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Background: Identifying animal behaviors, life history states, and movement patterns is a prerequisite for many animal behavior analyses and effective management of wildlife and habitats. Most approaches classify short-term movement patterns with high frequency location or accelerometry data. However, patterns reflecting life history across longer time scales can have greater relevance to species biology or management needs, especially when available in near real-time. Given limitations in collecting and using such data to accurately classify complex behaviors in the long-term, we used hourly GPS data from 5 waterfowl species to produce daily activity classifications with machine-learned models using "automated modelling pipelines"., Methods: Automated pipelines are computer-generated code that complete many tasks including feature engineering, multi-framework model development, training, validation, and hyperparameter tuning to produce daily classifications from eight activity patterns reflecting waterfowl life history or movement states. We developed several input features for modeling grouped into three broad categories, hereafter "feature sets": GPS locations, habitat information, and movement history. Each feature set used different data sources or data collected across different time intervals to develop the "features" (independent variables) used in models., Results: Automated modelling pipelines rapidly developed easily reproducible data preprocessing and analysis steps, identification and optimization of the best performing model and provided outputs for interpreting feature importance. Unequal expression of life history states caused unbalanced classes, so we evaluated feature set importance using a weighted F1-score to balance model recall and precision among individual classes. Although the best model using the least restrictive feature set (only 24 hourly relocations in a day) produced effective classifications (weighted F1 = 0.887), models using all feature sets performed substantially better (weighted F1 = 0.95), particularly for rarer but demographically more impactful life history states (i.e., nesting)., Conclusions: Automated pipelines generated models producing highly accurate classifications of complex daily activity patterns using relatively low frequency GPS and incorporating more classes than previous GPS studies. Near real-time classification is possible which is ideal for time-sensitive needs such as identifying reproduction. Including habitat and longer sequences of spatial information produced more accurate classifications but incurred slight delays in processing., (© 2022. The Author(s).)

The COVID-19 pandemic could have major effects on already vulnerable individuals with psychiatric disorders. It is important to assess how different patient groups respond to stress related to the pandemic, and what additional factors influence it, including family-related stress, migration background, and sex. We conducted a survey in a sample of 294 psychiatric patients in a large outpatient clinic in Berlin, measuring level of distress in relation to COVID-19 lockdown as well as family-related distress. We also measured potential influencing factors such as media consumption and medical support. In the migration background group, we found that women had more lockdown related psychological distress than men. This was not apparent in those patients with a German background. We found that females were more strongly affected by family-related distress, particularly those with a migration background. People with PTSD were most strongly affected by family-related distress, whereas people with psychotic disorders and addiction reported the least distress. There were no effects of media consumption. There were no differences in ability to abide by the lockdown related restrictions across diagnoses. Our results support earlier findings on differential vulnerability of diagnostic groups to these stressors. Thus, clinicians can optimize treatment by taking family-related stressors into account particularly for females and people with a migrant background., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer SW declared a shared affiliation, though no other collaboration, with the authors JM, JB, JW, SG, EB, MS-O, to the handling editor., (Copyright © 2021 Moran, Bretz, Winkler, Gutwinski, Brandl and Schouler-Ocak.)

Background: The outbreak of the COVID-19 disease and the rapid spread of the inducing coronavirus SARS-CoV‑2 threatens not only people's physical health but also their mental health. Its influence on incidence and course of existing illnesses in the psychiatric outpatient sector in Germany is still unknown., Methods: The medical reports of 682 persons in psychiatric treatment were retrospectively investigated, regarding their subjective response to this pandemic and its clinical relevance., Results: Of the patients 60.5% (n = 378) experienced greater psychological stress, 14.5% (n = 99) reported fear of the SARS-CoV‑2 and the possible danger of infection, 25.5% (n = 174) reported fear resulting from the protective measures taken (lock down) and 4.3% (n = 29) reported fear of both. This differed significantly across diagnoses: people with anxiety disorders reported significantly greater stress as well as greater fear of the virus, whereas people with psychoses were significantly less affected than the other patients. Of the participants 43.7% (n = 132) were so strongly affected that acute treatment had to be implemented and 6.0% (n = 18) had to be referred to inpatient care., Discussion: People with mental illnesses are particularly vulnerable to the psychological strain of the COVID-19 pandemic. Long-term studies on the further course of disease will be necessary. Additional studies that test interventions to build resilience in this population will also be needed.

