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BackgroundGuided Internet-based interventions (IBIs) are typically found to be more effective than unguided ones, but the reasons behind this are not well understood. The therapist-client working alliance, crucial in face-to-face psychotherapy, is also increasingly recognized as an important factor in IBIs. This study examines trajectories of the working alliance and its relationship to therapeutic guidance through a secondary analysis of a randomized controlled trial (RCT) on Selfapy, a 12-week IBI based on cognitive behavioral therapy for depressive disorders. The trial compared a therapist-guided version (with weekly calls) to an unguided version (n = 301, mean age 37 years, 83% female, mean BDI-II = 30.09).MethodsBased on an intention-to-treat approach, this study investigates within- and between-group differences in the quality of the working alliance, assessed with the WAI-SR questionnaire at mid- and post-treatment via repeated measures ANOVA. Furthermore, correlations and mediation analyses were conducted to explore the relationship between the working alliance and outcomes, as well as adherence parameters.ResultsFindings indicate that the IBI was successful in fostering a robust working alliance in both intervention groups, with similar ratings at mid-treatment but significantly higher ratings in the guided group at post-treatment (Cohen’s d = -0.38). Post-treatment working alliance scores were positively linked to symptom reduction at post-treatment (guided: r = .25, unguided r = .15) and follow-up (guided: r = .25, unguided: r = .17). In the unguided group, the association was primarily driven by the subscale task. Serial mediation analysis indicated that the relationship between guidance and outcomes at follow-up was mediated by working alliance (b = 0.59; 95% CI: 0.14, 1.22) and a link between working alliance and adherence (b = 0.15; 95% CI: 0.04, 0.34).ConclusionsConsidering limitations like using a questionnaire developed for face-to-face therapy, findings support the importance of the working alliance in guided IBIs, while also providing new insights into its role and formation in unguided IBIs. The potential benefits of a strong working alliance, notably by improving adherence, may prove crucial for integrating guided as well as unguided IBIs into routine use, indicating the need for additional research in this context.Clinical Trial Registrationhttps://tinyurl.com/2p9h5hnx, German Clinical Trials Register DRKS00017191.

ABSTRACT Bacteria of the genus Brucella are responsible for human and animal brucellosis worldwide and comprise the well-characterized, so-called classical species belonging to the core clade, with a host range limited to mammals, and the novel atypical strains mainly considered as non-zoonotic to date, but able to colonize non-traditional hosts such as amphibians. Despite marked phenotypical differences between the two groups, Brucella species display a high degree of genome identity, including genes encoding reductases involved in the denitrification pathway, a respiratory process able to reduce nitrate to nitrogen under anoxic conditions. Brucella spp. have always been considered as strictly aerobic pathogens. Our study, however, describes for the first time that atypical Brucella spp. grow well under anoxia, but in a strictly nitrate-dependent manner, whereas classical species show a heterogeneous behavior. The rate of anaerobic growth of the atypical species Brucella microti was dependent on nitrate concentration, highlighting a more efficient denitrification pathway with rapid consumption of intermediate nitrite, whereas the classical species Brucella suis exhibited lower, nitrate concentration-independent growth coupled with nitrite accumulation. Transcriptional studies performed under anoxic conditions revealed a higher expression of genes participating in the last three denitrification steps in B. microti, as compared to B. suis, which correlates with the rapid and efficient consumption of nitrite in this atypical species and its rapid growth. IMPORTANCE Respiration is a fundamental and complex process that bacteria use to produce energy. Despite aerobic respiration being the most common, some bacteria make use of a mode of respiration in the absence of oxygen, called anaerobic respiration, which can yield advantages in adaptation to various environmental conditions. Denitrification is part of this respiratory process ensuring higher respiratory flexibility under oxygen depletion. Here, we report for the first time the evidence of anaerobic growth of Brucella spp. under denitrifying conditions, which implies that this genus should be reconsidered as facultative anaerobic. Our study further describes that efficient denitrification is not equally found within the Brucella genus, with atypical species showing a greater ability to denitrify, correlated with higher expression of the genes involved, as compared to classical species.

