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Land-use changes threaten ecosystems and are a major driver of species loss. Plants may adapt or migrate to resist global change, but this can lag behind rapid anthropogenic changes to the environment. Our data show that natural modulations of the microbiome of grassland plants in response to experimental land-use change in a common garden directly affect plant phenotype and performance, thus increasing plant tolerance. In contrast, direct effects of fertilizer application and mowing on plant phenotypes were less strong. Land-use intensity-specific microbiomes caused clearly distinguishable plant phenotypes also in a laboratory experiment using gnotobiotic strawberry plants in absence of environmental variation. Therefore, natural modulations of the plant microbiome may be key to species persistence and ecosystem stability. We argue that a prerequisite for this microbiome-mediated tolerance is the availability of diverse local sources of microorganisms facilitating rapid modulations in response to change. Thus, conservation efforts must protect microbial diversity, which can help mitigate the effects of global change and facilitate environmental and human health., (© The Author(s) 2025. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)

Background: Whipple's disease (WD) is a rare infection with Tropheryma whipplei that is fatal if untreated. Diagnosis is challenging and currently based on invasive sampling. In a case of WD diagnosed from a kidney biopsy, we observed morphologically-intact bacteria within the glomerular capsular space and tubular lumens. This raised the questions of whether renal filtration of bacteria is common in WD and whether polymerase chain reaction (PCR) testing of urine might serve as a diagnostic test for WD., Methods: We prospectively investigated urine samples of 12 newly-diagnosed and 31 treated WD patients by PCR. As controls, we investigated samples from 110 healthy volunteers and patients with excluded WD or acute gastroenteritis., Results: Out of 12 urine samples from independent, therapy-naive WD patients, 9 were positive for T. whipplei PCR. In 3 patients, fluorescence in situ hybridization visualized T. whipplei in urine. All control samples were negative, including those of 11 healthy carriers with T. whipplei-positive stool samples. In our study, the detection of T. whipplei in the urine of untreated patients correlated in all cases with WD., Conclusions: T. whipplei is detectable by PCR in the urine of the majority of therapy-naive WD patients. With a low prevalence but far-reaching consequences upon diagnosis, invasive sampling for WD is mandatory and must be based on a strong suspicion. Urine testing could prevent patients from being undiagnosed for years. Urine may serve as a novel, easy-to-obtain specimen for guiding the initial diagnosis of WD, in particular in patients with extra-intestinal WD., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Case fatality rates among hospitalized patients diagnosed with human immunodeficiency virus (HIV)-associated tuberculosis remain high, and tuberculosis mycobacteremia is common. Our aim was to define the nature of innate immune responses associated with 12-week mortality in this population., Methods: This prospective cohort study was conducted at Khayelitsha Hospital, Cape Town, South Africa. Hospitalized HIV-infected tuberculosis patients with CD4 counts <350 cells/µL were included; tuberculosis blood cultures were performed in all. Ambulatory HIV-infected patients without active tuberculosis were recruited as controls. Whole blood was stimulated with Escherichia coli derived lipopolysaccharide, heat-killed Streptococcus pneumoniae, and Mycobacterium tuberculosis. Biomarkers of inflammation and sepsis, intracellular (flow cytometry) and secreted cytokines (Luminex), were assessed for associations with 12-week mortality using Cox proportional hazard models. Second, we investigated associations of these immune markers with tuberculosis mycobacteremia., Results: Sixty patients were included (median CD4 count 53 cells/µL (interquartile range [IQR], 22-132); 16 (27%) died after a median of 12 (IQR, 0-24) days. Thirty-one (52%) grew M. tuberculosis on blood culture. Mortality was associated with higher concentrations of procalcitonin, activation of the innate immune system (% CD16+CD14+ monocytes, interleukin-6, tumour necrosis factor-ɑ and colony-stimulating factor 3), and antiinflammatory markers (increased interleukin-1 receptor antagonist and lower monocyte and neutrophil responses to bacterial stimuli). Tuberculosis mycobacteremia was not associated with mortality, nor with biomarkers of sepsis., Conclusions: Twelve-week mortality was associated with greater pro- and antiinflammatory alterations of the innate immune system, similar to those reported in severe bacterial sepsis., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Mortality rates remain high for human immunodeficiency virus (HIV)-associated tuberculosis, and our knowledge of contributing mechanisms is limited. We aimed to determine whether hemostatic changes in HIV-tuberculosis were associated with mortality or decreased survival time and the contribution of mycobacteremia to these effects., Methods: We conducted a prospective study in Khayelitsha, South Africa, in hospitalized HIV-infected patients with CD4 cell counts <350/µL and microbiologically proved tuberculosis. HIV-infected outpatients without tuberculosis served as controls. Plasma biomarkers reflecting activation of procoagulation and anticoagulation, fibrinolysis, endothelial cell activation, matricellular protein release, and tissue damage were measured at admission. Cox proportional hazard models were used to assess variables associated with 12-week mortality rates., Results: Of 59 patients with HIV-tuberculosis, 16 (27%) died after a median of 12 days (interquartile range, 0-24 days); 29 (64%) of the 45 not receiving anticoagulants fulfilled criteria for disseminated intravascular coagulation. Decreased survival time was associated with higher concentrations of markers of fibrinolysis, endothelial activation, matricellular protein release, and tissue damage and with decreased concentrations for markers of anticoagulation. In patients who died, coagulation factors involved in the common pathway were depleted (factor II, V, X), which corresponded to increased plasma clotting times. Mycobacteremia modestly influenced hemostatic changes without affecting mortality., Conclusions: Patients with severe HIV-tuberculosis display a hypercoagulable state and activation of the endothelium, which is associated with mortality., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America)

