Submillimeter Studies of Prestellar Cores and Protostars: Probing the Initial Conditions for Protostellar Collapse

Improving our understanding of the initial conditions and earliest stages of protostellar collapse is crucial to gain insight into the origin of stellar masses, multiple systems, and protoplanetary disks. Observationally, there are two complementary approaches to this problem: (1) studying the structure and kinematics of prestellar cores observed prior to protostar formation, and (2) studying the structure of young (e.g. Class 0) accreting protostars observed soon after point mass formation. We discuss recent advances made in this area thanks to (sub)millimeter mapping observations with large single-dish telescopes and interferometers. In particular, we argue that the beginning of protostellar collapse is much more violent in cluster-forming clouds than in regions of distributed star formation. Major breakthroughs are expected in this field from future large submillimeter instruments such as Herschel and ALMA.Comment: 12 pages, 9 figures, to appear in the proceedings of the conference "Chemistry as a Diagnostic of Star Formation" (C.L. Curry & M. Fich eds.

Opportunities for seagrass research derived from remote sensing : a review of current methods

Seagrass communities provide critical ecosystem and provisioning services for both human populations and a wide range of associated species globally. However, it has been reported that seagrass area is decreasing at a rapid rate in many parts of the world, mostly due to anthropogenic activities including global change (pollution and climate change). The aim of this review article is to highlight the range of current tools for studying seagrasses as well as identify the benefits and limitations of a range of remote sensing and traditional methodologies. This paper provides a discussion of the ecological importance of seagrass meadows, and recent trends and developments in seagrass research methods are discussed including the use of satellite images and aerial photographs for seagrass monitoring and various image processing steps that are frequently utilised for seagrass mapping. The extensive use of various optical, Radar and LiDAR data for seagrass research in recent years has also been described in detail. The review concludes that the recent explosion of new methods and tools available from a wide range of platforms combined with the recent recognition of the importance of seagrasses provides the research community with an excellent opportunity to undertake a range of timely research. This research should include mapping the extent and distribution of seagrasses, identifying the drivers of change and factors that confer resilience, as well as quantification of the ecosystem services provided. Whilst remotely sensed data provides an important new tool it should be used in conjunction with traditional methods for validation and with a knowledge of the limitations of results and careful interpretation

Reproducibility of histopathological findings in experimental pathology of the mouse: a sorry tail

Reproducibility of $\textit{in vivo}$ research using the mouse as a model organism depends on many factors, including experimental design, strain or stock, experimental protocols, and methods of data evaluation. Gross and histopathology are often the endpoints of such research and there is increasing concern about the accuracy and reproducibility of diagnoses in the literature. To reproduce histopathological results, the pathology protocol, including necropsy methods and slide preparation, should be followed by interpretation of the slides by a pathologist familiar with reading mouse slides and familiar with the consensus medical nomenclature used in mouse pathology. Likewise, it is important that pathologists are consulted as reviewers of manuscripts where histopathology is a key part of the investigation. The absence of pathology expertise in planning, executing and reviewing $\textit{in vivo}$ research using mice leads to questionable pathology-based findings and conclusions from studies, even in high-impact journals. We discuss the various aspects of this problem, give some examples from the literature and suggest solutions.This work was supported in part by US National Institutes of Health grants R01 AR049288, CA089713 and R21 AR063781 (to J.P.S.) and by The Warden and Fellows of Robinson College, Cambridge (to P.N.S.)

Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase

Objectives (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action. Methods Biomimetic Pictet–Spengler or Bischler–Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds. Results In this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis. Conclusions As the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis

Virulence related sequences: insights provided by comparative genomics of Streptococcus uberis of differing virulence

Background: Streptococcus uberis, a Gram-positive, catalase-negative member of the family Streptococcaceae is an important environmental pathogen responsible for a significant proportion of subclinical and clinical bovine intramammary infections. Currently, the genome of only a single reference strain (0140J) has been described. Here we present a comparative analysis of complete draft genome sequences of an additional twelve S. uberis strains. Results: Pan and core genome analysis revealed the core genome common to all strains to be 1,550 genes in 1,509 orthologous clusters, complemented by 115-246 accessory genes present in one or more S. uberis strains but absent in the reference strain 0140J. Most of the previously predicted virulent genes were present in the core genome of all 13 strains but gene gain/loss was observed between the isolates in CDS associated with clustered regularly interspaced short palindromic repeats (CRISPRs), prophage and bacteriocin production. Experimental challenge experiments confirmed strain EF20 as non-virulent; only able to infect in a transient manner that did not result in clinical mastitis. Comparison of the genome sequence of EF20 with the validated virulent strain 0140J identified genes associated with virulence, however these did not relate clearly with clinical/non-clinical status of infection. Conclusion: The gain/loss of mobile genetic elements such as CRISPRs and prophage are a potential driving force for evolutionary change. This first “whole-genome” comparison of strains isolated from clinical vs non-clinical intramammary infections including the type virulent vs non-virulent strains did not identify simple gene gain/loss rules that readily explain, or be confidently associated with, differences in virulence. This suggests that a more complex dynamic determines infection potential and clinical outcome not simply gene content

Design and Evaluation of Meningococcal Vaccines through Structure-Based Modification of Host and Pathogen Molecules

Neisseria meningitis remains a leading cause of sepsis and meningitis, and vaccines are required to prevent infections by this important human pathogen. Factor H binding protein (fHbp) is a key antigen that elicits protective immunity against the meningococcus and recruits the host complement regulator, fH. As the high affinity interaction between fHbp and fH could impair immune responses, we sought to identify non-functional fHbps that could act as effective immunogens. This was achieved by alanine substitution of fHbps from all three variant groups (V1, V2 and V3 fHbp) of the protein; while some residues affected fH binding in each variant group, the distribution of key amino underlying the interaction with fH differed between the V1, V2 and V3 proteins. The atomic structure of V3 fHbp in complex with fH and of the C-terminal barrel of V2 fHbp provide explanations to the differences in the precise nature of their interactions with fH, and the instability of the V2 protein. To develop transgenic models to assess the efficacy of non-functional fHbps, we determined the structural basis of the low level of interaction between fHbp and murine fH; in addition to changes in amino acids in the fHbp binding site, murine fH has a distinct conformation compared with the human protein that would sterically inhibit binding to fHbp. Non-functional V1 fHbps were further characterised by binding and structural studies, and shown in non-transgenic and transgenic mice (expressing chimeric fH that binds fHbp and precisely regulates complement system) to retain their immunogenicity. Our findings provide a catalogue of non-functional fHbps from all variant groups that can be included in new generation meningococcal vaccines, and establish proof-in-principle for clinical studies to compare their efficacy with wild-type fHbps

Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry

Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3-4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n = 6062). Significant associations were tested for replication in the Penn Medicine Biobank (n = 5737) and the Million Veteran Program (n = 82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR] = 6.4, 95% confidence interval [CI] 2.6-15.6, p = 4.2 × 10-5), which was replicated in the Penn Medicine Biobank (OR = 1.6, 95% CI 1.2-2.4, p = 6.0 × 10-3) and Million Veteran Program (OR = 1.5, 95% CI 1.2-1.8, p = 1.8 × 10-4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR = 2.8, 95% CI 1.7-4.5, p = 2.6 × 10-5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment

First observations of separated atmospheric nu_mu and bar{nu-mu} events in the MINOS detector

The complete 5.4 kton MINOS far detector has been taking data since the beginning of August 2003 at a depth of 2070 meters water-equivalent in the Soudan mine, Minnesota. This paper presents the first MINOS observations of nuµ and [overline nu ]µ charged-current atmospheric neutrino interactions based on an exposure of 418 days. The ratio of upward- to downward-going events in the data is compared to the Monte Carlo expectation in the absence of neutrino oscillations, giving Rup/downdata/Rup/downMC=0.62-0.14+0.19(stat.)±0.02(sys.). An extended maximum likelihood analysis of the observed L/E distributions excludes the null hypothesis of no neutrino oscillations at the 98% confidence level. Using the curvature of the observed muons in the 1.3 T MINOS magnetic field nuµ and [overline nu ]µ interactions are separated. The ratio of [overline nu ]µ to nuµ events in the data is compared to the Monte Carlo expectation assuming neutrinos and antineutrinos oscillate in the same manner, giving R[overline nu ][sub mu]/nu[sub mu]data/R[overline nu ][sub mu]/nu[sub mu]MC=0.96-0.27+0.38(stat.)±0.15(sys.), where the errors are the statistical and systematic uncertainties. Although the statistics are limited, this is the first direct observation of atmospheric neutrino interactions separately for nuµ and [overline nu ]µ