The Greater Boston Housing Report Card 2015: The Housing Cost Conundrum

Why has housing supply not kept up with housing demand? This is the question we decided to finally tackle head-on in this edition of the "Greater Boston Housing Report Card" by undertaking an in-depth study of detailed housing cost data that we have collected from housing agencies and developers. The answer to our question is an unsettling one. We have failed to meet housing production targets because there is no way to do so given the high cost of producing housing for working and middle-income households. In part, this is because of the extreme barriers to new construction, especially in the form of severely restrictive zoning at the local level across much of Massachusetts.Solving this problem of insufficient housing supply will require a battery of new approaches to zoning and construction techniques -- something that has eluded developers and policymakers alike. We suggest in these pages some new approaches to increase housing supply

Obesity, Attention Deficit-Hyperactivity Disorder and the Dopaminergic Reward System

The obesity epidemic has focused attention on obesity’s health consequences beyond cardio-vascular disease and diabetes. To evaluate the potential consequences of obesity for Attention Deficit-Hyperactivity Disorder (ADHD), we surveyed the literature. Current findings link both obesity and ADHD to the dopamine system and implicate dopamine genes in body weight, eating, and ADHD. Detailed consideration suggests that dopaminergic changes in the prefrontal cortex among individuals with the ADHD subtype Attention Deficit Disorder (ADD) may increase their risk for obesity. Thus, individuals and populations with a high prevalence of hyperdopaminergic genes may experience higher rates of obesity in the presence of abundant food. From an evolutionary perspective, alterations in the dopamine system appear to effect a wide range of behavioral phenotypes. We suggest that recent evolutionary changes in the dopamine receptor genes selected to increase cognitive and behavioral flexibility may now be associated with attention problems and increased food consumption in an obesogenic environment

The Effect of Ongoing Exposure Dynamics in Dose Response Relationships

Characterizing infectivity as a function of pathogen dose is integral to microbial risk assessment. Dose-response experiments usually administer doses to subjects at one time. Phenomenological models of the resulting data, such as the exponential and the Beta-Poisson models, ignore dose timing and assume independent risks from each pathogen. Real world exposure to pathogens, however, is a sequence of discrete events where concurrent or prior pathogen arrival affects the capacity of immune effectors to engage and kill newly arriving pathogens. We model immune effector and pathogen interactions during the period before infection becomes established in order to capture the dynamics generating dose timing effects. Model analysis reveals an inverse relationship between the time over which exposures accumulate and the risk of infection. Data from one time dose experiments will thus overestimate per pathogen infection risks of real world exposures. For instance, fitting our model to one time dosing data reveals a risk of 0.66 from 313 Cryptosporidium parvum pathogens. When the temporal exposure window is increased 100-fold using the same parameters fitted by our model to the one time dose data, the risk of infection is reduced to 0.09. Confirmation of this risk prediction requires data from experiments administering doses with different timings. Our model demonstrates that dose timing could markedly alter the risks generated by airborne versus fomite transmitted pathogens

Structure-based inhibitors of amyloid beta core suggest a common interface with tau.

Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline

Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity.

hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP

The longitudinal development of emotion regulation capacities in children at risk for externalizing disorders

The development of emotional regulation capacities in children at high versus low risk for externalizing disorder was examined in a longitudinal study investigating: a) whether disturbances in emotion regulation precede and predict the emergence of externalizing symptoms; and b) whether sensitive maternal behavior is a significant influence on the development of child emotion regulation. Families experiencing high (n=58) and low (n=63) levels of psychosocial adversity were recruited to the study during pregnancy. Direct observational assessments of child emotion regulation capacities and maternal sensitivity were completed in early infancy, at 12 and 18-months, and at 5-years. Key findings were as follows. First, high risk children showed poorer emotion regulation capacities than their low risk counterparts at every stage of assessment. Second, from 12-months onwards, emotion regulation capacities showed a degree of stability, and were associated with behavioral problems, both concurrently and prospectively. Third, maternal sensitivity was related to child emotion regulation capacities throughout development, with poorer emotion regulation in the high risk group being associated with lower maternal sensitivity. The results are consistent with a causal role for problems in the regulation of negative emotions in the etiology of externalizing psychopathology, and highlight insensitive parenting as a potentially key developmental influence

Cycling and Female Sexual and Urinary Function: Results From a Large, Multinational, Cross-Sectional Study.

BACKGROUND:Bicycle riding has become an increasingly popular mode of transportation and exercise, especially among women, and previous studies have demonstrated a relationship between cycling and sexual dysfunction, albeit using non-validated questionnaires. AIM:We aimed to explore the relationship between cycling and sexual and urinary dysfunction. METHODS:Cyclists were recruited to complete a survey through Facebook advertisements and outreach to sporting clubs across 5 English-speaking countries. Swimmers and runners were recruited as a comparison group. OUTCOMES:Participants were queried using validated questionnaires, including the Female Sexual Function Index, the American Urological Association Symptom Index, and non-validated questions about history of urinary tract infections (UTIs), genital numbness, and genital saddle sores (all self-reported). RESULTS:3,118 (53.3%) Women completed the survey, comprising 1,053 (34%) non-cyclists, 1,656 (53%) low-intensity cyclists, and 409 (13%) high-intensity cyclists. After adjusting for age, body mass index, hypertension, diabetes, ischemic heart disease, tobacco use, race, marital status, urinary symptoms, and sexual activity, high-intensity cyclists had lower odds of self-reported sexual dysfunction compared to non-cyclists (adjusted odds ratio [aOR] 0.7, P = .02). There were no statistically significant differences in urinary symptoms across groups. Compared to non-cyclists, both low- and high-intensity cyclists had higher odds of reporting a previous UTI (aOR 1.4, P < .001, and aOR 1.4, P = .009, respectively), genital numbness (odds ratio [OR] 6.5, P < .001, and OR 9.1, P < .001, respectively), and saddle sores (OR 6.3, P < .001, and OR 22.7, P < .001, respectively). CLINICAL TRANSLATION:Women cyclists were more likely to report other genitourinary conditions, including UTIs, genital numbness, and saddle sores. CONCLUSIONS:This is the largest study comparing cyclists to other athletes with respect to sexual and urinary function. The study is limited by its cross-sectional design and sampling methods. We found that women cyclists were no more likely to report sexual dysfunction or urinary symptoms than swimmers or runners. Gaither TW, Awad MA, Murphy GP, et al. Cycling and Female Sexual and Urinary Function: Results From a Large, Multinational, Cross-Sectional Study. J Sex Med 2018;15:510-518

In silico comparative genomics analysis of Plasmodium falciparum for the identification of putative essential genes and therapeutic candidates.

A sequence of computational methods was used for predicting novel drug targets against drug resistant malaria parasite Plasmodium falciparum. Comparative genomics, orthologous protein analysis among same and other malaria parasites and protein-protein interaction study provide us new insights into determining the essential genes and novel therapeutic candidates. Among the predicted list of 21 essential proteins from unique pathways, 11 proteins were prioritized as anti-malarial drug targets. As a case study, we built homology models of two uncharacterized proteins using MODELLER v9.13 software from possible templates. Functional annotation of these proteins was done by the InterPro databases and from ProBiS server by comparison of predicted binding site residues. The model has been subjected to in silico docking study with screened potent lead compounds from the ZINC database by Dock Blaster software using AutoDock 4. Results from this study facilitate the selection of proteins and putative inhibitors for entry into drug design production pipelines