Cryo-EM structure of the potassium-chloride cotransporter KCC4 in lipid nanodiscs.

Cation-chloride-cotransporters (CCCs) catalyze transport of Cl- with K+ and/or Na+across cellular membranes. CCCs play roles in cellular volume regulation, neural development and function, audition, regulation of blood pressure, and renal function. CCCs are targets of clinically important drugs including loop diuretics and their disruption has been implicated in pathophysiology including epilepsy, hearing loss, and the genetic disorders Andermann, Gitelman, and Bartter syndromes. Here we present the structure of a CCC, the Mus musculus K+-Cl- cotransporter (KCC) KCC4, in lipid nanodiscs determined by cryo-EM. The structure, captured in an inside-open conformation, reveals the architecture of KCCs including an extracellular domain poised to regulate transport activity through an outer gate. We identify binding sites for substrate K+ and Cl- ions, demonstrate the importance of key coordinating residues for transporter activity, and provide a structural explanation for varied substrate specificity and ion transport ratio among CCCs. These results provide mechanistic insight into the function and regulation of a physiologically important transporter family

Career Support Network

Project Overview: This project is funded under the Robert Wood Johnson Foundation’s Local Funding Partnerships Annual Program in support of innovative, community-based projects that improve the health and health care for underserved and vulnerable populations.Philadelphia currently confronts an unprecedented employment crisis. InSouth Philadelphia, the unemployment rate is 35%. Those who are unemployed present with multiple health problems that are barriers to retaining jobs and achieving economic stability. The Career Support Network was conceived to help underserved, newly-employed adults to overcome these barriers and succeed in long-term careers. It will accomplish this mission by creating an integrated, one-stop center that weaves together occupational counseling, job training, peer support, and mental and physical health services. Project Objectives: The goal of the CSN is to enable vulnerable adults with limited skills, physical and/or behavioral health problems to become independent and productive members of the community through retaining sustainable jobs. Objectives to meet these goals focus on: 1) increasing healthy lifestyle behaviors related to chronic disease prevention and/or management among program participants, 2) improving chronic disease self-management such as diabetes and hypertension, asthma, and arthritis, among program participants, and 3) assisting participants in developing skills and obtaining the supports necessary for independent productive living and job retention. Expected Outcomes: Vulnerable adults who participate in the CSN will: 1) demonstrate improved physical, mental and behavioral health through improved knowledge, skills and self-efficacy in managing chronic health conditions, practicing healthy lifestyle behaviors, and managing life and work-related stresses; 2) be employed in jobs that pay family-sustaining wages for a minimum of one year, and for those participants with a chronic disease, the absenteeism rate, due to personal illness, will be no more than 6 per year, and 3) experience a reduction in criminal recidivism rates among ex-offenders participating in the Network. Learning Objectives: Participants attending this session will be able to: 1. Organize an approach to providing chronic disease management/ prevention and work enhancement programs in a workforce development and jobs program utilizing an interdisciplinary team 2. Apply a methodology of engaging community organizations and funders to address job retention 3 Identify the challenges of incorporating chronic disease management/ prevention and work enhancement programs in a workforce development and jobs program utilizing an interdisciplinary tea

Reproductive sharing in animal societies: reproductive incentives or incomplete control by dominant breeders?