Aim: The present study compares the attitude towards psychotherapy of persons living in Germany with or without Turkish background. In this context, gender-related, disorder-specific and sociodemographic differences in openness towards psychotherapy are taken into account., Methods: Individuals of Turkish origin (n=129) and individuals without migration background (n=129) were interviewed with the Questionnaire on Attitudes towards Psychotherapeutic Treatment, the Social Support Questionnaire, a short version of the Symptom-Checklist with the subscales anxiety, depression and somatization, and a sociodemographic questionnaire., Results: The attitude towards psychotherapy is less positive in Turkish migrants than in people without migration background. Females, depressive individuals, persons with high social support, with children and a high level of education are more open towards psychotherapy., Discussion: The attitude towards psychotherapy is influenced by gender, socio-demographic and disorder-specific factors and in particular by cultural factors., Conclusion: These results elucidate the need for better information about psychotherapy and the development of intercultural consulting services for migrants in Germany., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: A better understanding of specific sociodemographic and clinical factors in patients with migration background may help to significantly improve psychiatric treatment outcome of these patients. Therefore, we investigated these factors in a large sample of psychiatric outpatients., Methods: N = 423 psychiatric patients of a large outpatient service were assessed for sociodemographic variables as well as clinical variables including diagnosis, psychopharmacological treatment, treatment duration and current symptom load (SCL-14)., Results: We found significant differences between patients with and without migration background in terms of sociodemographic and clinical factors such as education, employment and main diagnose. Patients with migration background had a significantly higher current symptom load, especially for somatic symptoms., Conclusion: The data underline the large differences between patients with and without migration background regarding sociodemographic and clinical factors. These differences should be considered in psychiatric treatment of these patients., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Clinical diagnostics of mental disorders especially among refugees and asylum seekers come with unique difficulties: language barriers, different forms of expression and concepts of the understanding of mental illness as well as a different cultural background. Therefore professional interpreters are needed but associated with a higher effort related to costs and time. We conducted a retrospective analysis of costs, which incurred by the use of professional interpreters in our outpatient clinic in Berlin, Germany, in the first quarter 2016 for the treatment of refugees and asylum seekers. The sample consisted of 110 refugees and asylum seekers; the highest costs in the use of interpreters incurred among Neurotic, stress-related and somatoform disorders (53.04%), especially Posttraumatic Stress Disorder (39.04%), as well as affective disorders (38.47%), especially major depressive episodes (25.23%). Our data point out the crucial need of a regulation of costs with regard to the service of professional interpreters in Germany., (© Georg Thieme Verlag KG Stuttgart · New York.)

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.

Inhibition of Cdk4/Cdk6 by p18(INK4c) (p18) is pivotal for generation of noncycling immunoglobulin (Ig)-secreting plasma cells (PCs). In the absence of p18, CD138(+) plasmacytoid cells continue to cycle and turnover rapidly, suggesting that p18 controls PC homeostasis. We now show that p18 selectively acts in a rare population of rapidly cycling CD138(hi)/B220(hi) intermediate PCs (iPCs). While retaining certain B-cell signatures, iPCs are poised to differentiate to end-stage PCs although the majority undergo apoptosis. p18 is dispensable for the development of the PC transcriptional circuitry, and Blimp-1 and Bcl-6 are expressed fully and mutually exclusively in individual iPCs. However, a minor proportion of iPCs express both, and they are preferentially protected by p18 or Bcl-xL overexpression, consistent with expansion of the iPC pool by Bcl-xL overexpression, or loss of proapoptotic Bim or Noxa. Expression of Noxa is induced during B-cell activation, peaks in iPCs, and selectively repressed by p18. It is required to promote apoptosis of cycling B cells, especially in the absence of p18. These findings define the first physiologic function for Noxa and suggest that by repressing Noxa, induction of G₁ arrest by p18 bypasses a homeostatic cell-cycle checkpoint in iPCs for PC differentiation.

