Warped Kaluza-Klein Dark Matter

Warped compactifications of type IIB string theory contain natural dark matter candidates: Kaluza-Klein modes along approximate isometry directions of long warped throats. These isometries are broken by the full compactification, including moduli stabilization; we present a thorough survey of Kaluza-Klein mode decay rates into light supergravity modes and Standard Model particles. We find that these dark matter candidates typically have lifetimes longer than the age of the universe. Interestingly, some choices for embedding the Standard Model in the compactification lead to decay rates large enough to be observed, so this dark matter sector may provide constraints on the parameter space of the compactification.Comment: 37pp; v2. references, minor clarificatio

The fracture toughness of small animal cortical bone measured using arc-shaped tension specimens: Effects of bisphosphonate and deproteinization treatments

Small animal models, and especially transgenic models, have become widespread in the study of bone mechanobiology and metabolic bone disease, but test methods for measuring fracture toughness on multiple replicates or at multiple locations within a single small animal bone are lacking. Therefore, the objective of this study was to develop a method to measure cortical bone fracture toughness in multiple specimens and locations along the diaphysis of small animal bones. Arc-shaped tension specimens were prepared from the mid-diaphysis of rabbit ulnae and loaded to failure to measure the radial fracture toughness in multiple replicates per bone. The test specimen dimensions, crack length, and maximum load met requirements for measuring the plane strain fracture toughness. Experimental groups included a control group, bisphosphonate treatment group, and an ex vivo deproteinization treatment following bisphosphonate treatment (5 rabbits/group and 15 specimens/group). The fracture toughness of ulnar cortical bone from rabbits treated with zoledronic acid for six months exhibited no difference compared with the control group. Partially deproteinized specimens exhibited significantly lower fracture toughness compared with both the control and bisphosphonate treatment groups. The deproteinization treatment increased tissue mineral density (TMD) and resulted in a negative linear correlation between the measured fracture toughness and TMD. Fracture toughness measurements were repeatable with a coefficient of variation of 12–16% within experimental groups. Retrospective power analysis of the control and deproteinization treatment groups indicated a minimum detectable difference of 0.1 MPa·m1/2. Therefore, the overall results of this study suggest that arc-shaped tension specimens offer an advantageous new method for measuring the fracture toughness in small animal bones

NOTES ON THE NEST, BREEDING SEASON, AND ELEVATIONAL RANGE OF A RARE HUMMINGBIRD, THE PURPLE-BACKED SUNBEAM (AGLAEACTIS ALICIAE)

Abstract The breeding biology and phenology of the endangered hummingbird Purple-backed Sunbeam (Aglaeactis aliciae) are not well known. We report observations of nesting A. aliciae near El Molino, in La Libertad Department, Peru. On 11 March 2018, we found a female building a nest while on 10 March 2019 we found an incubating female. We describe specific characteristics of the nest and breeding behavior of nesting females. Based on our observations and that of others, the timing of nesting for this species seems to correspond to the mid-to-late rainy season, extending from at least March to May. Additionally, our sightings suggest a higher upper elevational range limit for this range-restricted Andean hummingbird than previously reported; the elevational range should be considered to be 2900–3700 m a.s.l.Resumen ∙ Notas sobre el nido, temporada reproductiva y rango elevacional del Colibrí de Alicia (Aglaeactis aliciae) La biología reproductiva y la fenología del Colibrí de Alicia (Aglaeactis aliciae) – una especie de colibrí amenazada – son poco conocidas. Aquí reportamos observaciones de nidificación de A. aliciae en El Molino, Departamento La Libertad, Perú. El 11 de marzo de 2018 encontramos una hembra construyendo un nido, mientras que el 10 de marzo de 2019 encontramos a una hembra incubando. Describimos las características del nido y el comportamiento reproductivo de las hembras. En base a nuestras observaciones e información previa sugerimos que la temporada de nidificación se desarrolla desde mediados a fines de la temporada húmeda, extendiéndose desde marzo a mayo. Nuestras observaciones también indican que la especie se encuentra a mayores altitudes que lo reportado previamente y que su rango altitudinal seria 2900–3700 m s.n.m

