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Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes
No full textNote: This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process-not the products-of γ-secretase cleavage of substrates in FAD pathogenesis
A single amino acid polymorphism in natural Metchnikowin alleles of Drosophila results in systemic immunity and life history tradeoffs
No full textAntimicrobial peptides (AMPs) are at the interface of interactions between hosts and microbes and are therefore expected to be rapidly evolving in a coevolutionary arms race with pathogens. In contrast, previous work demonstrated that insect AMPs tend to evolve more slowly than the genome average. Metchikowin (Mtk) is a Drosophila AMP that has a single amino acid residue that segregates as either proline (P) or arginine (R) in populations of four different species, some of which diverged more than 10 million years ago. These results suggest that there is a distinct functional importance to each allele. The most likely hypotheses are driven by two main questions: does each allele have a different efficacy against different specific pathogens (specificity hypothesis)? Or, is one allele a more potent antimicrobial, but with a host fitness cost (autoimmune hypothesis)? To assess their functional differences, we created D. melanogaster lines with the P allele, R allele, or Mtk null mutation using CRISPR/Cas9 genome editing and performed a series of life history and infection assays to assess them. In males, testing of systemic immune responses to a repertoire of bacteria and fungi demonstrated that the R allele performs as well or better than the P and null alleles with most infections. Females show some results that contrast with males, with Mtk alleles either not contributing to survival or with the P allele outperforming the R allele. In addition, measurements of life history traits demonstrate that the R allele is more costly in the absence of infection for both sexes. These results are consistent with both the specificity hypothesis (either allele can perform better against certain pathogens depending on context), and the autoimmune hypothesis (the R allele is generally the more potent antimicrobial in males, and carries a fitness cost). These results provide strong in vivo evidence that differential fitness with or without infection and sex-based functional differences in alleles may be adaptive mechanisms of maintaining immune gene polymorphisms in contrast with expectations of rapid evolution. Therefore, a complex interplay of forces including pathogen species and host sex may lead to balancing selection for immune genotypes. Strikingly, this selection may act on even a single amino acid polymorphism in an AMP
Enantioselective Total Syntheses of (+)-Kasugamycin and (+)-Kasuganobiosamine Highlighting a Sulfamate-Tethered Aza-Wacker Cyclization Strategy
No full textThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Letters, Copyright © 2024 American Chemical Society, after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.orglett.4c01726Here, we present the first enantioselective total syntheses of the natural products (+)-kasugamycin, a potent antifungal antibiotic, and (+)-kasuganobiosamine, a compound that results from the degradation of kasugamycin. Salient features of these syntheses include a second-generation enantioselective preparation of a kasugamine derivative (efficiency much improved relative to that of our first chiral-pool effort) and our laboratory's sulfamate-tethered -Wacker cyclization
Cacao sustainability: The case of cacao swollen-shoot virus co-infection
No full textThe cacao swollen shoot virus disease (CSSVD) is among the most economically damaging diseases of cacao trees and accounts for almost 15-50% of harvest losses in Ghana. This virus is transmitted by several species of mealybugs (Pseudococcidae, Homoptera) when they feed on cacao plants. One of the mitigation strategies for CSSVD investigated at the Cocoa Research Institute of Ghana (CRIG) is the use of mild-strain cross-protection of cacao trees against the effects of severe strains. In this study, simple deterministic, delay, and stochastic ordinary differential equation-based models to describe the dynamic of the disease and spread of the virus are suggested. Model parameters are estimated using detailed empirical data from CRIG. The modeling outcomes demonstrate a remarkable resemblance between real and simulated dynamics. We have found that models with delay approximate the data better and this agrees with the knowledge that CSSVD epidemics develop slowly. Also, since there are large variations in the data, stochastic models lead to better results. We show that these models can be used to gain useful informative insights about the nature of disease spread
MRI Accurately Predicts Quadrupled Semitendinosus Autograft Size Using Posterior Hamstring Harvest for ACL Reconstruction
No full textPurpose
To determine the effectiveness of preoperative magnetic resonance imaging (MRI) measurements of the cross-sectional area (CSA) of the semitendinosus tendon in predicting the intraoperative quadrupled semitendinosus graft diameter of a posteriorly harvested hamstring autograft for anterior cruciate ligament (ACL) reconstruction.
Methods
A retrospective review of patients who underwent ACL reconstruction with autograft using a posterior hamstring harvest was performed. Patient demographics and operative reports were reviewed, and measurements of the CSA of the semitendinosus on MRI were performed. Multiple linear regression was used to analyze the predictors for graft diameter. A P value < .05 was considered statistically significant. Interrater and intrarater reliability were calculated.
Results
280 patients were included. Patient height (P < .0001), and CSA of the semitendinosus (P < .0001) were significant predictors. Patients shorter than 63 inches had an average graft diameter of 7.89 mm compared to 8.69 mm for patients above 63 in (P < .001). The formula for the model is as follows: Graft diameter (mm2) = 2.74 + .067·Height (in) + .00009 · Weight (lbs) + .0018 · Age (years) +.12·Gender (1 if M, 0 if F) + 8.56 · CSA (cm2). The R2 for the model (0.5620), was greater than models using only height (R2 = .4092) or only CSA Semitendinosus (R2 = .3932). None of the interaction terms between covariates (e.g., height, weight, age, gender) were significant. Age (P =.6400), weight (P = .9970), and gender (P = .6700) were not significant predictors. Both intraclass (ICC = 0.864, 95% CI=[0.791, 0.912]) and interclass correlation (ICC=0.827, 95% CI=[0.715, 0.894]) showed good reliability.
Conclusion
CSA semitendinosus tendon and patient height independently perform similarly as predictors of graft diameter. When used together, CSA and height accurately predict the graft diameter. In particular, for patients under 63 in tall who demonstrated an average graft diameter below the minimum 8 mm, as suggested by the literature, this may be a useful tool for preoperative planning of patients intending to undergo ACL reconstruction with posterior hamstring harvest.
Level of Evidence
Level III, diagnostic: retrospective cohort study
Beethoven in the Architecture of Frank Lloyd Wright
No full textThe key common element between Beethoven’s composition and Wright’s architecture was the concept of building. Wright emphasized this particular understanding of Beethoven with an emphatic repetition: Beethoven was “building, building, building, building a great edifice of sound.” This Wright learned from his father, who impressed Wright, when he was still a child, explaining how Beethoven composed. Hence Wright presented the observer with an extraordinary challenge: to believe that the architect was able to translate in his mind Beethoven’s mysterious “building” in music into the physical form of his architecture
Kansas Title X 2024 needs assessment
No full textTitle X is the only federal grant program dedicated to providing individuals with comprehensive reproductive health and related preventive health services. For more than 50 years, Title X funded health centers have provided high-quality cost-effective reproductive health and related preventive health services to low-income, under-insured and uninsured women and men who may otherwise lack access to health care. These health centers play a critical role in ensuring access to voluntary family planning information and services for their clients regardless of their ability to pay. The Kansas Title X Program partnered with The University of Kansas Center for Public Partnerships and Research (KU-CPPR) to conduct a mixed-methods Title X Needs Assessment to understand and address the reproductive health needs of Kansans. The 2024 Kansas Title X needs assessment process helps to ensure that the state’s safety net for sexual and reproductive health services continues to meet the needs of women’s and men’s reproductive health, particularly those of the most vulnerable. The comprehensive overview provided by the needs assessment, covering aspects such as population distribution, racial and ethnic diversity, socioeconomic determinants of health, and economic disparities, offers valuable insights into the unique challenges faced by different communities across the state. The findings of the assessment highlight the essential role Title X funded clinics play in addressing family health needs, particularly among underserved and vulnerable groups. The identification of gaps in service delivery, areas for improvement, and recommendations provided in the assessment lay the groundwork for enhancing the effectiveness and reach of Title X services in Kansas and improving reproductive health statewide
Quantitative Evaluation of the Damage to RC Buildings Caused 1 by the 2023 South-East Turkey Earthquake Sequence
No full textData from 15 earthquakes that occurred in 12 different countries are presented showing that, without better drift control, structures built with building codes allowing large seismic drifts are likely to keep leaving a wide wake of damage ranging from cracked partitions to building overturning. Following the earthquake sequence affecting South-East Turkey in 2023, a team led by Committee 133 of the American Concrete Institute surveyed nearly 250 reinforced concrete buildings in the area extending from Antakya to Malatya. Buildings ranging from 2 to 16 stories were surveyed to assess their damage and evaluate the robustness of their structures in relation to overall stiffness, as measured by the relative cross-sectional areas of structural walls and columns. The majority of the buildings were estimated to have been built in the past 10 years. Yet, the structures surveyed were observed to have amounts of structural walls and columns comparable with amounts reported after the Erzincan (1992), Duzce (1999), and Bingol (2003) Earthquakes in Turkey These amounts are, on average, much smaller than the wall and column amounts used in Chile and Japan. Because of that lack of robustness and given the intensities of the motions reported from Antakya to Malatya (with 10 stations with PGV of 100 cm/s or more), it is concluded that structures in this region experienced large drifts. Excessive drift 1) exposed a myriad of construction and detailing problems leading to severe structural damage and collapse, 2) induced overturning caused by p-delta for some buildings, and 3) caused widespread damage to brittle masonry partitions. The main lesson is simple: ductility is necessary but not sufficient. It is urgent that seismic drift limits are tightened in high-seismicity regions worldwide
The role of discourse in Mandarin-speaking children's comprehension of ambiguous wh-adjuncts
No full textThis poster was presented at THE 49th ANNUAL BOSTON UNIVERSITY CONFERENCE ON LANGUAGE DEVELOPMENT on 11/09/2024.Children have been argued to acquire why-adjuncts later than how-adjuncts across languages (de Villiers, 1991; Spinner & Grinstead, 2006). Li & Zhou (2020) examined Mandarin-acquiring children’s interpretation of zenme, a wh-operator which is ambiguous between why(cause)- and how(manner)-interpretations (1a). The ambiguity of zenme can be syntactically resolved; a modal verb hui (‘will/would’) appears structurally lower than the why¬-zenme in Spec-CP (1b), but higher than the how-zenme within vP (1c) (Tsai, 2008; Rizzi, 1997). In Question-after-Story experiments with Mandarin-speaking children aged 3-5 and adults, Li & Zhou examined their comprehension of zenme-questions about picture-stories comprising manner and cause of an event. When zenme-questions are ambiguous like (1a), children and adults preferred the how-interpretation. When zenme was syntactically disambiguated as (1b-c), only 5-year-olds and adults accessed both interpretations as syntactically cued by hui; 3- and 4-year-olds preferred the how-interpretation regardless of the position of hui, confirming children’s initial challenges with Mandarin why-adjuncts.
The current study focuses on the role of discourse in zenme disambiguation. The why-interpretation of zenme is discourse-driven, conveying a “why-on-earth” interpretation when the discourse marks the unexpectedness of the cause. Li & Zhou presented the unexpectedness of the cause, and they also counterbalanced the order of mention for presenting manner and cause across stories. However, they did not directly examine whether the discourse salience of manner and cause, as modulated by order-of-mention, may influence children’s interpretation, constituting a question calling for investigation given the discourse-driven nature of zenme disambiguation. Our study, thus, manipulated the ‘Order-of-mention’ as a between-subject independent variable, adopting their Question-after-Story paradigm.
Experiment 1 investigated the Order-of-mention effects with 27 Mandarin-speaking children (age mean=4;2, range=3;4-5;2) and 22 adults. They viewed stories where manner and cause were presented in either ‘Cause-and-then-Manner’ (CM) order (2a), or ‘Manner-and-then-Cause’ (MC) order (2b) where the unexpectedness is marked by the cause following the manner, and then answered ambiguous zenme questions like (1a). Overall, children and adults preferred the how-interpretation (Figure 1), while adults accessed why-interpretation more robustly than children (p=.032). Importantly, whereas the main effect of the Order-of-mention was not significant, a significant Order-of-mention × Age interaction (p=.03) was yielded for children (not for adults, p = .68), revealing 4-year-olds’ more effective use of the MC order as a cue for accessing why-interpretation than 3-year-olds.
Experiment 2 examined both discourse (Order-of-mention) and syntactic (hui) cues, involving 51 children (age mean=4;3, range=3;4-5;3) and 33 adults. After viewing stories in either CM-order (2a) or MC-order (2b), they answered unambiguous zenme-questions (1b) or (1c). As Figure 2 shows, adults interpreted unambiguous zenme-questions (1b-c) as cued by the position of hui, but children correctly interpreted unambiguous why-zenme (1b) only 41% of the time, while showing ceiling for unambiguous how-zenme (1c) interpretation. Crucially, an Order-of-mention × Syntax interaction (p=.07) was revealed for children’s why-interpretation, indicating that, when the syntax cues why-interpretation, children showed significantly more why-interpretations in MC stories than in CM stories.
Taken together, our findings suggest that discourse cues, interacting with syntactic cues, affect children’s why-interpretations of zenme, helping younger children access why-adjuncts more successfully
Third Spaces in Crisis: Social Isolation and Drug-Related Mortality During the COVID-19 Pandemic
No full textThese are the slides from a presentation given at Southern Demography Association Annual Meeting on 10/17/2024.The importance of social connection for well-being is well established in the social demographic literature, with social isolation linked to negative health outcomes such as substance use, domestic violence, as well as worse mental and physical health (Holt-Lunstad et al. 2017). However, social isolation became a necessary public health action to prevent the transmission of infection during the COVID-19 pandemic. As a consequence, places of informal social interaction outside of home and work, or third places, such as coffee shops, bars, restaurants, libraries, and gyms, were forced to close. Increased social isolation during the pandemic and subsequent closures of community third places may contribute to negative health behaviors and outcomes such as substance use and related mortality since overdoses are more likely to happen when using alone. Utilizing various data sets including third place data from the National Neighborhood Data Archive, New York Times COVID death data, county level demographic data from the American Community Survey, and other county level measurements, this project aims to examine the moderating effect of COVID-19 social isolation mandates on drug-related mortalities across areas with varying definitions of third space availability. Identifying the role of third spaces as a facilitator of social connection in vulnerable communities may give insight for future public health interventions aimed at reducing the negative health effects of social isolation on drug use mortality