A related series of styryllactones with small functional and stereochemical variations were compiled for a comparative study of their apoptotic activities toward two tumorigenic and one non-tumorigenic control cell line. While a substantial range of intrinsic activity was observed, the relative order of activity of the different compounds toward the cell types varied somewhat as did the relative ratios of apoptosis and necrosis observed in conjunction with the loss of cell viability. While some of the styryllactones showed substantial activity, a small but significant apoptosis-induced synergism was demonstrated with (-)-altholactone and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The progesterone receptor (PR) is an important regulator of female reproduction. Consequently, PR modulators have found numerous pharmaceutical utilities in women's reproductive health. In the process of identifying more receptor-specific and tissue-selective PR modulators, we discovered a novel nonsteroidal, 6-aryl benzoxazinone compound, PRA-910, that displays unique in vitro and in vivo activities. In a PR/PRE reporter assay in COS-7 cells, PRA-910 shows potent PR antagonist activity with an IC50 value of approximately 20 nM. In the alkaline phosphatase assay in the human breast cancer cell line T47D, PRA-910 is a partial progesterone antagonist at low concentrations and is also an effective PR agonist at higher concentrations (EC50 value of approximately 700 nM). PRA-910 binds to the human PR with high affinity (Kd = 4 nM) and was previously shown to exhibit greater than 100-fold selectivity for the PR versus other steroid receptors. In the adult ovariectomized rat, PRA-910 is a potent PR antagonist. It inhibits progesterone-induced uterine decidual response with an ED50 value of 0.4 mg/kg, p.o., and reverses progesterone suppression of estradiol-induced complement C3 expression with potency similar to RU-486. In the nonhuman primate, however, PRA-910 is a PR agonist. The effect on endometrial histology strongly resembles that of progesterone. This unique compound also suppresses estradiol-induced epithelial cell proliferation and both estrogen and progesterone receptor expression in the uterine endometrium as a PR agonist would. In summary, PRA-910 is a structurally and biologically novel selective PR modulator with either PR agonist or antagonist activity, depending on context, concentration, and species.

The central conserved region of the Pseudomonas syringae hrp pathogenicity island encodes a type III protein secretion system (TTSS) that is required for pathogenicity in plants. Expression of the hrp TTSS is controlled by the alternative sigma factor, HrpL, whose expression, in turn, is positively controlled by two truncated enhancer binding proteins, HrpR and HrpS. Although a number of environmental conditions are known to modulate hrp TTSS expression, such as stringent conditions and pathogenesis, the mechanism by which the activities of these transcriptional factors are modulated had not been established. In this study, HrpR and HrpS were found to be constitutively expressed under conditions in which the hrpL promoter was inactive. To identify a postulated negative regulator of hrpL expression, transposome (Tz) mutagenesis was used to isolate hrp constitutive mutants. P. syringae Pss61 and DC3000 hrp constitutive mutants were identified that carried lon::Tz insertions and exhibited increased cell length and UV sensitivity typical of Delta lon mutants. The P. syringae Lon protease retained structural features of its homologues found in other bacteria and was capable of complementing an Escherichia coli Delta lon mutant. P. syringae lon::Tz mutants exhibited enhanced expression of the hrpL promoter, suggesting an effect on HrpR and/or HrpS. HrpR was observed to be unstable in wild-type P. syringae strains grown in non-inductive media. However, the apparent half-life increased more than 10-fold in the P. syringae lon::Tz mutants or upon transfer to an inductive medium. The P. syringae lon mutants elicited rapidly developing plant responses and were shown to hypersecrete effector proteins, such as AvrPto. These results indicate that expression of the hrp regulon and type III secretion are negatively regulated by Lon-mediated degradation of HrpR.