Increasing synergistic effects of habitat destruction and hunting on mammals over three decades in the Gran Chaco

Habitat destruction and overexploitation are the main threats to biodiversity and where they co-occur, their combined impact is often larger than their individual one. Yet, detailed knowledge of the spatial footprints of these threats is lacking, including where they overlap and how they change over time. These knowledge gaps are real barriers for effective conservation planning. Here, we develop a novel approach to reconstruct the individual and combined footprints of both threats over time. We combine satellite-based land-cover change maps, habitat suitability models and hunting pressure models to demonstrate our approach for the community of larger mammals (48 species > 1 kg) across the 1.1 million km2 Gran Chaco region, a global deforestation hotspot covering parts of Argentina, Bolivia and Paraguay. This provides three key insights. First, we find that the footprints of habitat destruction and hunting pressure expanded considerably between 1985 and 2015, across ~40% of the entire Chaco – twice the area affected by deforestation. Second, both threats increasingly acted together within the ranges of larger mammals in the Chaco (17% increase on average, ± 20% SD, cumulative increase of co-occurring threats across 465 000 km2), suggesting large synergistic effects. Conversely, core areas of high-quality habitats declined on average by 38%. Third, we identified remaining priority areas for conservation in the northern and central Chaco, many of which are outside the protected area network. We also identify hotspots of high threat impacts in central Paraguay and northern Argentina, providing a spatial template for threat-specific conservation action. Overall, our findings suggest increasing synergistic effects between habitat destruction and hunting pressure in the Chaco, a situation likely common in many tropical deforestation frontiers. Our work highlights how threats can be traced in space and time to understand their individual and combined impact, even in situations where data are sparse.Fil: Romero-Muñoz, Alfredo. Humboldt-Universität zu Berlin; AlemaniaFil: Benítez-López, Ana. Consejo Superior de Investigaciones Científicas. Estación Biológica de Doñana; EspañaFil: Zurell, Damaris. Humboldt-Universität zu Berlin; AlemaniaFil: Baumann, Matthias. Humboldt-Universität zu Berlin; AlemaniaFil: Camino, Micaela. Proyecto Quimilero; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Centro de Ecología Aplicada del Litoral. Universidad Nacional del Nordeste. Centro de Ecología Aplicada del Litoral; ArgentinaFil: Decarre, Julieta. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación de Recursos Naturales. Instituto de Recursos Biológicos; ArgentinaFil: Castillo, Hugo del. Guyra Paraguay; ParaguayFil: Giordano, Anthony J.. University of California; Estados UnidosFil: Gómez-Valencia, Bibiana. Instituto de Investigación de Recursos Biológicos Alexander Von Humboldt, Bogota; Colombia. Universidad de Buenos Aires; ArgentinaFil: Levers, Christian. Humboldt-Universität zu Berlin; AlemaniaFil: Noss, Andrew J.. University of Florida; Estados UnidosFil: Quiroga, Verónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; ArgentinaFil: Thompson, Jeffrey J.. Guyra Paraguay; ParaguayFil: Torres, Ricardo Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; ArgentinaFil: Velilla, Marianela. Guyra Paraguay; ParaguayFil: Weiler, Andrea. Universidad Nacional de Asunción; ParaguayFil: Kuemmerle, Tobias. Humboldt-Universität zu Berlin; Alemani

