Attachment insecurities, emotion dynamics and stress in intimate relationships during the transition to parenthood.

BACKGROUND: In intimate relationships, which are characterized by emotional interdependence, partners act as attachment figures which serve emotion regulation functions. The experience of emotions as well as the strategies that partners use to regulate them and to respond to relational experiences, especially during stressful periods, differ greatly according to their attachment orientation. An important aspect in emotion dynamics is emotional inertia, which reflects the degree to which a person's current affective state is resistant to change on a moment-to-moment basis. Inertia has been related to maladaptive emotion regulation strategies, like suppression and rumination, preferentially used by highly anxious and avoidant individuals. The aim of this study is to examine associations between attachment orientations and reports on the experience of positive and negative affect, and their dynamics in daily life across the transition to parenthood. METHODS: Longitudinal data from a sample of 152 mixed-gender couples collected across the transition to parenthood was analyzed. We predicted that individuals with a more insecure attachment would report more negative and less positive affect, and that their emotional experience would be more resistant to change over time. We explored effects when participants reported feeling stressed. RESULTS: The data suggested that attachment anxiety was associated with less positive and more negative affect and that attachment avoidance was associated with more positive affect. Anxious individuals showed lower emotional inertia and not higher as we expected. Reported stress for anxious and avoidant individuals was significantly associated with more negative but not less positive affect. CONCLUSIONS: Results are discussed in the light of their impact on couples during stressful periods. Differences between anxiety and avoidance are found, emphasizing the importance of attachment insecurities on the experience of emotion. Furthermore, our findings on momentary fluctuating affect offer complementary insight into the emotional functioning of individuals with different attachment orientations.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed DrugMap , an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway.

Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway.

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it's unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H 2 O 2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H 2 O 2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.

Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines-an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.

Work situation of rheumatologists and residents in times of COVID-19 : Findings from a survey in Germany.

BACKGROUND AND OBJECTIVE: The work situation is an important dimension of professional life and wellbeing, and a policy lever to strengthen recruitment and retention. This study aims to explore the work situation of physicians and residents in internal medical rheumatology, considering the impact of the coronavirus pandemic COVID-19. METHODS: A questionnaire-based online survey was conducted in early 2021 at the Hannover Medical School, supported by the German Society of Rheumatology. Target groups were all rheumatology physicians and residents in Germany. The main areas of investigation included work hours, task delegation, and collaboration; workload and mental health issues; discrimination and sexual harassment experiences; and the impact of COVID-19. Descriptive statistical analysis was performed for the standardized items and qualitative content analysis for the free-text information. RESULTS: The respondents (n = 101) expressed positive attitudes towards cooperation and task delegation to medical assistants, especially those specialized in rheumatology, while attitudes towards cooperation with GPs pointed to blockades. There was a strong mismatch between actual and desired work hours both in the group of women and in the group of men. 81% rated their workload as high or very high; every sixth rheumatologist has suffered from stress or burnout syndromes at least once in the past. Experiences of gender discrimination and sexual harassment/violence were frequently reported, mostly by women. COVID-19 was an amplifier of stress, with major stressors being digitalization and increased demand for communication and patient education. CONCLUSION: There is an urgent need to improve the work situation of rheumatologists and reduce stress and mental health risks.

Competing effects of spreading rate, crystal fractionation and source variability on Fe isotope systematics in mid-ocean ridge lavas.

Two-thirds of the Earth is covered by mid-ocean ridge basalts, which form along a network of divergent plate margins. Basalts along these margins display a chemical diversity, which is consequent to a complex interplay of partial mantle melting in the upper mantle and magmatic differentiation processes in lower crustal levels. Igneous differentiation (crystal fractionation, partial melting) and source heterogeneity, in general, are key drivers creating variable chemistry in mid-ocean ridge basalts. This variability is reflected in iron isotope systematics (expressed as δ57Fe), showing a total range of 0.2 ‰ from δ57Fe = + 0.05 to + 0.25 ‰. Respective contributions of source heterogeneity and magma differentiation leading to this diversity, however, remain elusive. This study investigates the iron isotope systematics in basalts from the ultraslow spreading Gakkel Ridge in the Arctic Ocean and compares them to existing data from the fast spreading East Pacific Rise ridge. Results indicate that Gakkel lavas are driven to heavier iron isotope compositions through partial melting processes, whereas effects of igneous differentiation are minor. This is in stark contrast to fast spreading ridges showing reversed effects of near negligible partial melting effects followed by large isotope fractionation along the liquid line of descent. Gakkel lavas further reveal mantle heterogeneity that is superimposed on the igneous differentiation effects, showing that upper mantle Fe isotope heterogeneity can be transmitted into erupting basalts in the absence of homogenisation processes in sub-oceanic magma chambers.