In Pseudomonas syringae strains, the hrp-hrc pathogenicity island consists of an HrpL-dependent regulon that encodes a type III protein translocation complex and translocated effector proteins required for pathogenesis. HrpR and HrpS function as positive regulatory factors for the hrpL promoter, but their mechanism of action has not been established. Both HrpR and HrpS are structurally related to enhancer-binding proteins, but they lack receiver domains and do not appear to require a cognate protein kinase for activity. hrpR and hrpS were shown to be expressed as an operon: a promoter was identified 5' to hrpR, and reverse transcriptase PCR detected the presence of an hrpRS transcript. The hrpR promoter and coding sequence were conserved among P. syringae strains. The coding sequences for hrpR and hrpS were cloned into compatible expression vectors, and their activities were monitored in Escherichia coli transformants carrying an hrpL'-lacZ fusion. HrpS could function as a weak activator of the hrpL promoter, but the activity was only 2.5% of the activity detected when both HrpR and HrpS were expressed in the reporter strain. This finding is consistent with a requirement for both HrpR and HrpS in the activation of the hrpL promoter. By using a yeast two-hybrid assay, an interaction between HrpR and HrpS was detected, suggestive of the formation of a heteromeric complex. Physical interaction of HrpR and HrpS was confirmed by column-binding experiments. The results show that HrpR and HrpS physically interact to regulate the sigma(54)-dependent hrpL promoter in P. syringae strains.

Apoptosis is a highly regulated mechanism of cell death involved in normal development, immune regulation, and homeostasis. Abnormal apoptotic activity has been implicated in a variety of diseases including cancer, autoimmunity, and degenerative disorders. In the thyroid, altered cell death may play a role in the pathogenesis of autoimmune disorders such as Hashimoto's thyroiditis and Graves' disease. Apoptosis-signaling pathways can be initiated through activation of death receptors or in response to cellular damage, such as in gamma irradiation. It has been demonstrated that Fas, tumor necrosis factor, and tumor necrosis factor-related apoptosis-inducing ligand pathways are present and functional in the thyroid, although the expression of these molecules and their roles in thyroid autoimmunity have been debated. Thyroid apoptosis is regulated at multiple levels, including receptor and ligand expression, and the expression of antiapoptotic proteins, such as FAP-1 and Bcl-2. These factors may provide potential mechanisms for modifying the pathogenesis of autoimmune thyroid disease.

Human thyrocytes are resistant to Fas-mediated programmed cell death (PCD). It has been reported that a labile protein inhibitor is involved in the protection of thyrocytes from PCD, and its action can be reversed by incubation of thyrocytes with cycloheximide (CHX) during treatment with agonist anti-Fas Ab. Fas-associated phosphatase-1 (FAP-1) is a protein that has been shown to interact with the negative regulatory domain of Fas and block Fas-mediated apoptosis in FAP-1 transfected Jurkat cells. We investigated the possibility that FAP-1 might be involved in protection against Fas-mediated PCD in human thyrocytes. FAP-1 mRNA was detected in primary thyrocytes using a ribonuclease protection assay. The presence of FAP-1 protein was confirmed by immunohistochemical staining and flow cytometry using a polyclonal anti-FAP-1 Ab. FAP-1 protein also disappeared from thyroid cells in response to CHX. To determine whether FAP-1 is a functional inhibitor of PCD in thyrocytes, we incubated thyrocytes with synthetic SLV (Ac-SLV) tripeptide to compete with Fas for interaction with FAP-1. Thyrocytes treated with Ac-SLV tripeptide showed significantly increased cell death as compared to cells treated with control tripeptide. In addition, in the presence of a suboptimal concentration of CHX, the Ac-SLV tripeptide yielded a strong, synergistic increase in Fas-mediated PCD as compared to thyrocytes treated with control tripeptide. These results implicate FAP-1 as a regulator of Fas-induced PCD in thyrocytes.