CMBPol Mission Concept Study: Probing Inflation with CMB Polarization

We summarize the utility of precise cosmic microwave background (CMB) polarization measurements as probes of the physics of inflation. We focus on the prospects for using CMB measurements to differentiate various inflationary mechanisms. In particular, a detection of primordial B-mode polarization would demonstrate that inflation occurred at a very high energy scale, and that the inflaton traversed a super-Planckian distance in field space. We explain how such a detection or constraint would illuminate aspects of physics at the Planck scale. Moreover, CMB measurements can constrain the scale-dependence and non-Gaussianity of the primordial fluctuations and limit the possibility of a significant isocurvature contribution. Each such limit provides crucial information on the underlying inflationary dynamics. Finally, we quantify these considerations by presenting forecasts for the sensitivities of a future satellite experiment to the inflationary parameters.Comment: 107 pages, 14 figures, 17 tables; Inflation Working Group contribution to the CMBPol Mission Concept Study; v2: typos fixed and references adde

The DNA-recognition fold of Sso7c4 suggests a new member of SpoVT-AbrB superfamily from archaea

Organisms growing at elevated temperatures face the challenge of maintaining the integrity of their genetic materials. Archaea possess unique chromatin proteins for gene organization and information processing. We present the solution structure of Sso7c4 from Sulfolobus solfataricus, which has a homodimeric DNA-binding fold forming a swapped β-loop-β ‘Tai-Chi’ topology. The fold is reminiscent of the N-terminal DNA-binding domain of AbrB and MazE. In addition, several amide resonances in the heteronuclear single quantum coherence spectra of Sso7c4 are shifted and broadened with the addition of small amounts of duplex DNA oligomers. The locations of the corresponding amides in the Sso7c4 structure define its DNA-interacting surface. NMR spectra of DNA titrated with the protein further indicated that Sso7c4 interacts with DNA in the major groove. Taken together, a plausible model for the Sso7c4–DNA complex is presented, in which the DNA double helix is curved around the protein dimer

Reproducibility in modeling and simulation of the knee:Academic, industry, and regulatory perspectives

Stakeholders in the modeling and simulation (M&amp;S) community organized a workshop at the 2019 Annual Meeting of the Orthopaedic Research Society (ORS) entitled “Reproducibility in Modeling and Simulation of the Knee: Academic, Industry, and Regulatory Perspectives.” The goal was to discuss efforts among these stakeholders to address irreproducibility in M&amp;S focusing on the knee joint. An academic representative from a leading orthopedic hospital in the United States described a multi-institutional, open effort funded by the National Institutes of Health to assess model reproducibility in computational knee biomechanics. A regulatory representative from the United States Food and Drug Administration indicated the necessity of standards for reproducibility to increase utility of M&amp;S in the regulatory setting. An industry representative from a major orthopedic implant company emphasized improving reproducibility by addressing indeterminacy in personalized modeling through sensitivity analyses, thereby enhancing preclinical evaluation of joint replacement technology. Thought leaders in the M&amp;S community stressed the importance of data sharing to minimize duplication of efforts. A survey comprised 103 attendees revealed strong support for the workshop and for increasing emphasis on computational modeling at future ORS meetings. Nearly all survey respondents (97%) considered reproducibility to be an important issue. Almost half of respondents (45%) tried and failed to reproduce the work of others. Two-thirds of respondents (67%) declared that individual laboratories are most responsible for ensuring reproducible research whereas 44% thought that journals are most responsible. Thought leaders and survey respondents emphasized that computational models must be reproducible and credible to advance knee M&amp;S.</p

Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study

BACKGROUND: The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. METHODS AND FINDINGS: We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p \u3c 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD-positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4-38.9; p = 0.02) compared to utDNA MRD-negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD-positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. CONCLUSIONS: utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future

Managing granulomatous-lymphocytic interstitial lung disease in common variable immunodeficiency disorders : e-GLILDnet International Clinicians Survey

Background Granulomatous-lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking. Aims The European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up. Methods The e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February-April 2020. Results were analyzed using SPSS. Results One hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82-maximum 500) CVID patients, of which a median of 5 (IQR 8-max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up. Conclusions These data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients