Development of primary invasive pneumococcal disease caused by serotype 1 pneumococci is driven by early increased type I interferon response in the lung

The pneumococcus is the world's foremost respiratory pathogen, but the mechanisms allowing this pathogen to proceed from initial asymptomatic colonization to invasive disease are poorly understood. We have examined the early stages of invasive pneumococcal disease (IPD) by comparing host transcriptional responses to an invasive strain and a noninvasive strain of serotype 1 Streptococcus pneumoniae in the mouse lung. While the two strains were present in equal numbers in the lung 6 h after intranasal challenge, only the invasive strain (strain 1861) had invaded the pleural cavity at that time point; this correlated with subsequent development of bacteremia in mice challenged with strain 1861 but not the noninvasive strain (strain 1). Progression beyond the lung was associated with stronger induction of the type I interferon (IFN-I) response in the lung at 6 h. Suppression of the IFN-I response through administration of neutralizing antibody to IFNAR1 (the receptor for type I interferons) led to significantly reduced invasion of the pleural cavity by strain 1861 at 6 h postchallenge. Our data suggest that strong induction of the IFN-I response is a key factor in early progression of invasive serotype 1 strain 1861 beyond the lung during development of IPD

Overlapping functionality of the Pht proteins in zinc homeostasis of streptococcus pneumoniae

Streptococcus pneumoniae is a globally significant pathogen that causes a range of diseases, including pneumonia, sepsis, meningitis, and otitis media. Its ability to cause disease depends upon the acquisition of nutrients from its environment, including transition metal ions such as zinc. The pneumococcus employs a number of surface proteins to achieve this, among which are four highly similar polyhistidine triad (Pht) proteins. It has previously been established that these proteins collectively aid in the delivery of zinc to the ABC transporter substrate-binding protein AdcAII. Here we have investigated the contribution of each individual Pht protein to pneumococcal zinc homeostasis by analyzing mutant strains expressing only one of the four pht genes. Under conditions of low zinc availability, each of these mutants showed superior growth and zinc accumulation profiles relative to a mutant strain lacking all four genes, indicating that any of the four Pht proteins are able to facilitate delivery of zinc to AdcAII. However, optimal growth and zinc accumulation in vitro and pneumococcal survival and proliferation in vivo required production of all four Pht proteins, indicating that, despite their overlapping functionality, the proteins are not dispensable without incurring a fitness cost. We also show that surface-attached forms of the Pht proteins are required for zinc recruitment and that they do not contribute to defense against extracellular zinc stress

The developmental basis of evolutionary changes in limb proportions

Mammalian limbs are complex morphological structures that exhibit an astonishing amount of diversity. This diversity is driven by changes in the relative proportions of the three limb segments that are conserved among mammals. Despite the importance of limb proportions to mammalian evolution, the developmental mechanisms that regulate mammalian limb proportions remain largely unknown. In this study, I address three questions whose answers will provide insights into the mechanisms through which mammalian segment proportion is determined: when and how does the forelimb achieve its adult proportions, when and how does the hind limb achieve its adult proportions, and when and how does the proportions of the fore-and hind limb diverge. I address these questions using mouse, the model mammalian species. Results of this study indicate that adult forelimb segment proportions are achieved through differing rates of segment growth after their initial condensation, adult hind limb segment proportions are achieved through differing rates of growth after their initial condensations, and fore- and hind limb proportions diverge by the time of the initial cartilage condensation of segments. These findings suggest that the proportions of mammalian limb segments are not established until well after their cartilage condensation, and sets up future research on the specific cellular and molecular mechanisms driving proportion differences among species

The first histidine triad motif of phtd is critical for zinc homeostasis in Streptococcus pneumoniae

Streptococcus pneumoniae is the world's foremost human pathogen. Acquisition of the first row transition metal ion zinc is essential for pneumococcal colonization and disease. Zinc is acquired via the ATP-binding cassette transporter AdcCB and two zinc-binding proteins, AdcA and AdcAII. We have previously shown that AdcAII is reliant upon the polyhistidine triad (Pht) proteins to aid in zinc recruitment. Pht proteins generally contain five histidine (His) triad motifs that are believed to facilitate zinc binding and therefore play a significant role in pneumococcal metal ion homeostasis. However, the importance and potential redundancy of these motifs have not been addressed. We examined the effects of mutating each of the five His triad motifs of PhtD. The combination of in vitro growth assays, active zinc uptake, and PhtD expression studies show that the His triad closest to the protein's amino terminus is the most important for zinc acquisition. Intriguingly, in vivo competitive infection studies investigating the amino- and carboxyl-terminal His triad mutants indicate that the motifs have similar importance in colonization. Collectively, our new insights into the contributions of the individual His triad motifs of PhtD, and by extension the other Pht proteins, highlight the crucial role of the first His triad site in zinc acquisition. This study also suggests that the Pht proteins likely play a role beyond zinc acquisition in pneumococcal virulence

Intensive therapy and remissions in rheumatoid arthritis: a systematic review.

