lung injury.

DLC-1 facilitates germ granule assembly in Caenorhabditis elegans embryo.

Germ granules are cytoplasmic assemblies of RNA-binding proteins (RBPs) required for germ cell development and fertility. During the first four cell divisions of the Caenorhabditis elegans zygote, regulated assembly of germ (P) granules leads to their selective segregation to the future germ cell. Here we investigate the role of DLC-1, a hub protein implicated in stabilization and function of diverse protein complexes, in maintaining P granule integrity. We find that DLC-1 directly interacts with several core P granule proteins, predominantly during embryogenesis. The loss of dlc-1 disrupts assembly of P granule components into phase-separated organelles in the embryos, regardless of whether or not DLC-1 directly interacts with these proteins. Finally, we infer that P granule dispersal in the absence of dlc-1 is likely independent of DLC-1's function as a subunit of the dynein motor and does not result from a loss of cell polarity.

Living with pathological narcissism: core conflictual relational themes within intimate relationships.

BACKGROUND: Pathological narcissism is a severe mental health condition that includes disturbances in interpersonal functioning. Interpersonal difficulties by those affected include aggressive, domineering, cold and coercive behaviours which often result in strong negative reactions from others. We sought to examine the moment-to-moment patterns that emerge within close relationships between intimate partners and family members. METHODS: Participants (N = 15) were romantic partners (73.3%) and family members (26.6%) in a close and long-term relationship (+ 10 years) with an individual with pathological narcissism. Participants told verbatim relationship narratives involving five narrative interactions with their relative with pathological narcissism and five narrative interactions with others. Transcripts were coded using the using Core Conflictual Relationship Theme method. Participants also completed three versions of the Relationship Questionnaire, reporting on 1. their relationship style 'in general', 2. their relationship style 'with their relative' and 3. the relationship style of their relative. RESULTS: A total of 133 relationship episodes were analysed, comprising 783 components (wishes, responses of others and responses of self). While the identified wishes (e.g., for love, for support) were consistent between relative and non-relative narratives, there was significantly higher disharmony and lower harmony in narratives involving relatives with pathological narcissism. Described disharmony in these relationships involved the relative's rejecting, subjugating and attacking behaviours, and participants rejecting and withdrawing behaviours. There was a prominent deactivation of participants attachment system when interacting with their relative with pathological narcissism, endorsing predominately dismissing relationship styles. Individuals with pathological narcissism were similarly rated as predominately dismissing. CONCLUSIONS: Together, these results reflect the cycles of interpersonal dysfunction for individuals with pathological narcissism and their partners and family members. Treatment implications point to the risk of therapists withdrawing and dismissing a patient with high pathological narcissism in the countertransference. Strategies to monitor and manage these core relational themes in treatment remain a challenge.

Pathological narcissism: An analysis of interpersonal dysfunction within intimate relationships.

Pathological narcissism is marked by deficits in psychosocial functioning. Difficulties in relationships include instances of aggression, devaluation and control; however, few studies have examined these relationships from the perspective of partners and family members. We studied participants who were in relationships with relatives high in narcissistic traits (N = 436; current romantic partners [57.3%]; former romantic partners [21.1%]; family members [15.4%]). Participant responses were analysed thematically, and their underlying mental health problems were also measured. Thematic analysis of participant responses indicated themes of abuse from the relative with narcissism (physical, verbal, emotional and sexual) as well as the relative imposing challenging financial and sexual behaviours. There were complex interpersonal themes of mutual idealization but also devaluation. In response, participants reported high levels of anxiety, depression, self-aggression, sickness and somatic concerns. Further, participants expressed overt outward hostility towards their relative with narcissism, but also dependency strivings and frustrated dependency themes. Partners and their relative with narcissism appeared locked into interpersonal and intrapersonal dynamic conflicts. Clinical implications include specific attendance to alliance issues, dependency themes, and a focus on limit setting to establish personal safety.

Mass spectrometry-based direct detection of multiple types of protein thiol modifications in pancreatic beta cells under endoplasmic reticulum stress.