Optimal skew models explain reproductive sharing within social groups as resulting from reproductive incentives given by controlling dominants to subordinates in return for peaceful cooperation. We explore two versions of an alternative, the incomplete control model, for the evolution of reproductive sharing within groups. In this model, dominants have only limited control over the allocation of reproduction and must expend effort to increase their share of the total group output We show that, when the relatedness between dominant and subordinate is symmetrical, (1) the subordinate's fraction of reproduction either increases with, or is insensitive to, the subordinate's genetic relatedness, r, to the dominant in both versions of the incomplete control model, whereas the subordinate's fraction of reproduction decreases with increasing r in the optimal skew model, (2) the subordinate's share of reproduction in the incomplete control model must exceed that in the optimal skew model, and (3) ecological factors affecting solitary breeding success do not directly affect the subordinate's share of reproduction in incomplete control model but do in the optimal skew model. When dominant-subordinate relatedness is asymmetrical (as is often the case in parent-offspring associations), the incomplete control model predicts no reproduction by the subordinate offspring regardless of group size for groups containing any mixture of unrelated and full-sibling subordinates, whereas the optimal skew models predict that such reproduction is possible when the group size is three or more. The available evidence indicates a negative relationship between relatedness and a subordinate's reproductive share in both vertebrate and hymenopteran societies, apparently supporting the predictions of the optimal skew, not incomplete control, class of models. However, such a negative relationship is not necessarily inconsistent with the incomplete control model when, as is true for some vertebrate studies, it results from a comparison of skews in genetically monogamous, nonincestuous groups of parents and their offspring (asymmetric relatednesses) with skews in groups of nonkin (symmetric relatednesses). Both models predict higher skews in parent-offspring associations. Occasional reproduction by subordinate offspring in groups of asymmetrical relatedness when such groups are larger than dyads is more consistent with the optimal skew model, however. Overall, current data on reproductive skew and its relationships to intragroup aggression and ecological constraints support the optimal skew model, but more data are needed to rule out the incomplete control model. These models are examples of two different general views of intrasocietal evolution: the tug-of-war view, in which group members engage in a struggle over resources, and the transactional view, in which group members exchange parcels of reproduction to induce beneficial behavior from each othe

Equity REIT IPOs, 1991-1993

Thesis (M.S.)--Massachusetts Institute of Technology, Dept. of Urban Studies and Planning, 1993.Includes bibliographical references (leaves 89-94).by Stephen F. Kern.M.S

Customised broadband metamaterial absorbers for arbitrary polarisation

This paper shows that customised broadband absorption of electromagnetic waves having arbitrary polarisation is possible by use of lossy cut-wire (CW) metamaterials. These useful features are confirmed by numerical simulations in which different lengths of CW pairs are combined as one periodic metamaterial unit and placed near to a perfect electric conductor (PEC). So far metamaterial absorbers have exhibited some interesting features, which are not available from conventional absorbers, e.g. straightforward adjustment of electromagnetic properties and size reduction. The paper shows how with proper design a broad range of absorber characteristics may be obtained.Comment: 12 pages, 5 figures, submitted to Optics Expres

Career Support Network

Seminar (44 PowerPoint Slides) Project Overview: This project is funded under the Robert Wood Johnson Foundation’s Local Funding Partnerships Annual Program in support of innovative, community-based projects that improve the health and health care for underserved and vulnerable populations.Philadelphia currently confronts an unprecedented employment crisis. InSouth Philadelphia, the unemployment rate is 35%. Those who are unemployed present with multiple health problems that are barriers to retaining jobs and achieving economic stability. The Career Support Network was conceived to help underserved, newly-employed adults to overcome these barriers and succeed in long-term careers. It will accomplish this mission by creating an integrated, one-stop center that weaves together occupational counseling, job training, peer support, and mental and physical health services. Project Objectives: The goal of the CSN is to enable vulnerable adults with limited skills, physical and/or behavioral health problems to become independent and productive members of the community through retaining sustainable jobs. Objectives to meet these goals focus on: 1) increasing healthy lifestyle behaviors related to chronic disease prevention and/or management among program participants, 2) improving chronic disease self-management such as diabetes and hypertension, asthma, and arthritis, among program participants, and 3) assisting participants in developing skills and obtaining the supports necessary for independent productive living and job retention. Expected Outcomes: Vulnerable adults who participate in the CSN will: 1) demonstrate improved physical, mental and behavioral health through improved knowledge, skills and self-efficacy in managing chronic health conditions, practicing healthy lifestyle behaviors, and managing life and work-related stresses; 2) be employed in jobs that pay family-sustaining wages for a minimum of one year, and for those participants with a chronic disease, the absenteeism rate, due to personal illness, will be no more than 6 per year, and 3) experience a reduction in criminal recidivism rates among ex-offenders participating in the Network. Learning Objectives: Participants attending this session will be able to: 1. Organize an approach to providing chronic disease management/ prevention and work enhancement programs in a workforce development and jobs program utilizing an interdisciplinary team 2. Apply a methodology of engaging community organizations and funders to address job retention 3 Identify the challenges of incorporating chronic disease management/ prevention and work enhancement programs in a workforce development and jobs program utilizing an interdisciplinary tea