Apoptosis is a carefully regulated mechanism of cell death that differs from necrosis and plays an important role in normal tissue development and homeostasis, as well as disease processes. Apoptosis also plays an important role in autoimmunity. Defective apoptosis can cause systemic autoimmunity by allowing the survival of autoreactive lymphocytes. It may also be involved in the pathogenesis of organ-specific autoimmune diseases, such as Hashimoto's thyroiditis, through altered target organ susceptibility. Apoptosis signaling pathways can be initiated through activation of death receptors. One of these pathways employs the death receptor Fas and its ligand (FasL). Fas expression and death pathway signaling have been demonstrated in the thyroid, but there is controversy surrounding the expression of FasL and its role in thyroid autoimmunity. A number of proteins, including FAP-1, Bcl-2 and I-FLICE may regulate the Fas pathway in the thyroid and provide potential mechanisms for modifying the pathogenesis of autoimmune thyroid disease.

To determine whether thyroid cell apoptosis observed in autoimmune thyroid disease could be related to activation of the Fas pathway, we examined the expression and function of Fas on thyroid follicular cells in vitro. Fas messenger RNA was found to be present using two different techniques and was expressed at equal levels in thyrocytes cultured either in the presence or absence of TSH. Fas antigen protein expression was demonstrated by Western blot of thyroid cell lysates and by immunohistochemical staining of thyrocytes, and the amount of Fas protein present did not appear to vary regardless of culture conditions. Despite expressing substantial amounts of Fas protein, thyrocytes treated with anti-Fas monoclonal antibody failed to undergo apoptosis. The addition of either interferon-gamma or interleukin-1beta to the anti-Fas-treated cell cultures also did not promote apoptotic signaling through this pathway. In contrast, the concomitant administration of cycloheximide allowed the induction of apoptosis through the activation of Fas in thyrocytes. These results suggest that Fas is constitutively expressed in thyrocytes, but that the induction of apoptosis through the Fas pathway is blocked by a labile protein inhibitor.

To identify CAP3 and CAP4, components of the CD95 (Fas/APO-1) death-inducing signaling complex, we utilized nano-electrospray tandem mass spectrometry, a recently developed technique to sequence femtomole quantities of polyacrylamide gel-separated proteins. Interestingly, CAP4 encodes a novel 55 kDa protein, designated FLICE, which has homology to both FADD and the ICE/CED-3 family of cysteine proteases. FLICE binds to the death effector domain of FADD and upon overexpression induces apoptosis that is blocked by the ICE family inhibitors, CrmA and z-VAD-fmk. CAP3 was identified as the FLICE prodomain which likely remains bound to the receptor after proteolytic activation. Taken together, this is unique biochemical evidence to link a death receptor physically to the proapoptotic proteases of the ICE/CED-3 family.

Recent reports of "lineage switching" from a lymphoid to macrophage phenotype have left unresolved the question of whether such cells are functional macrophages or nonfunctional products of differentiation gone awry. This study demonstrates that several "macrophage-like" cell lines derived from v-Ha-ras-transformed pre-B cells have gained the capacity to effectively present antigen in MHC-restricted fashion. Using an assay involving the cocultivation of putative antigen-presenting cells with chicken ovalbumin (cOVA) and a cOVA-specific T-cell hybridoma, "lineage switch" cell lines were found to present antigen as effectively as macrophage-containing peritoneal exudates. Neither the original pre-B-cell precursors nor B-cell lymphomas derived from them present antigen. Thus, we have demonstrated that these "lineage switch" macrophages are capable of antigen presentation, a mature differentiated function. While gaining macrophage characteristics, these cells have also rearranged their kappa light-chain immunoglobulin locus, suggesting that macrophage differentiation and immunoglobulin rearrangement are not mutually exclusive processes. The existence of both lymphoid and myeloid characteristics in a cell fully capable of antigen presentation suggests greater plasticity in hematopoietic lineage commitment than conventionally thought to be the case.

Household heads who grew up as members of large families and/or as natives of small towns or rural areas tend to have less education and are more likely to be poor than those coming from small families and/or large cities. Data to support these conclusions have been drawn from two independent sources--a special Social Security Administration supplement to the April 1968 Current Population Survey and findings from the Retirement History Study conducted by the Social Security Administration.