Thiol-based post-translational modifications (PTMs) play a key role in redox-dependent regulation and signaling. Functional cysteine (Cys) sites serve as redox switches, regulated through multiple types of PTMs. Herein, we aim to characterize the complexity of thiol PTMs at the proteome level through the establishment of a direct detection workflow. The LC-MS/MS based workflow allows for simultaneous quantification of protein abundances and multiple types of thiol PTMs. To demonstrate its utility, the workflow was applied to mouse pancreatic ß-cells (ß-TC-6) treated with thapsigargin to induce endoplasmic reticulum (ER) stress. This resulted in the quantification of >9000 proteins and multiple types of thiol PTMs, including intra-peptide disulfide (S-S), S-glutathionylation (SSG), S-sulfinylation (SO2H), S-sulfonylation (SO3H), S-persulfidation (SSH), and S-trisulfidation (SSSH). Proteins with significant changes in abundance were observed to be involved in canonical pathways such as autophagy, unfolded protein response, protein ubiquitination pathway, and EIF2 signaling. Moreover, ~500 Cys sites were observed with one or multiple types of PTMs with SSH and S-S as the predominant types of modifications. In many cases, significant changes in the levels of different PTMs were observed on various enzymes and their active sites, while their protein abundance exhibited little change. These results provide evidence of independent translational and post-translational regulation of enzyme activity. The observed complexity of thiol modifications on the same Cys residues illustrates the challenge in the characterization and interpretation of protein thiol modifications and their functional regulation.

Resin-Assisted Capture Coupled with Isobaric Tandem Mass Tag Labeling for Multiplexed Quantification of Protein Thiol Oxidation.

Reversible oxidative modifications on protein thiols have recently emerged as important mediators of cellular function. Herein we describe the detailed procedure of a quantitative redox proteomics method that utilizes resin-assisted capture (RAC) in combination with tandem mass tag (TMT) isobaric labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to allow multiplexed stochiometric quantification of oxidized protein thiols at the proteome level. The site-specific quantitative information on oxidized cysteine residues provides additional insight into the functional impacts of such modifications. The workflow is adaptable across many sample types, including cultured cells (e.g., mammalian, prokaryotic) and whole tissues (e.g., heart, lung, muscle), which are initially lysed/homogenized and with free thiols being alkylated to prevent artificial oxidation. The oxidized protein thiols are then reduced and captured by a thiol-affinity resin, which streamlines and simplifies the workflow steps by allowing the proceeding digestion, labeling, and washing procedures to be performed without additional transfer of proteins/peptides. Finally, the labeled peptides are eluted and analyzed by LC-MS/MS to reveal comprehensive stoichiometric changes related to thiol oxidation across the entire proteome. This method greatly improves the understanding of the role of redox-dependent regulation under physiological and pathophysiological states related to protein thiol oxidation.

Stoichiometric Thiol Redox Proteomics for Quantifying Cellular Responses to Perturbations.

Post-translational modifications regulate the structure and function of proteins that can result in changes to the activity of different pathways. These include modifications altering the redox state of thiol groups on protein cysteine residues, which are sensitive to oxidative environments. While mass spectrometry has advanced the identification of protein thiol modifications and expanded our knowledge of redox-sensitive pathways, the quantitative aspect of this technique is critical for the field of redox proteomics. In this review, we describe how mass spectrometry-based redox proteomics has enabled researchers to accurately quantify the stoichiometry of reversible oxidative modifications on specific cysteine residues of proteins. We will describe advancements in the methodology that allow for the absolute quantitation of thiol modifications, as well as recent reports that have implemented this approach. We will also highlight the significance and application of such measurements and why they are informative for the field of redox biology.

Living with pathological narcissism: a qualitative study.

Background: Research into the personality trait of narcissism have advanced further understanding of the pathological concomitants of grandiosity, vulnerability and interpersonal antagonism. Recent research has established some of the interpersonal impacts on others from being in a close relationship with someone having such traits of pathological narcissism, but no qualitative studies exist. Individuals with pathological narcissism express many of their difficulties of identity and emotion regulation within the context of significant interpersonal relationships thus studying these impacts on others is warranted. Method: We asked the relatives of people high in narcissistic traits (indexed by scoring above a cut-off on a narcissism screening measure) to describe their relationships (N = 436; current romantic partners [56.2%]; former romantic partners [19.7%]; family members [21.3%]). Participants were asked to describe their relative and their interactions with them. Verbatim responses were thematically analysed. Results: Participants described 'grandiosity' in their relative: requiring admiration, showing arrogance, entitlement, envy, exploitativeness, grandiose fantasy, lack empathy, self-importance and interpersonal charm. Participants also described 'vulnerability' of the relative: contingent self-esteem, hypersensitivity and insecurity, affective instability, emptiness, rage, devaluation, hiding the self and victimhood. These grandiose and vulnerable characteristics were commonly reported together (69% of respondents). Participants also described perfectionistic (anankastic), vengeful (antisocial) and suspicious (paranoid) features. Instances of relatives childhood trauma, excessive religiosity and substance abuse were also described. Conclusions: These findings lend support to the importance of assessing the whole dimension of the narcissistic personality, as well as associated personality patterns. On the findings reported here, the vulnerable aspect of pathological narcissism impacts others in an insidious way given the core deficits of feelings of emptiness and affective instability. These findings have clinical implications for diagnosis and treatment in that the initial spectrum of complaints may be misdiagnosed unless the complete picture is understood. Living with a person with pathological narcissism can be marked by experiencing a person who shows large fluctuations in affect, oscillating attitudes and contradictory needs.

Antagonistic control of Caenorhabditis elegans germline stem cell proliferation and differentiation by PUF proteins FBF-1 and FBF-2.

Stem cells support tissue maintenance, but the mechanisms that coordinate the rate of stem cell self-renewal with differentiation at a population level remain uncharacterized. We find that two PUF family RNA-binding proteins FBF-1 and FBF-2 have opposite effects on Caenorhabditis elegans germline stem cell dynamics: FBF-1 restricts the rate of meiotic entry, while FBF-2 promotes both cell division and meiotic entry rates. Antagonistic effects of FBFs are mediated by their distinct activities toward the shared set of target mRNAs, where FBF-1-mediated post-transcriptional control requires the activity of CCR4-NOT deadenylase, while FBF-2 is deadenylase-independent and might protect the targets from deadenylation. These regulatory differences depend on protein sequences outside of the conserved PUF family RNA-binding domain. We propose that the opposing FBF-1 and FBF-2 activities serve to modulate stem cell division rate simultaneously with the rate of meiotic entry.

Measuring the shadows: A systematic review of chronic emptiness in borderline personality disorder.

BACKGROUND: Chronic feelings of emptiness is an under-researched symptom of borderline personality disorder (BPD), despite indications it may be central to the conceptualisation, course, and outcome of BPD treatment. This systematic review aimed to provide a comprehensive overview of chronic feelings of emptiness in BPD, identify key findings, and clarify differences between chronic feelings of emptiness and related constructs like depression, hopelessness, and loneliness. METHOD: A PRISMA guided systematic search of the literature identified empirical studies with a focus on BPD or BPD symptoms that discussed chronic feelings of emptiness or a related construct. RESULTS: Ninety-nine studies met criteria for inclusion in the review. Key findings identified there were significant difficulties in defining and measuring chronic emptiness. However, based on the studies reviewed, chronic emptiness is a sense of disconnection from both self and others. When experienced at frequent and severe levels, it is associated with low remission for people with BPD. Emptiness as a construct can be separated from hopelessness, loneliness and intolerance of aloneness, however more research is needed to explicitly investigate these experiences. Chronic emptiness may be related to depressive experiences unique to people with BPD, and was associated with self-harm, suicidality, and lower social and vocational function. CONCLUSIONS AND IMPLICATIONS: We conclude that understanding chronic feelings of emptiness is central to the experience of people with BPD and treatment focusing on connecting with self and others may help alleviate a sense of emptiness. Further research is required to provide a better understanding of the nature of chronic emptiness in BPD in order to develop ways to quantify the experience and target treatment. Systematic review registration number: CRD42018075602.