IntroductionIn recent decades, various new psychotherapy approaches have been developed in an effort to overcome issues of non-response, referred to as “third-wave psychotherapies.” How third-wave therapies perform in comparison to each other, to classical CBT, or other common comparators in the treatment of depression has not yet been systematically assessed.MethodsWe firstly determined the scope of the term “third-wave” by conducting a systematic search. The identified approaches were then used as search terms for the systematic review and network meta-analysis (NMA). We searched MEDLINE, CENTRAL, PsychINFO and Web of Science from inception until 31 July 2022. We assessed randomized controlled trials comparing third-wave psychotherapies to each other, CBT, treatment as usual (TAU), medication management, active control conditions, or waitlist (WL) in adult populations with depressive disorders. The treatments included were acceptance and commitment therapy, behavioral activation, cognitive behavioral analysis system of psychotherapy, dialectical behavioral therapy, mindfulness-based cognitive therapy, meta-cognitive therapy, positive psychotherapy and schema therapy. The primary outcome was depression severity (efficacy) at study endpoint, and the secondary outcome was all-cause discontinuation (acceptability). This review was registered in PROSPERO, identifier CRD42020147535.ResultsOf 7,971 search results, 55 trials were included in our NMA (5,827 patients). None of the third-wave therapies were more efficacious than CBT but most were superior to TAU [standardized mean differences (SMD) ranging between 0.42 (95% CI −0.37; 1.19) and 1.25 (0.48; 2.04)]. Meta-cognitive therapy (MCT) was more efficacious than three other third-wave therapy approaches. None of the third-wave treatments were more acceptable than WL or CBT. Twenty-seven percent of the trials were rated as low risk of bias. Confidence in the evidence was largely low according to GRADE. Inconsistency emerged for a small number of comparisons.InterpretationsThird-wave therapies are largely efficacious and acceptable alternatives to CBT when compared to TAU, with few differences between them. The evidence so far does not point toward superiority or inferiority over CBT. Patient-level research may offer possibilities for tailoring individual psychotherapies to the needs of individual patients and future trials should make this data available. The evidence base needs to be broadened by sufficiently powered trials.

Abstract Background Patients with mild to moderate depressive symptoms can have limited access to regular treatment; to ensure appropriate care, low-threshold treatment is needed. Effective online interventions could increase the supply of low-threshold treatment. Further research is needed to evaluate the effectiveness of online interventions. This study aims to evaluate the online-based self-help programme “Selfapy” on a sample of depressive subjects and compares the impact of the programme’s unaccompanied version with its therapeutic accompanied version. Methods A sample of 400 subjects that have a mild to severe depressive episode (Becks Depression Inventory - II and Hamilton Depression Scale) will be used. Subjects are randomly assigned to immediate access to an unaccompanied course (no support from psychologist via weekly phone calls), immediate access to an accompanied course (support from a psychologist via weekly phone calls) or a waiting list control group (access to the intervention after 24 weeks). The intervention will last for a period of 12 weeks. Depressive symptoms as a primary parameter, as well as various secondary parameters, such as life satisfaction, therapeutic relationships, social activation, self-esteem, attitudes towards Internet interventions and drop-out rates, are recorded at four different points in time: at baseline (T1), 6 weeks after the start of the intervention (T2), 12 weeks after the start of the intervention (T3) and 3 months after completion of the treatment follow-up (T4). Conclusion This randomized and controlled, blinded study will make use of a “dismantled” approach to adequately compare the accompanied and unaccompanied versions of the intervention. Positive and meaningful results are expected that could influence the acceptance and implementation of online interventions. Trial registration German Clinical Trials Register DRKS00017191. Registered on 14 June 2019

