Grants

Cambridge Performance Project, Inc.

Back Pocket Dancers

Pro Arte Chamber Orchestra

Back to Classical

Cambridge Educational Access

Back to the 'Bridge: CRLS Alumni Artists in Residence

Artspace Committee

The Artspace Committee will host a free public event featuring games, food, art, and karaoke based on a 1980's cultural theme. It will be held at Artspace Hiawatha Lofts located at 843 Hiawatha Pl S. The event will take place on May 26, 2018 from 5 pm - 10 pm.

City of Cannon Beach

Backbone Resiliency Project Phase 1

NEI - National Eye Institute

PROJECT SUMMARY / ABSTRACT Bacterial eye infections cause a significant number of cases of blindness worldwide. Bacteria secrete an armamentarium of virulence factors that protect them from killing by immune cells. Most pathogens that infect the eye produce a polysaccharide capsule that covers the bacterial surface. This “cloaking” renders them invisible to receptors and pathways that would otherwise incite an immune response, protecting them from killing by immune cells. Unhindered growth results in virulence factor production. In the eye, this can manifest as an irreversibly damaged retina and significant vision loss. To make matters worse, many of these pathogens belong to the ESKAPE group (Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, Enterobacter) and are at the top of the CDC’s list of Antibiotic Resistance Threats in the US. Multidrug resistance is common in ocular isolates, elevating the risk of infections that are difficult to treat. Our program investigates the pathogenic mechanisms underlying ocular bacterial infections. For bacteria, animal infection models and ocular cell lines are used to investigate the areas noted above. We have a very good idea of the virulence factors that directly damage the retina and the innate pathways involved in inflammation. This proposal is focused on a common virulence factor which may be involved in cloaking bacteria during the earliest stages of endophthalmitis, events that, to date, have drawn minimal attention. This new R01 proposal is based on the overarching hypothesis that ocular pathogens are cloaked from the intraocular immune response by capsule expression in the eye during infection. The scientific premise is based on data demonstrating that: 1) capsule genes are expresssed in intraocular environments and in infected eyes of mice, 2) capsule-deficient mutants are not as virulent as bacteria that express capsule, 3) capsules are potential PAMPs and may interact with TLRs, and 4) anti-capsule antibody improves the clinical outcome of endophthalmitis caused by streptococci and non-ocular infections caused by encapsulated pathogens. These gaps are investigated in three separate but related aims focused on capsule-mediated cloaking of ocular pathogens in endophthalmitis. We will use well-characterized capsule-deficient mutants in in vitro and in vivo models in rigorous and straightforward experiments designed to define the role of capsule in endophthalmitis and the potential value of therapeutically targeting capsule to improve clinical outcome. For patients with eye infections, ineffective treatment often equates with vision loss. Our approach to addressing these gaps in our field are innovative, translationally relevant, and will move the ocular infectious disease field forward by focusing on a common bacterial virulence factor that is targeted in FDA-approved vaccines which have improved the health of millions. These studies are a logical extension of our ocular infection research program, and we are well positioned to contribute new and important information that will improve options for preventing infection and preserving vision.

NEI - National Eye Institute

We are at a watershed moment in human biology were we have identified that we have an axillary microbial genome that affects how our cells function and we can leverage this genome to tackle complex diseases such as diabetic retinopathy (DR). Thus, the human host is inextricably linked to its microbiome and has coevolved with it resulting in the outsourcing of approximately 60% of human metabolism to microbiota. The gut provides the dominant microbiome in the body, representing approximately a 3000 microbial species that are responsible for the generation of biologically active metabolites that dramatically impact host health. Microbiota-derived metabolites such as tryptophan (Trp) metabolites, short-chain fatty acids, and bile acid derivatives are crucial for gut health, beneficially influencing gut barrier function, immune responses, energy metabolism and lipid digestion. We have identified specific beneficial microbe derived metabolites of Trp that are decreased and other deleterious metabolites that are increased in the plasma of diabetic individuals with retinopathy. Using liquid chromatography–mass spectrometry (LC-MS) for targeted metabolomics, we show that individuals with DR have markedly reduced levels of the protective Trp metabolite, indole 3- proprionic acid (IPA) and elevated levels of toxic metabolite Indole sulfate. Exogenous administration IPA prevented the development of DR in db/db mice, a model of type 2 diabetes. IPA administration activated pregnane X receptor (PXR) receptors to enhance intestinal and retinal barrier function. IPA suppressed NF-κB signaling and NLRP-3 activation and downregulated pro-inflammatory cytokines such as IL-6 and TNF-α in the retina and reduced Th17 cells migration from the gut to the retina. We propose the following hypothesis: Key beneficial microbial derived metabolites such as IPA generated by the gut microbes enter the systemic circulation and retina activating PXR receptors on retinal endothelial cells and retinal pigment epithelial cells to main integrity of blood retinal barrier and modulate local retinal immune responses. These protective mechanisms are lost in DR. We postulate that Trp supplementation in the form of Trp containing dipeptides and/or genetically modified bacteria that generate beneficial Trp metabolites will prevent DR. Impact: nutraceutical supplementation with Trp or Trp containing dipeptides or intake of food grade probiotics that generate beneficial bacterial metabolites represent novel strategies for prevention of DR and are timely approaches for this era of personalized medicine.