An Early Cretaceous subduction-modified mantle underneath the ultraslow spreading Gakkel Ridge, Arctic Ocean.

Earth's upper mantle, as sampled by mid-ocean ridge basalts (MORBs) at oceanic spreading centers, has developed chemical and isotopic heterogeneity over billions of years through focused melt extraction and re-enrichment by recycled crustal components. Chemical and isotopic heterogeneity of MORB is dwarfed by the large compositional spectrum of lavas at convergent margins, identifying subduction zones as the major site for crustal recycling into and modification of the mantle. The fate of subduction-modified mantle and if this heterogeneity transmits into MORB chemistry remains elusive. Here, we investigate the origin of upper mantle chemical heterogeneity underneath the Western Gakkel Ridge region in the Arctic Ocean through MORB geochemistry and tectonic plate reconstruction. We find that seafloor lavas from the Western Gakkel Ridge region mirror geochemical signatures of an Early Cretaceous, paleo-subduction zone, and conclude that the upper mantle can preserve a long-lived, stationary geochemical memory of past geodynamic processes.

Social Representations of People with Gambling Problems: The Influence of Prevention Classes on Non-gamblers.

In the present study, we examine the impact of prevention classes on non-gambling males. Specifically, we measure whether attending a prevention class influences how non-gambling participants perceive people who gamble problematically. Participants (N = 545) were all lifetime non-gamblers, and were all conscripts attending a two-day military recruitment program. On the first day participants either attended or did not attend a gambling prevention class. On the second day, they all completed a questionnaire that contained questions on how they perceived people who gamble problematically. Results showed that their representations were organized in terms of mental status (i.e. mentally disordered or not) and person-centeredness (i.e. self-centered or not). Results also showed that participants who attended the gambling prevention class saw problem-gambling individuals as more mentally disordered and self-centered than those who did not attend the class. The implications of these results are discussed in terms of social support and their applicability to problem gambling prevention programs.

A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations.

Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies had unilateral or bilateral retina dysplasia and/or optic nerve hypoplasia. The four litters shared the same father or grandfather suggesting a heritable condition with an autosomal dominant mode of inheritance. The genome of one affected dog was sequenced and compared to 601 control genomes. A heterozygous private nonsense variant, c.487C>T, was found in the SIX6 gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*). We genotyped all available family members and 464 unrelated Golden Retrievers. All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases. The SIX6 protein is a homeobox transcription factor with a known role in eye development. In humans and other species, SIX6 loss of function variants were reported to cause congenital eye malformations. This strongly suggests that the c.487C>T variant detected contributed to the observed eye malformations. We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs.

Parachlamydia acanthamoebae in domestic cats with and without corneal disease.

Corneal samples of cats with and without corneal diseases were screened with a pan-Chlamydiales PCR and specific PCRs for Parachlamydia, Protochlamydia, Chlamydophila felis, Acanthamoeba and feline herpesviruses (FHV-1). Several corneal samples tested positive for Parachlamydia and related Chlamydiales, indicating cat exposure to these intracellular bacteria.

Clinical presentation, treatment, and outcome of dacryocystitis in rabbits: a retrospective study of 28 cases (2003-2007).

OBJECTIVE: To document the clinical presentation, diagnostics, treatment, and clinical outcome of rabbits with dacryocystitis. MATERIALS AND METHODS: This retrospective study included 28 rabbits diagnosed with dacryocystitis. Available records of clinical and ophthalmological examinations, bacteriological samplings, diagnostic imaging, and treatment were reviewed. A telephone survey of the owners was conducted to evaluate recovery and recurrences. RESULTS: The mean age of the 28 rabbits presenting with ocular discharge from the nasolacrimal duct was 4.4 years. In 25 rabbits (89%), dacryocystitis was a unilateral finding. No underlying cause could be determined in 10 animals (35%). Dental malocclusion was observed in 14 rabbits (50%) and rhinitis in two animals (7%), with one animal showing both symptoms (4%). One rabbit (4%) presented with panophthalmitis. Most animals (96%) received topical antibiotic treatment. If necessary, additional topical (acetylcysteine, vitamin A ointment, nonsteroidals) or systemic treatment (antibiotics, nonsteroidals, paramunity inducer, and glucocorticoids) was provided. The mean duration of therapy was 5.8 weeks. The nasolacrimal duct was flushed in 27 of 31 affected eyes (87%). Dentistry was performed in 80% of the animals suffering from malocclusion. Regarding the clinical outcome, 12 animals (43%) showed complete recovery, eight rabbits (28%) were euthanized, three (11%) died due to unrelated causes, and three (11%) were lost to follow-up. Two rabbits (7%) continue to display signs of dacryocystitis and are being treated symptomatically by the owners. CONCLUSIONS: This study reports the clinical presentation, treatment, and outcome of dacryocystitis in rabbits and outlines the importance of examination of the oral cavity, diagnostic imaging, and bacteriologic sampling.

Surgical removal of a retrobulbar adenoma in an African grey parrot (Psittacus erithacus).

An African grey parrot (Psittacus erithacus) was presented with exophthalmos and a semisolid mass dorsomedial to the left eye that led to ventrotemporal deviation of the globe. Ultrasonography of the eye revealed a well-demarcated mass of cystic appearance, retrobulbar to the left eye. Cultures of samples of the mass acquired by fine needle aspiration were negative for bacteria and Mycoplasma species. Metaplasia of a periorbital gland caused by hypovitaminosis A was suspected, and vitamin A supplementation was initiated. Because of unresponsiveness to therapy, the cystic mass was surgically removed. The histologic diagnosis was adenoma. The surgical wound healed well, and no recurrence was observed 10 months later. To our knowledge, this is the first report of surgical removal of a retrobulbar adenoma in this species with the eye remaining intact and functional.

Clinical, virological, and immunological parameters associated with superinfection of latently with FeHV-1 infected cats.

Infections with feline herpesvirus type 1 (FeHV-1) are frequently associated with recurrent ocular disease, which may occur even in vaccinated cats. The underlying pathogenesis is poorly understood. Specifically, the role of circulating, superinfecting virus strains is unknown. To begin addressing this complex question, we reconstituted a marker-tagged mutant FeHV-1 from a bacterial artificial chromosome (BAC) harboring the FeHV-1 genome. This mutant was deleted for the glycoprotein G gene (DeltagG) but carried instead a gene encoding the green fluorescent protein (GFP). Nine latently with wild-type (wt) FeHV-1-infected cats were superinfected with this mutant and monitored for clinical, virological, and immunological parameters. While the mutant virus replicated locally, induced a rise in neutralizing antibody titers, and stimulated the interferon system, no evidence for ocular illness or reactivation of the underlying wtFeHV-1-infection was detected. However, cyclophosphamide-dexamethasone (C-D) treatment, applied 16 months after the superinfection, was able to reactivate wtFeHV-1. Reactivation was accompanied by recrudescence of ocular disease signs. In contrast, reactivation of the superinfecting mutant virus was not detected. Since kittens are normally infected with wtFeHV-1 prior to the first immunization, the data described in this study may be valuable for designing future live attenuated FeHV-1 vaccines.

Ocular and multicentric lymphoma in a young racehorse.