BackgroundDigital health apps are efficacious treatment options for mild-to-moderate depressive disorders. However, the extent to which psychological guidance increases the efficacy of these apps is controversial. ObjectiveWe evaluated the efficacy of a web-based intervention, called Selfapy, for unipolar depression. We also investigated differences between psychotherapist-guided and unguided versions. MethodsSelfapy is a cognitive behavioral therapy–based intervention for depressive disorders. Participants with mild-to-severe depressive disorders were assigned randomly to participate in either guided (weekly 25-minute duration telephone calls) intervention, unguided version, or waiting list (control group) for 12 weeks. We assessed depressive symptoms at the start of the study, midway through the intervention (6 weeks), at the end of the intervention (12 weeks), and at follow-up (6 months). The main outcome was difference in the Beck Depression Inventory score between the start of the study and the end of the intervention. Secondary outcomes were the Quick Inventory of Depressive Symptomatology—Self Report, the Hamilton Rating Depression Scale, and the Beck Anxiety Inventory. ResultsOf 401 participants, 301 participants (75.1%) completed the intervention. Changes in the Beck Depression Inventory from baseline differed significantly between groups at the postintervention (F2,398=37.20, P.999; unguided: F1,176=0.13, P>.999). ConclusionsBoth guided and unguided versions of the intervention were highly effective in reducing depressive symptoms. Follow-up data suggest that these effects could be maintained. The guided version was not superior to the unguided version. Trial RegistrationGerman Clinical Trials Register DRKS00017191; https://tinyurl.com/2p9h5hnx International Registered Report Identifier (IRRID)RR2-10.1186/s13063-021-05218-4

Abstract Background Although the individual and economic disease burden of depression is particularly high for long-term symptoms, little is known of the lifetime course of chronic depression. Most evidence derives from clinical samples, and the diagnostic distinction between persistent depressive disorder (PDD) and non-chronic major depression (NCMDD) is still debated. Thus, we examined characteristics of PDD among clinical vs. non-clinical cases, and the associated disease burden at a population level. Methods Data were drawn from the mental health module of the German Health Interview and Examination Survey for Adults (DEGS1-MH, 2009–2012, n = 4483) and a clinical sample of PDD inpatients at Charité – Universitätsmedizin Berlin (2018–2019, n = 45). The DSM-5 definition of PDD was operationalized a priori to the study using interview-based DSM-IV diagnoses of dysthymia and major depression lasting at least 2 years in both surveys. Additional depression characteristics (depression onset, self-classified course, suicidality, comorbid mental disorders, treatment history and current depressive symptoms [Patient Health Questionnaire-9]) were assessed. In the DEGS1-MH, health-related quality of life (Short Form Health Survey-36, SF-36), chronic somatic conditions, number of sick days (past 12 months) or days with limitations in normal daily life activities (past 4 weeks), and health service utilization (past 12 months) were compared for PDD vs. NCMDD. Results PDD cases from the clinical sample had a significantly earlier depression onset, a higher proportion of self-classification as persistent course, and treatment resistance than PDD and NCMDD cases in DEGS1-MH. At a population level, PDD cases showed worse outcomes compared with NCMDD cases in terms of somatic comorbidity, SF-36 mental component score, and activity limitations owing to mental health problems, as well as a higher risk for outpatient mental health care contact. Conclusions The distinction between PDD and NCMDD proposed for DSM-5 seems warranted. Early onset depression, self-classification as persistent depressive course, and treatment resistance are suggested as markers of more severe and chronic depression courses. At a population level, PDD is associated with remarkably higher individual and economic disease burden than NCMDD, highlighting the need to improve medical recognition of chronic courses and establish specific treatment concepts for chronic depression.

Brucellae are facultative intracellular coccobacilli causing brucellosis, one of the most widespread bacterial zoonosis affecting wildlife animals, livestock and humans. The genus Brucella comprises classical and atypical species, such as Brucella suis and Brucella microti, respectively. The latter is characterized by increased metabolic activity, fast growth rates, and extreme acid resistance at pH 2.5, suggesting an advantage for environmental survival. In addition, B. microti is more acid-tolerant than B. suis at the intermediate pH of 4.5. This acid-resistant phenotype of B. microti may have major implications for fitness in soil, food products and macrophages. Our study focused on the identification and characterization of acid resistance determinants of B. suis and B. microti in Gerhardt’s minimal medium at pH 4.5 and 7.0 for 20 min and 2 h by comparative RNA-Seq-based transcriptome analysis, validated by RT-qPCR. Results yielded a common core response in both species with a total of 150 differentially expressed genes, and acidic pH-dependent genes regulated specifically in each species. The identified core response mechanisms comprise proton neutralization or extrusion from the cytosol, participating in maintaining physiological intracellular pH values. Differential expression of 441 genes revealed species-specific mechanisms in B. microti with rapid physiological adaptation to acid stress, anticipating potential damage to cellular components and critical energy conditions. Acid stress-induced genes encoding cold shock protein CspA, pseudogene in B. suis, and stress protein Dps were associated with survival of B. microti at pH 4.5. B. suis response with 284 specifically regulated genes suggested increased acid stress-mediated protein misfolding or damaging, triggering the set-up of repair strategies countering the consequences rather than the origin of acid stress and leading to subsequent loss of viability. In conclusion, our work supports the hypothesis that increased acid stress resistance of B. microti is based on selective pressure for the maintenance of functionality of critical genes, and on specific differential gene expression, resulting in rapid adaptation.