NIGMS - National Institute of General Medical Sciences

SUMMARY/ABSTRACT Treatment of pathogens depends upon their genetic resistance to antibiotics as well as non-genetic heteroresistance, but it is unclear whether there are inherited non-genetic factors that influence their susceptibility. One physiological change known to influence antibiotic sensitivity is the heat shock response: the coordinated upregulation of protein chaperones that reverse misfolded protein aggregates. Misfolded proteins sensitize cells to antibiotics, such that concurrent treatment with heat potentiates their use, whereas a pre- exposure to heat leaves cells better able to handle a later challenge. Although eukaryotes have epigenetic mechanisms to pass their heat shock response to later generations, to date no report of a similar phenomenon has been made for bacteria. Our proposed project takes advantage of our discovery of epigenetic memory of heat shock response in Methylobacterium extorquens. We uncovered this phenomenon using a novel, high-throughput assay for epigenetic inheritance and collateral effects in alternative environments. Exposure to a heat shock leaves an imprint on cells 15 generations later that improves their ability to handle another heat shock but otherwise decreases their growth in all other environments. We hypothesize that the formation of protein aggregates triggers memory, and that memory is maintained via a heritable, alternative DNA methylation at one or more loci, with that methylation state resulting in a higher baseline expression of chaperones and other heat shock proteins. The overall objective of this proposed research is to understand how the heat shock response is inherited and how it leads to altered antibiotic sensitivity. The outcome of this proposed work will be the development of a general framework and novel methodology that can be used to explore the potential for epigenetic memory of heat shock across bacteria. The intersection between multiple empirical approaches and statistical analysis of the quantitative physiological data provides an excellent trans-disciplinary training ground for undergraduates. The positive impacts of this research will be to weave epigenetic inheritance into more effective antibiotic treatment strategies.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary The host lipid environment is a well-described barrier to bacterial infection at several sites including the skin, lung, and upper airways. In addition, both bacterial and host lipids serve as signals that promote inflammation. Bacterial lipids activate Toll-like receptors which initiates cytokine production, immune cell recruitment, and induction of oxidative burst to control infection. Several pathogenic bacteria evade these lipid-mediated defenses by secreting lipolytic enzymes (lipases). Bacterial lipases can cause host membrane dissolution, facilitate escape from cellular compartments, disrupt physical barriers, detoxify antimicrobial lipids, and release nutrient fatty acids. Despite these established contributions of lipases to infection there exist critical gaps in knowledge on how lipases drive host immunity and physiology. This is especially true for Staphylococcus aureus which produces three lipases that have long been presumed to promote virulence, despite scant mechanistic studies. Recent work from our lab started to fill this gap by providing evidence for a direct role for lipases in immune evasion and nutrient acquisition during infection. We made the unexpected observation that the S. aureus secreted lipase, Geh, inhibited activation of innate immune cells in culture. Further, Geh blunted pro-inflammatory cytokine production during infection and was responsible for bacterial persistence in some tissues but not others, highlighting tissue-specific contributions of Geh to survival. The blunted cytokine response was not due to direct functions of Geh on mammalian cells, but rather a result of inactivation of S. aureus lipoproteins, a major pathogen-associated molecular pattern (PAMP) of Gram-positive bacteria, via ester hydrolysis. While our studies indicate S. aureus uses lipases to inactivate lipoprotein PAMPs containing saturated straight and branched chain fatty acids that it synthesizes de novo, it can also acquire host unsaturated fatty acids in a lipase-dependent manner and use them for lipoprotein biogenesis. We found that S. aureus uptake of host fatty acids disrupted innate immune responses and infection dynamics in tissues involved in lipid metabolism via attachment of host fatty acids to bacterial lipoproteins. This deleterious response correlated well with Toll-like receptor 2 signaling. Finally, infections of the skin uncovered a role for Geh that appeared to be independent of Toll-like receptor 2 and instead was linked to liberation of host fatty acid esters that promoted fitness. Altogether, our data support the hypothesis that S. aureus lipases modify both bacterial and host lipids to calibrate innate immunity and promote a fitness advantage that allows adaptation to a wide range of tissues during infection. Aim 1 will determine the cellular and molecular basis for Geh-mediated infection persistence. Aim 2 will test the roles of the three lipases secreted by S. aureus in virulence, lipid utilization, and immune defense. Aim 3 will determine how lipases disrupt immunity and allow S. aureus to adapt to increased circulating lipids in the host.