Although the rate of new tuberculosis (TB) cases has been falling worldwide, progress toward the targets for diagnosis and treatment of drug-resistant TB is far off-track. In countries with no reliable TB surveillance system, setbacks and progression of TB control is barely reflected and little is known on the situation in the field. Interviews with health professionals in Gabon revealed limited access to first- and second-line TB drugs and important deficiencies in basic TB control. National and international action needs to be taken to meet the global TB control targets., (© The Author 2014. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Question: Is first trimester phthalate exposure associated with anogenital distance (AGD), a biomarker of prenatal androgen exposure, in newborns?, Summary Answer: Concentrations of diethylhexyl phthalate (DEHP) metabolites in first trimester maternal urine samples are inversely associated with AGD in male, but not female, newborns., What Is Known Already: AGD is a sexually dimorphic measure reflecting prenatal androgen exposure. Prenatal phthalate exposure has been associated with shorter male AGD in multiple animal studies. Prior human studies, which have been limited by small sample size and imprecise timing of exposure and/or outcome, have reported conflicting results., Study Design, Size, Duration: The Infant Development and the Environment Study (TIDES) is a prospective cohort study of pregnant women recruited in prenatal clinics in San Francisco, CA, Minneapolis, MN, Rochester, NY and Seattle, WA in 2010-2012. Participants delivered 787 infants; 753 with complete data are included in this analysis., Participants/materials, Setting, Methods: Any woman over 18 years old who was able to read and write English (or Spanish in CA), who was <13 weeks pregnant, whose pregnancy was not medically threatened and who planned to deliver in a study hospital was eligible to participate. Analyses include all infants whose mothers provided a first trimester urine sample and who were examined at or shortly after birth. Specific gravity (SpG) adjusted concentrations of phthalate metabolites in first trimester urine samples were examined in relation to genital measurements. In boys (N = 366), we obtained two measures of anogenital distance (AGD) (anoscrotal distance, or AGDAS and anopenile distance, AGDAP) as well as penile width (PW). In girls (N = 373), we measured anofourchette distance (AGDAF) and anoclitoral distance (AGDAC). We used multivariable regression models that adjusted for the infant's age at exam, gestational age, weight-for-length Z-score, time of day of urine collection, maternal age and study center., Main Results and the Role of Chance: Three metabolites of DEHP were significantly and inversely associated with both measures of boys' AGD. Associations (β, 95% confidence interval (CI)) between AGDAS and (log10) SpG-adjusted phthalate concentrations were: -1.12 (-2.16, -0.07) for mono-2-ethylhexyl phthalate (MEHP), -1.43, (-2.49, -0.38) for mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and -1.28 (-2.29, -0.27) for mono-2-ethyl-5-hydroxyhexyl (MEHHP). Associations were of similar magnitude for AGDAP. Associations were weaker and not statistically significant for PW. No other phthalate metabolites were associated with any genital measurement in boys. No phthalate metabolites were associated with either AGD measure in girls., Limitations, Reasons for Caution: Exposure assessment was based on a single first trimester urine sample, which may have introduced exposure misclassification. In addition, significant between-center differences suggest that this measurement is difficult to standardize., Wider Implications of the Findings: Our findings are consistent with multiple rodent studies and most human studies which were far smaller. The data we report here suggest that even at current low levels, environmental exposure to DEHP can adversely affect male genital development resulting in reproductive tract changes that may impact reproductive health later in life. These findings have important implications for public policy since most pregnant women are exposed to this ubiquitous chemical., Study Funding/competing Interests: Funding for TIDES was provided by the following grants from the National Institute of Environmental Health Sciences: R01ES016863-04 and R01 ES016863-02S4. The authors report no conflict of interest., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Motivation: Abstract shape analysis, first proposed in 2004, allows one to extract several relevant structures from the folding space of an RNA sequence, preferable to focusing in a single structure of minimal free energy. We report recent extensions to this approach., Results: We have rebuilt the original RNAshapes as a repository of components that allows us to integrate several established tools for RNA structure analysis: RNAshapes, RNAalishapes and pknotsRG, including its recent extension pKiss. As a spin-off, we obtain heretofore unavailable functionality: e. g. with pKiss, we can now perform abstract shape analysis for structures holding pseudoknots up to the complexity of kissing hairpin motifs. The new tool pAliKiss can predict kissing hairpin motifs from aligned sequences. Along with the integration, the functionality of the tools was also extended in manifold ways., Availability and Implementation: As before, the tool is available on the Bielefeld Bioinformatics server at http://bibiserv.cebitec.uni-bielefeld.de/rnashapesstudio., Contact: bibi-help@cebitec.uni-bielefeld.de., (© The Author 2014. Published by Oxford University Press.)