Brucella microti was isolated a decade ago from wildlife and soil in Europe. Compared to the classical Brucella species, it exhibits atypical virulence properties such as increased growth in human and murine macrophages and lethality in experimentally infected mice. A spontaneous rough (R) mutant strain, derived from the smooth reference strain CCM4915T, showed increased macrophage colonization and was non-lethal in murine infections. Whole-genome sequencing and construction of an isogenic mutant of B. microti and Brucella suis 1330 revealed that the R-phenotype was due to a deletion in a single gene, namely wbkE (BMI_I539), encoding a putative glycosyltransferase involved in lipopolysaccharide (LPS) O-polysaccharide biosynthesis. Complementation of the R-strains with the wbkE gene restored the smooth phenotype and the ability of B. microti to kill infected mice. LPS with an intact O-polysaccharide is therefore essential for lethal B. microti infections in the murine model, demonstrating its importance in pathogenesis.

Student sex work is a current phenomenon all over the world, increasingly reported by the media in recent years. However, student sex work remains under-researched in Germany and is lacking direct first-hand reports from the people involved. Further, sex work remains stigmatized, and therefore, students practicing it could be at risk of social isolation and emotional or physical danger. Therefore, this study examines students working in the sex industry focusing on their personal experiences and attitudes toward them. An online questionnaire was completed by 4386 students from Berlin universities. Students who identified themselves as sex workers (n = 227) were questioned with respect to their motivations to enter the sex industry, characteristics of their job, feelings after the intercourse, and perceived risks. Student non-sex workers (n = 2998) were questioned regarding knowledge of and attitudes toward student sex workers. Most student sex workers reported that they entered the sex industry due to financial reasons (35.7%). The majority reported offering services involving direct sexual intercourse. Disclosing their job to friends, family, or others was associated with less problems with social isolation and in romantic relationships. With a total of 22.9%, student non-sex workers reported never having heard about students working in the sex industry. The most frequent emotions mentioned by them with regard to student sex workers were compassion and dismay (48.9%). There was no difference in happiness between student sex workers and non-sex working students. Through this research, it becomes evident that there are similarities between the student’s motivations to enter the sex industry, their feelings, and the problems they have to face. Moreover, prejudices still prevail about the life of student sex workers. Increasing understanding of student sex work might help those sex workers to live a less stigmatized life and thereby to make use of support from others. The universities as institutions could form the basis for this, e.g., by openly supporting student sex workers. This could help to encourage the rights of student sex workers and to gain perspective with respect to the sex industry.

Background: The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been tailored specifically to the demands of patients with persistent depressive disorder (PDD). According to the CBASP model, PDD patients are supposed to live perceptually disconnected from their social environment, which consequently maintains depression. While initially developed as an individual treatment modality, the adaptation for group therapy yields an important interpersonal space. However, little is known about the specific factors that contribute to patients' benefit from the CBASP group modality.Methods: The analyzed sample comprised N = 87 PDD patients who completed a 12 week multimodal inpatient treatment including 2 weekly CBASP-specific individual and group sessions, respectively, as well as CBASP-unspecific medical contacts, pharmacotherapy and complementary therapies. Group sessions included trainings in situational analysis and interpersonal skills. Interpersonal change over therapy was examined based on the patients' self-perceived interpersonal problems (IIP) and the impact messages as perceived by their individual therapists (IMI). Pre and post-treatment data were compared using within-sample t-tests. Additionally, patients evaluated CBASP group therapy on a feedback form. They were invited to reflect on individual benefits and its helpful and unhelpful aspects. Qualitative content analysis with inductive category development was used to analyze feedback. Inter-rater reliability was computed to confirm categories before summarizing the frequencies of reported factors.Results: Self-perceived interpersonal distress significantly decreased over therapy. Patients reported reduced interpersonal problems and therapists reported more friendly and dominant impact messages. Interestingly, patients who showed a significant depressive symptom reduction described higher change scores. Regarding qualitative data, patients reported five main benefits from group therapy: Gain in social competence, self-confidence, self-reflection, interpersonal dynamics, and optimism/universality. Patients responding to CBASP identified significantly more factors than non-responders.Conclusions: Compared to studies with individual CBASP only, the present findings suggest that CBASP group therapy may contribute to the improvement of interpersonal behavior. Group therapy is discussed as a potential boosting effect for individual CBASP. However, as the present data were collected in a multimodal inpatient setting without competitor, randomized controlled trials are warranted that investigate the specific benefits of the group modality or the combined individual and group therapy over individual CBASP only.