Hyperfiltration and renal disease in glycogen storage disease, type I

Hyperfiltration and renal disease in glycogen storage disease, type I. A prospective study of 14 patients (ages 6 months to 33 years) with glycogen storage disease, Type I (GSD-I) was carried out in order to define the character and frequency of renal dysfunction. A marked increase in the glomerular filtration rate (GFR) was documented in virtually all subjects, with the mean GFR raised by approximately 50%, to the range of 170 ml/min/1.73m2. While this constituted the only renal abnormality found in the younger patients, a significant increase in urinary albumin excretion was seen in three teen-aged individuals; three patients over 20 years of age exhibited frank proteinuria (2 to 8 g/day). Renal biopsy on two of the proteinuric subjects revealed focal and global glomerulosclerosis and interstitial fibrosis. Evaluation of factors known to cause an increase in GFR did not define the precise etiology for its elevation in GSD-I. These studies suggest that: (1) glomerular damage and chronic renal disease are common in older patients with GSD-I; (2) the renal injury appears to be specifically related to GSD-I and is not secondary to the treatment of the disease; and (3) the natural history of the renal lesion in GSD-I may be analogous to that seen in insulin-dependent diabetes, with a “silent” period where hyperfiltration is the only demonstrable renal abnormality, followed by evidence of increasing glomerular damage progressing from microalbuminuria to frank proteinuria

Photolytic and Reductive Activations of 2‐Arsaethynolate in a Uranium‐Triamidoamine Complex: Decarbonylative Arsenic Group‐Transfer Reactions and Trapping of a Highly Bent and Reduced Form

Little is known about the chemistry of the 2-arsaethynolate anion, but to date it has exclusively undergone fragmentation reactions when reduced. Herein, we report the synthesis of [U(Tren(TIPS))(OCAs)] (2, Tren(TIPS)=N(CH(2)CH(2)NSiiPr(3))(3)), which is the first isolable actinide-2-arsaethynolate linkage. UV-photolysis of 2 results in decarbonylation, but the putative [U(Tren(TIPS))(As)] product was not isolated and instead only [{U(Tren(TIPS))}(2)(mu-eta(2):eta(2)-As2H2)] (3) was formed. In contrast, reduction of 2 with [U(Tren(TIPS))] gave the mixed-valence arsenido [{U(Tren(TIPS))}(2)(mu-As)] (4) in very low yield. Complex 4 is unstable which precluded full characterisation, but these photolytic and reductive reactions testify to the tendency of 2-arsaethynolate to fragment with CO release and As transfer. However, addition of 2 to an electride mixture of potassium-graphite and 2,2,2-cryptand gives [{U(Tren(TIPS))}(2){mu-eta(2)(OAs):eta(2)(CAs)-OCAs}][K(2,2,2-cryptand)] (5). The coordination mode of the trapped 2-arsaethynolate in 5 is unique, and derives from a new highly reduced and bent form of this ligand with the most acute O-C-As angle in any complex to date (O-C-As angle approximate to 128 degrees). The trapping rather than fragmentation of this highly reduced O-C-As unit is unprecedented, and quantum chemical calculations reveal that reduction confers donor-acceptor character to the O-C-As unit