Background: Deworming human immunodeficiency virus (HIV)-infected individuals on antiretroviral therapy (ART) may be beneficial, particularly during pregnancy. We determined the efficacy of targeted and nontargeted antihelminth therapy and its effects on Plasmodium falciparum infection status, hemoglobin levels, CD4 counts, and viral load in pregnant, HIV-positive women receiving ART., Methods: Nine hundred eighty HIV-infected pregnant women receiving ART were examined at 2 visits during pregnancy and 2 postpartum visits within 12 weeks. Women were given antimalarials when malaria-positive whereas albendazole was given in a targeted (n = 467; treatment when helminth stool screening was positive) or nontargeted (n = 513; treatment at all time points, with stool screening) fashion., Results: No significant differences were noted between targeted and nontargeted albendazole treatments for the variables measured at each study visit except for CD4 counts, which were lower (P < .05) in the latter group at the final visit. Albendazole therapy was associated with favorable changes in subjects' hemoglobin levels, CD4 counts, and viral loads, particularly with helminth infections., Conclusions: Antihelminthic therapy reduces detectable viral load, and increases CD4 counts and hemoglobin levels in pregnant HIV-infected women with helminth coinfections receiving ART., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To ascertain childhood tuberculosis (TB) trends, human immunodeficiency virus (HIV) co-infection rates and multi-drug resistant TB (MDR-TB) prevalence rates in Zambia., Methods: A retrospective review of Zambian annual TB notification data and National TB Programme reports for a 7 year period (2004-2011). TB trends were stratified by age and HIV status., Results: The total number of children notified during this period with all forms of TB was 40 976. A total of 2670 of 40 976 (6%) were smear-positive cases. Notification rates of all forms of childhood TB show a decline in trends from 135 per 100 000 population in 2004, to 69 per 100 000 population in 2011., Conclusions: Childhood TB is an important but neglected problem in Zambia highlighted by the fact that no data exists on HIV co-infection and MDR-TB. Strengthening of the National TB Programme and diagnostics services/algorithms are required to accurately define the TB burden, HIV co-infection and MDR-TB rates in children in Zambia.

Motivation: Dynamic programming is ubiquitous in bioinformatics. Developing and implementing non-trivial dynamic programming algorithms is often error prone and tedious. Bellman's GAP is a new programming system, designed to ease the development of bioinformatics tools based on the dynamic programming technique., Results: In Bellman's GAP, dynamic programming algorithms are described in a declarative style by tree grammars, evaluation algebras and products formed thereof. This bypasses the design of explicit dynamic programming recurrences and yields programs that are free of subscript errors, modular and easy to modify. The declarative modules are compiled into C++ code that is competitive to carefully hand-crafted implementations. This article introduces the Bellman's GAP system and its language, GAP-L. It then demonstrates the ease of development and the degree of re-use by creating variants of two common bioinformatics algorithms. Finally, it evaluates Bellman's GAP as an implementation platform of 'real-world' bioinformatics tools., Availability: Bellman's GAP is available under GPL license from http://bibiserv.cebitec.uni-bielefeld.de/bellmansgap. This Web site includes a repository of re-usable modules for RNA folding based on thermodynamics.