NIGMS - National Institute of General Medical Sciences

PROJECT SUMMARY Bacteria have successfully colonized almost every niche on this planet, and their success is driven in large part by their ability to adapt to and survive environmental challenges. One example is excessive protons (or acidity, low pH), which can damage lipids, nucleic acids, and proteins. Bacteria that colonize the human body contend with many different pH gradients, especially in the gastrointestinal system. One way that bacteria survive this stress is by using amino acid catabolism to de-acidify their environment. We discovered that the bacterial second messenger c-di-GMP regulates both amino acid metabolism and acid resistance in the gastrointestinal bacteria E. coli and Shigella. One of these amino acids is isoleucine, and we have found that E. coli, but not Shigella, catabolizes isoleucine to resist acid stress. Bacterial isoleucine-mediated acid resistance has not been previously reported. In this application, we will investigate how isoleucine contributes to acid resistance, how c- di-GMP regulates acid resistance in these two organisms, and how these pathways are impacted by the evolutionary process of pathoadaptation. Methodologies proposed here are accessible for undergraduate researchers, who will complete the experiments outlined in this proposal. Because many bacteria use amino acid metabolism to resist acid stress, and because c-di-GMP signaling is so widely conserved, findings from this study will be widely generalizable for other gastrointestinal bacteria. Understanding how gastrointestinal bacteria adapt to pH stress is critical for many aspects of human health, including protecting our food supply chain, promoting symbiotic bacteria, and controlling human pathogens.

NIGMS - National Institute of General Medical Sciences

Project Summary/Abstract Microorganisms employ diverse stress response systems to enable rapid and specific adaptations to environmental challenges such as antimicrobial stress, nutrient limitation, and osmotic pressure. The second messenger cyclic di-AMP (c-di-AMP) is produced by more than 11,000 bacterial and archaeal species, with its concentration fluctuating in response to these external stimuli and regulating carbon metabolism, osmotic homeostasis, cell wall synthesis, and DNA integrity. However, how bacteria translate external stimuli to c-di-AMP metabolism, as well as how c-di- AMP regulates bacterial physiology to alleviate cell stress remain poorly understood. Our recent findings reveal that elevated c-di-AMP production is associated with bacterial thymineless death regulation, a DNA damage-induced programmed cell death mechanism observed across all living cells. Additionally, we have identified c-di-AMP elevation as a conserved cell response to DNA damage across different Firmicutes, highlighting the importance of c-di-AMP as a global regulator for DNA integrity in bacteria. The long-term goal of our lab is to unravel previously undescribed bacterial stress response and adaptation mechanisms. The goal of this proposal is to investigate how early and late DNA damage signals, including DNA supercoil relaxation and DNA breaks, regulate c-di-AMP metabolism and how subsequent changes in c-di-AMP concentration influence nucleotide synthesis and salvage to facilitate DNA repair and inhibit cell death. By uncovering novel DNA integrity surveillance mechanisms, this foundational research will advance our understanding of bacterial stress responses and inform new strategies for developing antimicrobial targets.

NIAID - National Institute of Allergy and Infectious Diseases

This application requests funding to support 8 second- and third-year students in the Harvard Graduate Program in Bacteriology (GPiB) T32 Training Program. The overarching goal of this program is to teach our students to identify important and outstanding biological questions while cultivating the technical skills and intellectual flexibility required to answer them. Students enter the GPiB through the Biological and Biomedical Sciences (BBS) parent PhD program at Harvard Medical School (HMS) or the Biological Sciences in Public Health (BPH) parent PhD program at the Harvard T.H. Chan School of Public Health (HSPH). Trainees are selected for GPiB based on their expressed interest during their first year of graduate school and their choice of dissertation laboratory. At the heart of this inter-school program is a vibrant and supportive community of microbiologists that draws its strength from decades of active collaborations and scientific exchange, training successes, research infrastructure, and long-standing friendships. The breadth of research in the 33 program faculty labs reflects the important roles of bacteriology in science and society, ranging from fundamental mechanisms of bacterial cell biology to the interactions between pathogenic and commensal bacteria and their host. Scientific training in the GPiB begins with foundational and quantitative coursework in the BBS and BPH umbrella programs and is then complemented by GPiB courses that focus on basic mechanisms in bacteriology and bacteria-host interaction. These classes use primary literature to teach students to be critical readers and thinkers while developing skills in experimental design and communication. GPiB students at all levels of training engage with each other and with program faculty on a weekly basis through regular seminars, work-in-progress talks, specialized nanocourses, and community events. Professional development workshops, a science communication mentoring program, and career exploration events help trainees identify future career opportunities and develop transferable skills to attain them. Mentoring support for GPiB faculty coupled with supplemental advising from Dissertation Advisory Committees, GPiB leadership, GPiB alumni, and senior students create strong networks of mentoring support for trainees of all interests and backgrounds. Finally, surveys, town halls, external reviews, and exit interviews provide regular assessment of uptake and efficacy of GPiB courses, paracurricular activities, and research training and environment. GPiB combines the passionate, tight-knit Harvard microbiology community with rigorous, evidence-based curriculum to support the training of future leaders in bacteriology.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Multidrug-resistant organisms (MDROs) remain major causes of morbidity and mortality in hematopoietic cell transplant (HCT) recipients. Because of the substantial use of antibiotics in these patients, their gut microbiome balance is perturbed and becomes dominated by MDROs, vancomycin-resistant enterococci (VRE) in particular. This disturbance is associated with subsequent invasive infections such as bacteremia that can lead to fatal outcome. Restoration of the normal balance of the gut flora and reduction or control of MDRO colonization may curtail these complications and improve outcomes. One innovative approach to restore the microbiome balance of the gut flora and reduce colonization with MDROs in HCT recipients is the administration of bacteriophages (i.e., phages). Phages are ubiquitous and natural entities, present in the environment and in our bodies, and capable of lysing specific pathogens without disturbing the host’s normal flora while averting the collateral damage of antimicrobial usage. My long-term research goal is to understand how phages contribute to host-microbe interactions and their overall impact on the health of HCT recipients. Our preliminary data indicate that VRE colonization can cause inflammation in the gut of germ-free wild-type mice. Additionally, we found that phages are present in high numbers in HCT patients’ stool samples and that VRE phages can be recovered from environmental samples and can lyse a variety of VRE strains in a larva model. The objective of the proposed research is to investigate the interactions between phages, the gut bacterial microbiome, and host responses in VRE-colonized HCT recipients and to identify biomarkers in the gut phage population predisposing patients to complications such as bacterial infections or graft versus host disease. The central hypothesis for this project is that VRE phages can restore balance in the gut microbiota by reducing inflammation and VRE colonization in HCT recipients. My ultimate goal is to generate significant findings and new hypotheses for an R01 application aiming at (1) optimizing the design of a chemotherapy- treated bone marrow-reconstituted mouse model mimicking the condition of HCT patients, (2) testing the efficacy of phages and phages+antibiotic synergy in preventing major MDRO infections in this mouse model, and (3) validating the role of certain phage populations in predicting and preventing poor outcomes. The rationale is that this line of work will provide supportive evidence for future development and evaluation of a phage-based intervention in humans. My long-term career goal is to become a leading investigator with expertise in the design of effective and safe phage-based natural therapeutic products that may restore a healthy gut microbiota and curtail serious complications encountered in HCT recipients (i.e., MDROs), thus improving their overall health outcomes. The proposal will aid in the fight against MDROs by curtailing the incidence of MDRO colonization and infections and by improving survival and quality-of-life of HCT recipients.