The genus Brucella currently comprises twelve species of facultative intracellular bacteria with variable zoonotic potential. Six of them have been considered as classical, causing brucellosis in terrestrial mammalian hosts, with two species originated from marine mammals. In the past fifteen years, field research as well as improved pathogen detection and typing have allowed the identification of four new species, namely Brucella microti, Brucella inopinata, Brucella papionis, Brucella vulpis, and of numerous strains, isolated from a wide range of hosts, including for the first time cold-blooded animals. While their genome sequences are still highly similar to those of classical strains, some of them are characterized by atypical phenotypes such as higher growth rate, increased resistance to acid stress, motility, and lethality in the murine infection model. In our review, we provide an overview of state-of-the-art knowledge about these novel Brucella sp., with emphasis on their phylogenetic positions in the genus, their metabolic characteristics, acid stress resistance mechanisms, and their behavior in well-established in cellulo and in vivo infection models. Comparison of phylogenetic classification and phenotypical properties between classical and novel Brucella species and strains finally lead us to propose a more adapted terminology, distinguishing between core and non-core, and typical versus atypical brucellae, respectively.

Lithium has been the treatment of choice for patients with bipolar disorder (BD) for nearly 70 years. It is recommended by all relevant guidelines as a first-line treatment for maintenance therapy. In this review, we outline the current state of evidence for lithium in the treatment of BD over the lifespan. First, we summarize the evidence on efficacy in general, from relapse prevention to acute anti-manic treatment and its role in treating mood episodes with mixed features and bipolar depression. As patients are often treated for many years and different aspects have to be considered in different phases of life, we discuss the particularities of lithium in the treatment of paediatric BD, in older aged individuals and in pregnant women. Lastly, we discuss the evidence on lithium's proposed suicide-preventive effects, the dangers of rapid discontinuation and lithium's adverse effects, particularly with regard to long-term treatment.

Carbonic anhydrases have started to emerge as new potential antibacterial targets for several pathogens. Two β-carbonic anhydrases, denominated bsCA I and bsCA II, have been isolated and characterized from the bacterial pathogen Brucella suis, the causative agent of brucellosis or Malta fever. These enzymes have been investigated in detail and a wide range of classical aromatic and heteroaromatic sulfonamides as well as carbohydrate-based compounds have been found to inhibit selectively and efficiently Brucella suis carbonic anhydrases. Inhibition of these metalloenzymes constitutes a novel approach for the potential development of new anti-Brucella agents. This review aims at discussing the recent literature on this topic.

BackgroundDespite the high clinical and epidemiological relevance of persistent depression, little is known about its specific psychopathology and whether it is distinct from recurrent depression. Depression in general has been associated with blunted affective reactivity but the evidence from previous studies is inconsistent. Here, we asked whether affective reactivity might differ between persistent and recurrent depression.MethodsTwenty patients with persistent depression, 20 patients with recurrent depression and 20 healthy controls (HC) were recruited. Both patient groups showed moderate symptom severity. All participants underwent a sad mood induction procedure. Affective reactivity was assessed with the Positive and Negative Affect Schedule (PANAS) before and after mood induction.ResultsWe found a striking difference in affective reactivity between patient groups. While the persistent group showed blunted reactivity to mood induction, the recurrent group demonstrated an affective response that was comparable to HC, with an increase in negative and a decrease in positive affect. Blunted affective reactivity was thus specifically associated with persistent in contrast to recurrent depression.ConclusionsThese results highlight affective reactivity as an important psychopathological feature that differs between the two patient groups. Preserved affective reactivity to emotional stimuli in the recurrent group might reflect a resilience factor against persistence of depression.