BACKGROUND: We systematically reviewed the effectiveness of intensive treatment strategies in achieving remission in patients with both early and established Rheumatoid Arthritis (RA). METHODS: A systematic literature review and meta-analysis evaluated trials and comparative studies reporting remission in RA patients treated intensively with disease modifying anti-rheumatic drugs (DMARDs), biologics and Janus Kinase (JAK) inhibitors. Analysis used RevMan 5.3 to report relative risks (RR) in random effects models with 95% confidence intervals (CI). RESULTS: We identified 928 publications: 53 studies were included (48 superiority studies; 6 head-to-head trials). In the superiority studies 3013/11259 patients achieved remission with intensive treatment compared with 1211/8493 of controls. Analysis of the 53 comparisons showed a significant benefit for intensive treatment (RR 2.23; 95% CI 1.90, 2.61). Intensive treatment increased remissions in both early RA (23 comparisons; RR 1.56; 1.38, 1.76) and established RA (29 comparisons RR 4.21, 2.92, 6.07). All intensive strategies (combination DMARDs, biologics, JAK inhibitors) increased remissions. In the 6 head-to-head trials 317/787 patients achieved remission with biologics compared with 229/671 of patients receiving combination DMARD therapies and there was no difference between treatment strategies (RR 1.06; 0.93. 1.21). There were differences in the frequency of remissions between early and established RA. In early RA the frequency of remissions with active treatment was 49% compared with 34% in controls. In established RA the frequency of remissions with active treatment was 19% compared with 6% in controls. CONCLUSIONS: Intensive treatment with combination DMARDs, biologics or JAK inhibitors increases the frequency of remission compared to control non-intensive strategies. The benefits are seen in both early and established RA.CH is a South Thames Rheumatology Specialist Registrar working in Kings College Hospital. FI is supported by the Academic department of Rheumatology. DLS is supported by TITRATE study programme. The TITRATE study is funded by the National Institute for Health Research (NIHR) as one of its Programme Grants For Applied Research (Grant Reference Number: RP-PG-0610-10066; Programme Title: Treatment Intensities and Targets in Rheumatoid Arthritis Therapy: Integrating Patients’ And Clinicians’ Views – The TITRATE Programme

GRADE-ADOLOPMENT process to develop 24-hour movement behavior recommendations and physical activity guidelines for the under 5s in the United Kingdom, 2019

Background: This article summarizes the approach taken to develop UK Chief Medical Officers' physical activity guidelines for the Under 5s, 2019. Methods: The Grading of Recommendations Assessment, Development and Evaluation (GRADE)- Adaptation, Adoption, De Novo Development (ADOLOPMENT) approach was used, based on the guidelines from Canada and Australia, with evidence updated to February 2018. Recommendations were based on the associations between (1) time spent in sleep, sedentary time, physical activity, and 10 health outcomes and (2) time spent in physical activity and sedentary behavior on sleep outcomes (duration and latency). Results: For many outcomes, more time spent in physical activity and sleep (up to a point) was beneficial, as was less time spent in sedentary behavior. The authors present, for the first time, evidence in GRADE format on behavior type-outcome associations for infants, toddlers, and preschoolers. Stakeholders supported all recommendations, but recommendations on sleep and screen time were not accepted by the Chief Medical Officers; UK guidelines will refer only to physical activity. Conclusions: This is the first European use of GRADE-ADOLOPMENT to develop physical activity guidelines. The process is robust, rapid, and inexpensive, but the UK experience illustrates a number of challenges that should help development of physical activity guidelines in future