Ray O'Herron Company, Inc.

Badges

NSF

Recognizing the growing pressure to deliver career-ready graduates at a reasonable cost, more community colleges are exploring online badges and micro-credentials to provide students and faculty with portable evidence of specific job-relevant competencies. The R&D team from SRI Education and Evergreen Valley College intends to investigate and develop an institutional level badging and micro-credentials program and system. Many badging and micro-credential programs document technical competencies, but the field lacks understanding of how such programs can increase institutional capacity to develop STEM technician students' professional skills competencies, such as communication, teamwork, capacity for life-long learning, and adapting to the workforce. The overarching goal of the project is to investigate and develop micro-credential programs for both students and faculty related to teaching and learning professional skills. STEM technical students will use badging to document their development of professional skills for future employment, sharing the badges digitally through LinkedIn and on their resumes. STEM technical faculty will use badging to document their learning of new instructional strategies to teach professional skills in their classes. Project objectives are to (a) design, test, and implement a badging sequence for professional skills micro-credentials for students to document satisfactory completion of instructional activities; (b) design, test, and implement a badging sequence that supports and documents instructors’ integration of activities and reflections into courses; (c) develop a strategy for engaging employers and linking to badging ecosystems to build acceptance and recognition of professional skills micro-credentials; and (d) explore ways for colleges to track participation, achievement, and workplace testimonials. The team intends the badging sequence framework to be adaptable for use in other college programs and settings. The mixed methods research and development effort is intended to produce three products to guide future badging and micro-credentialing programs for STEM technicians' professional skills: (1) a formative evaluation that documents and assesses how to assemble incentives to build capacity for instructors and students; (2) a mixed methods study that tracks how different levels of instructor and student engagement and achievement relate to instructors' teaching confidence and students' career readiness; and (3) a sub-study that disaggregates program trends by instructors' and students' backgrounds and professional experience. By targeting the development of professional skills, the approach aims to establish opportunities and system capacity to foster the participation of a diverse population of highly skilled technicians in STEM fields. The project is funded by the Advanced Technological Education program that focuses on the education of technicians for the advanced technology fields that drive the nation’s economy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

City of Richmond

MAX CAB MEDALLION 885

Wild Rivers Land Trust

Bagley Creek Mill Site environmental assessment

Wild Rivers Land Trust

Bagley Creek/Frmr Western States Plywood Mill Site

The Amigos School

Bailamos Juntos

North Haven

Bailey Road Baseball Field Backstop and Fencing Improvements

NYC Department of Cultural Affairs

Bailey's Cafe

Bainbridge Community Foundation

Bainbridge Community Foundation is an active grantmaking foundation based in Bainbridge Is, WA. Focus: philanthropy. Contact the foundation directly for current funding opportunities.

DEPT OF DEFENSE.DEPT OF THE ARMY.NATIONAL GUARD BUREAU.HQ NGB.HQ NGB DIR OF ACQUISITIONS.W39L USA NG READINESS CENTER

BAK-12 arrester engines and assembly kits

Baker County Library District

The Baker County Library District Pre-K Links projects will improve conditions for student success by increasing parental involvement with early learning activities. Identical, internet capable tablets will be placed in the public library and preschools, preloaded with early-learning applications that support the curriculum. A preliminary questionnaire will assess parents' information literacy skills regarding effective use of the internet to address family needs. Mandatory training prior to checking out a tablet will include instruction on how to use the device and learning apps, plus build skills in identifying online resources that target the needs indicated on the questionnaire. Changes in parental involvement will be tracked by the preschools, comparing attendance and participation levels pre and post project. Participating families will be registered for the Ready 2 Learn program to ensure an on-going connection with early learning resources and activities.