A 6-year-old thoroughbred gelding was presented with a history of blepharospasm and opacity in the OS of 1 weeks' duration. Ophthalmic examination findings were consistent with acute uveitis in the OS, and traditional treatment was initiated with systemic antibiotics and anti-inflammatory drugs, topical mydriatics, and corticosteroids. During the total treatment period of 4 weeks response to treatment was weak and the horse developed further problems such as cellulitis of the right hind limb with fever and eventually weight loss and dependent edema. Blood work was indicative of liver disease. Abdominal sonography revealed severe splenomegaly and slight hepatomegaly, and a liver biopsy confirmed malignant T-cell lymphoma. The horse was euthanized due to deteriorating general condition and subsequently underwent postmortem examination. Necropsy and histologic examination revealed a multicentric lymphoma with involvement of spleen, mesenteric lymph nodes, and OU. The findings in this case demonstrate that the differential diagnosis of intraocular and systemic lymphoma should be considered in any horse presenting with anterior uveitis, especially when uveitis is unresponsive to treatment and when additional systemic signs of illness such as lethargy, fever, weight loss, or dependent edema arise. Cytological examination of aqueous humor may provide a rapid diagnosis of intraocular lymphoma in eyes with clinical uveitis.

Pretreatment with feline interferon omega and the course of subsequent infection with feline herpesvirus in cats.

OBJECTIVE: Recombinant feline interferon omega (rFeIFN-omega), a type I IFN, may have the potential to limit virus replication and associated clinical signs when administered early on in the course of feline herpesvirus type 1 (FHV-1) infection and reactivation, respectively. The effect of rFeIFN-omega pretreatment on the course of subsequent FHV-1 infection in cats was investigated. ANIMALS STUDIED: Nine SPF cats were divided into an IFN group (n = 5) and a control-group (n = 4). PROCEDURES: The IFN group was pretreated for 2 days with 10 000 units rFeIFN-omega twice a day topically into both eyes and 20 000 units rFeIFN-omega once a day orally, whereas the control group was mock-treated. Subsequently all cats were infected with FHV-1. Samples for FHV-1 DNA detection and quantitation, virus isolation, and titration of FHV-1 antibodies were collected. Clinical and ocular signs were recorded and scored. RESULTS: Courses of median individual clinical and ocular scores and virus load did not differ significantly between both groups using anova for repeated measurements. Analysis (anova) of each individual ocular parameter revealed significantly high scores for epithelial keratitis (P = 0.016) in the IFN group compared to the control group. Periods of virus shedding did not differ significantly between both groups using the Wilcoxon rank sum test. CONCLUSIONS: Results indicated a lack of beneficial effects of rFeIFN-omega pretreatment in the course of primary FHV-1 infection in cats.

Activity of feline interferon-omega after ocular or oral administration in cats as indicated by Mx protein expression in conjunctival and white blood cells.

OBJECTIVE: To assess the biological response to recombinant feline interferon-omega (rFeIFN-omega) following ocular or oral administration in cats via estimation of Mx protein expression in conjunctival cells (CCs) and WBCs. ANIMALS: 10 specific pathogen-free cats. PROCEDURES: In multiple single-dose drug experiments, each cat received various concentrations of rFeIFN-omega administered topically into both eyes (50 to 10,000 U/eye) and orally (200 to 20,000 units). The same cats received saline (0.9% NaCl) solution topically and orally as control treatments. The CCs and WBCs were collected prior to treatment (day 0), on day 1, and every third or seventh day thereafter until samples yielded negative results for Mx protein. Samples were examined for Mx protein expression via immunohistochemistry and immunoblotting procedures involving murine anti-Mx protein monoclonal antibody M143. RESULTS: After topical application of 10,000 U of rFeIFN-omega/eye, CCs stained for Mx protein for a minimum of 7 days, whereas WBCs were positive for Mx protein for a minimum of 31 days. After topical application of lower concentrations, CCs did not express Mx protein, in contrast to WBCs, which stained for Mx protein at 1,000 units for at least 1 day. Following oral administration, Mx protein was expressed in WBCs at rFeIFN-omega concentrations as low as 200 units, whereas CCs did not stain for Mx protein at any concentration. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that Mx protein expression (a marker of the biological response to rFeIFN-omega) in CCs and WBCs of rFeIFN-omega-treated cats depends on the dose of rFeIFN-omega, site of administration, and cell type.