Gettysburg College Sustainability Proposal

In the fall of 2011, the Environmental Studies capstone class led by Professor Rutherford Platt was asked to write Gettysburg College’s first Sustainability Plan. The goal of the plan was to develop specific sustainable practices for the campus that were related to the three pillars of sustainability: economic, social, and environmental, and how integrating diligent sustainable practices into each of these respected pillars will result in a more conscious campus, community, and future. In 2010, Gettysburg College turned to the Sustainability Tracking Assessment and Rating System (STARS) to quantify the institution’s sustainability efforts, providing a self-check mechanism to encourage sustainability applications to all aspects of the College. The American College and University Presidents’ Climate Commitment was signed in 2007 by former Gettysburg College President Katherine Haley Will, declaring that Gettysburg College would become carbon neutral by 2032. Gettysburg College has made large strides in the search for sustainability, and aims to continue its dedication to furthering sustainable practice. The following plan outlines the six priority areas identified by the Capstone class: progress of the American College and University Presidents’ Climate Commitment, Dining Services, campus green space, community outreach, integration of sustainability into the Gettysburg College Curriculum, and the Sustainability Advisory Committee. The first priority area identified was monitoring and upholding the American College and University Presidents’ Climate Commitment (ACUPCC). Though creating new sustainability initiatives on campus is the driving force towards an increasingly sustainable college and community, it is imperative that these goals be carried out in full to maximize beneficial returns. In order to reach carbon neutrality, Gettysburg College hopes to increase energy efficiency in buildings, incorporate renewable energy sources on campus, and mitigate remaining emissions through the purchase of carbon offsets. To further the College’s progress, it is proposed that Gettysburg College continue its energy-efficient appliance purchasing policy, as well as create a policy to offset all greenhouse gas emissions generated by air travel for students study abroad. As stated by the ACUPCC, a Sustainability Committee should take responsibility for the updates and progress reports required to meet the goal of carbon neutrality. The second priority area identified was sustainability in Dining Services. Gettysburg College is home to 2,600 students, all of whom require three full meals a day. Dining Services accounts for a large fraction of Gettysburg College’s sustainability efforts, already implementing sustainability through composting, buying local produce, and using biodegradable products. The proposed on-campus sales cuts of non-reusable to-go items, a change in campus mentality on food waste, and improved composting practices will translate to an increasingly sustainable campus, as well as a well-fed campus body. The third priority was maintaining green space on campus. Ranked as the 23rd most beautiful campus in the United States by The Best Colleges, Gettysburg College utilizes campus green space to create an atmosphere that is conducive to activity as well as tranquility. The plan proposes that Gettysburg College and its grounds facilities continue their exceptional efforts, focusing on increasing the use of the student garden, creating a new rain garden or social area on campus, and converting unnecessary parking lots into green space. As these additions are completed, they must be introduced to the student body and faculty alike to assure these areas are known and utilized. The fourth priority was utilizing community outreach to spread awareness of sustainability initiatives on and off campus. To connect the sustainability-geared changes proposed in this plan, community outreach at Gettysburg College is assessed to estimate how well these initiatives are communicated and promoted to both potential and enrolled students, faculty, and other concerned parties. To evaluate the efficiency of communication at Gettysburg College, a quantitative assessment is presented to measure the ease of finding the sustainability webpage, the quality of sustainability-related topics available on the webpage, and quality of webpage design. The webpage is in need of improved text to image ratios, locations of sustainability topics, and data displays. Despite not having a link to the sustainability webpage on the Gettysburg College homepage, sustainability events should be covered and presented on the rotational news feed found on the homepage to maximize outreach to interested parties or simply to add to the definition of Gettysburg College. The fifth priority was integrating sustainability into the Curriculum to build a culture on campus that values academic rigor, supports students as they cultivate intellectual and civic passions, and promotes the development of healthy social relationships and behaviors. The proposed Sustainability Committee on Sustainability in the Curriculum (SCC) will hold sustainability workshops for faculty with the aim to instill sustainability into all academic disciplines, providing all Gettysburg graduates with a means to approach their professional careers in a fashion that is conscious of sustainability. The sixth and last priority was the Sustainability Advisory Committee. Established in 2007, the Sustainability Advisory Committee is currently under review, but it is recommended that the committee restructure itself in accordance with the new Sustainability Committee Bylaws. These bylaws aim to define the purposes, membership, governance, and involvement with the college. With a clearly defined set of goals and methodology, the Sustainability Advisory Committee will be able to improve the solidarity of the sustainability movement on campus as a whole. By following the propositions laid out in the Gettysburg College Sustainability Plan, the student body, faculty, and community alike will become a part of a multi-faceted progression toward a more sustainable future

The Geology of Inferno Chasm, Idaho: a Terrestrial Analog for Lunar Rilles?

Lunar sinuous rilles are thought to have formed by thermal erosion, mechanical erosion, construction, or a combination of these processes via emplacement by lava tubes or lava channels. The investigation of Hadley Rille by Apollo 15 provided the first field observations of a rille, but remote sensing observations remain our primary method for studying these features. Terrestrial volcanic features with similar morphologies to lunar rilles can provide insight into their formation on the Moon