[This corrects the article DOI: 10.1371/journal.pone.0208616.].

Background: The predictive therapeutic value of brain derived neurotrophic factor (BDNF) and its changes associated with the use of specific antidepressants are still unclear. In this study, we examined BDNF as a peripheral and NAA as a central biomarker over the time course of antidepressant treatment to specify both of their roles in the response to the medication and clinical outcome. Methods: We examined serum BDNF (ELISA kit) in a sample of 76 (47 female and 29 male) depressed patients in a naturalistic setting. BDNF was assessed before medication and subsequently after two, four and six weeks of antidepressant treatment. Additionally, in fifteen patients, N-acetylaspartate (NAA) was measured in the anterior cingulate cortex (ACC) with magnetic resonance spectroscopy (MRS). Over a time course of six weeks BDNF and NAA were also examined in a group of 41 healthy controls. Results: We found significant lower serum BDNF concentrations in depressed patients compared to the sample of healthy volunteers before and after medication. BDNF and clinical symptoms decreased significantly in the patients over the time course of antidepressant treatment. Serum BDNF levels at baseline predicted the symptom outcome after eight weeks. Specifically, responders and remitters had lower serum BDNF at baseline than the nonresponders and nonremitters. NAA was slightly decreased but not significantly lower in depressed patients when compared with healthy controls. During treatment period, NAA showed a tendency to increase. Limitations: A relative high drop-out rate and possibly, a suboptimal observation period for BDNF. Conclusion: Our data confirm serum BDNF as a biomarker of depression with a possible role in response prediction. However, our findings argue against serum BDNF increase being a prerequisite to depressive symptom reduction.

In recent years, various therapeutic interventions have been established that extended behavior and cognitive behavior therapy (CBT) by so-called “third-wave” strategies. In order to address specific therapeutic challenges in certain subgroups of patients who do not sufficiently respond to “classical CBT,” some of these third-wave strategies put particular emphasis on therapist self-disclosure. This article highlights therapeutic self-disclosure as a means to address interpersonal problems by comparing three third-wave strategies: (a) acceptance and change strategies as used in Dialectical Behavioral Therapy (DBT), (b) the concept of “limited reparenting” as used in Schema Therapy (ST), and (c) disciplined personal involvement as used in the Cognitive Behavioral Analysis System of Psychotherapy (CBASP). On the basis of a critical discussion on opportunities and challenges within these three concepts, self-disclosure is proposed to be a promising therapeutic tool that is worth to be investigated in more depth in future studies.

Neutralophilic bacteria have developed specific mechanisms to cope with the acid stress encountered in environments such as soil, fermented foods, and host compartments. In Escherichia coli, the glutamate decarboxylase (Gad)-dependent system is extremely efficient: it requires the concerted action of glutamate decarboxylase (GadA/GadB) and of the glutamate (Glu)/γ-aminobutyrate antiporter, GadC. Notably, this system is operative also in new strains/species of Brucella, among which Brucella microti, but not in the “classical” species, with the exception of marine mammals strains. Recently, the glutaminase-dependent system (named AR2_Q), relying on the deamination of glutamine (Gln) into Glu and on GadC activity, was described in E. coli. In Brucella genomes, a putative glutaminase (glsA)-coding gene is located downstream of the gadBC genes. We found that in B. microti these genes are expressed as a polycistronic transcript. Moreover, using a panel of Brucella genus-representative strains, we show that the AR2_Q system protects from extreme acid stress (pH ≤2.5), in the sole presence of Gln, only the Brucella species/strains predicted to have functional glsA and gadC. Indeed, mutagenesis approaches confirmed the involvement of glsA and gadC of B. microti in AR2_Q and that the acid-sensitive phenotype of B. abortus can be ascribed to a Ser248Leu substitution in GlsA, leading to loss of glutaminase activity. Furthermore, we found that the gene BMI_II339, of unknown function and downstream of the gadBC–glsA operon, positively affects Gad- and GlsA-dependent AR. Thus, we identified novel determinants that allow newly discovered and marine mammals Brucella strains to be better adapted to face hostile acidic environments. As for significance, this work may contribute to the understanding of the host preferences of Brucella species and opens the way to alternative diagnostic targets in epidemiological surveillance of brucellosis.

For aerobic human pathogens, adaptation to hypoxia is a critical factor for the establishment of persistent infections, as oxygen availability is low inside the host. The two-component system RegB/A of Brucella suis plays a central role in the control of respiratory systems adapted to oxygen deficiency, and in persistence in vivo. Using an original “in vitro model of persistence” consisting in gradual oxygen depletion, we compared transcriptomes and proteomes of wild-type and ΔregA strains to identify the RegA-regulon potentially involved in the set-up of persistence. Consecutive to oxygen consumption resulting in growth arrest, 12% of the genes in B. suis were potentially controlled directly or indirectly by RegA, among which numerous transcriptional regulators were up-regulated. In contrast, genes or proteins involved in envelope biogenesis and in cellular division were repressed, suggesting a possible role for RegA in the set-up of a non-proliferative persistence state. Importantly, the greatest number of the RegA-repressed genes and proteins, including aceA encoding the functional IsoCitrate Lyase (ICL), were involved in energy production. A potential consequence of this RegA impact may be the slowing-down of the central metabolism as B. suis progressively enters into persistence. Moreover, ICL is an essential determinant of pathogenesis and long-term interactions with the host, as demonstrated by the strict dependence of B. suis on ICL activity for multiplication and persistence during in vivo infection. RegA regulates gene or protein expression of all functional groups, which is why RegA is a key regulator of B. suis in adaptation to oxygen depletion. This function may contribute to the constraint of bacterial growth, typical of chronic infection. Oxygen-dependent activation of two-component systems that control persistence regulons, shared by several aerobic human pathogens, has not been studied in Brucella sp. before. This work therefore contributes significantly to the unraveling of persistence mechanisms in this important zoonotic pathogen.

Fibrinogen is a serum multi-chain protein which, when activated, aggregates to form fibrin, one of the main components of a blood clot. Fibrinolysis controls blood clot dissolution through the action of the enzyme plasmin, which cleaves fibrin at specific locations. Although the main biochemical factors involved in fibrin formation and lysis have been identified, a clear mechanistic picture of how these processes take place is not available yet. This picture would be instrumental, for example, for the design of improved thrombolytic or anti-haemorrhagic strategies, as well as, materials with improved biocompatibility. Here, we present extensive molecular dynamics simulations of fibrinogen which reveal large bending motions centered at a hinge point in the coiled-coil regions of the molecule. This feature, likely conserved across vertebrates according to our analysis, suggests an explanation for the mechanism of exposure to lysis of the plasmin cleavage sites on fibrinogen coiled-coil region. It also explains the conformational variability of fibrinogen observed during its adsorption on inorganic surfaces and it is supposed to play a major role in the determination of the hydrodynamic properties of fibrinogen. In addition the simulations suggest how the dynamics of the D region of fibrinogen may contribute to the allosteric regulation of the blood coagulation cascade through a dynamic coupling between the a- and b-holes, important for fibrin polymerization, and the integrin binding site P1.

Management actions often need to be taken in the absence of ecological information to mitigate the impact of pressing environmental problems. Managers counteracted the detrimental effects of cultural acidification on aquatic ecosystems during the industrial era using liming to salvage biodiversity and ecosystem services. However, historical contingencies, i.e., whether lakes were naturally acidic or degraded because of acidification, were largely unknown and therefore not accounted for in management. It is uncertain whether liming outcomes had a potentially detrimental effect on naturally acidic lakes. Evidence from paleolimnological reconstructions allowed us to analyze community structure in limed acidified and naturally acidic lakes, and acidified and circumneutral references. We analyzed community structure of phytoplankton, zooplankton, macroinvertebrates (littoral, sublittoral, profundal), and fish between 2000 and 2004. Naturally acidic limed lakes formed communities that were not representative of the other lake types. The occurrence of fish species relevant for ecosystem service provisioning (fisheries potential) in naturally acidic limed lakes were confounded by biogeographical factors. In addition, sustained changes in water quality were conducive to harmful algal blooms. This highlights a pathological outcome of liming lakes when their naturally acidic conditions are not accounted for. Because liming is an important social-ecological system, sustained ecological change of lakes might incur undesired costs for societies in the long term.