Motivation: Abstract shape analysis allows efficient computation of a representative sample of low-energy foldings of an RNA molecule. More comprehensive information is obtained by computing shape probabilities, accumulating the Boltzmann probabilities of all structures within each abstract shape. Such information is superior to free energies because it is independent of sequence length and base composition. However, up to this point, computation of shape probabilities evaluates all shapes simultaneously and comes with a computation cost which is exponential in the length of the sequence., Results: We device an approach called RapidShapes that computes the shapes above a specified probability threshold T by generating a list of promising shapes and constructing specialized folding programs for each shape to compute its share of Boltzmann probability. This aims at a heuristic improvement of runtime, while still computing exact probability values., Conclusion: Evaluating this approach and several substrategies, we find that only a small proportion of shapes have to be actually computed. For an RNA sequence of length 400, this leads, depending on the threshold, to a 10-138 fold speed-up compared with the previous complete method. Thus, probabilistic shape analysis has become feasible in medium-scale applications, such as the screening of RNA transcripts in a bacterial genome., Availability: RapidShapes is available via http://bibiserv.cebitec.uni-bielefeld.de/rnashapes

Background: Standard anti-proliferative chemotherapy is relatively ineffective against slowly proliferating androgen-independent prostate cancer cells within metastatic sites. In contrast, the lipophilic cytotoxin thapsigargin, which causes apoptosis by disrupting intracellular free Ca2+ levels, is effective against both proliferative and quiescent (i.e., G0-arrested) cells. However, thapsigargin's mechanism of action indicates that it is unlikely to be selective for cancer cells or prostate cells., Methods: We coupled a chemically modified form of thapsigargin, L12ADT, to a peptide carrier that is a substrate for the prostate-specific antigen (PSA) protease to produce a soluble, cell-impermeant latent prodrug that is specifically activated extracellularly within metastatic prostate cancer sites by PSA. We analyzed the kinetics of PSA hydrolysis of the prodrug, the in vitro cytotoxicity of the prodrug against PSA-producing LNCaP human prostate cancer and PSA non-producing HCT-116 human colon cancer cells, and the in vivo pharmacokinetics of the prodrug in mice. We also analyzed antitumor efficacy of the prodrug in nude mice xenograft models of prostate cancer (using LNCaP cells) and renal carcinoma (using human SN12C cells)., Results: The L12ADT peptide prodrug was hydrolyzed efficiently by PSA, was selectively toxic to PSA-producing prostate cancer cells in vitro, and was stable in human plasma. A single dose of 7 mg/kg resulted in a peak serum prodrug concentration of 15.4 +/- 1.1 microM and a half-life of approximately 2.8 hours. Over 24 hours, less than 0.5% of free L12ADT was observed in plasma. Levels of prodrug and liberated L12ADT in prostate cancer xenograft tumors were approximately eightfold and sixfold, respectively, higher than the in vitro LD50s. Prostate cancer xenograft tumors in mice treated with prodrug by intravenous administration were growth-inhibited without substantial host toxicity. Continuous subcutaneous prodrug administration in mice produced complete growth inhibition of established PSA-producing prostate cancer xenograft tumors but had no effect on PSA non-producing renal carcinoma xenograft tumors., Conclusion: Further development of PSA-activated thapsigargin prodrugs as therapy for metastatic prostate cancer is warranted.

To underline the role of echocardiography in the detection of cardiac involvement in patients with amyloidosis, physical examination, echocardiography and electrocardiography were performed in 30 patients with AA amyloidosis (amyloid protein A, associated with chronic inflammatory disease, usually without cardiomyopathy) and 24 patients with AL amyloidosis (the immunoglobulin light chain derived type, often associated with cardiomyopathy). All patients had histological confirmation of amyloidosis by rectal or subcutaneous abdominal fat biopsy. The combination of increased thickness of the left ventricular posterior wall and interventricular septum with a low voltage electrocardiographic pattern is highly specific for cardiac amyloidosis and was found in 3/30 (10%) of the AA patients and in 13/24 (54%) of the AL patients. The echocardiographic abnormalities were strongly related to the degree of clinical heart disease, showing mildly or moderately increased wall thickness in the early asymptomatic phase or severe thickening and hypokinesia of the left ventricular posterior wall and interventricular septum in clinically apparent cardiac dysfunction. Echocardiography appears to be a sensitive test for the detection of cardiac involvement in amyloidosis, in symptomatic as well as asymptomatic patients.