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The need for hollow microneedle arrays is important for both drug delivery and wearable sensor applications; however, their fabrication poses many challenges. Hollow metal microneedle arrays residing on a flexible metal foil substrate were created by combining additive manufacturing, micromolding, and electroplating approaches in a process we refer to as electromolding. A solid microneedle with inward facing ledge was fabricated with a two photon polymerization (2PP) system utilizing laser direct write (LDW) and then molded with polydimethylsiloxane. These molds were then coated with a seed layer of Ti/Au and subsequently electroplated with pulsed deposition to create hollow microneedles. An inward facing ledge provided a physical blocking platform to restrict deposition of the metal seed layer for creation of the microneedle bore. Various ledge sizes were tested and showed that the resulting seed layer void could be controlled via the ledge length. Mechanical properties of the PDMS mold was adjusted via the precursor ratio to create a more ductile mold that eliminated tip damage to the microneedles upon removal from the molds. Master structures were capable of being molded numerous times and molds were able to be reused. SEM/EDX analysis showed that trace amounts of the PDMS mold were transferred to the metal microneedle upon removal. The microneedle substrate showed a degree of flexibility that withstood over 100 cycles of bending from side to side without damaging. Microneedles were tested for their fracture strength and were capable of puncturing porcine skin and injecting a dye.
Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders.
One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes.
A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs.
Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.
Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock).
Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments.
Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging.
This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.
In Ramsey theory one wishes to know how large a collection of objects can be while avoiding a particular substructure. A problem of recent interest has been to study how large subsets of the natural numbers can be while avoiding three-term geometric progressions. Building on recent progress on this problem, we consider the analogous problem over quadratic number fields. We first construct high-density subsets of the algebraic integers of an imaginary quadratic number field that avoid three-term geometric progressions. When unique factorization fails, or over a real quadratic number field, we instead look at subsets of ideals of the ring of integers. Our approach here is to construct sets ‘greedily’, a generalization of the greedy set of rational integers considered by Rankin. We then describe the densities of these sets in terms of values of the Dedekind zeta function. Next, we consider geometric-progression-free sets with large upper density. We generalize an argument by Riddell to obtain upper bounds for the upper density of geometric-progression-free subsets, and construct sets avoiding geometric progressions with high upper density to obtain lower bounds for the supremum of the upper density of all such subsets. Both arguments depend critically on the elements with small norm in the ring of integers.
The drinking water infrastructure in the United States is ageing; extreme weather events place additional stress on water systems that can lead to interruptions in the delivery of safe drinking water. We investigated the association between household exposures to water service problems and acute gastrointestinal illness (AGI) and acute respiratory illness (ARI) in Alabama communities that experienced a freeze-related community-wide water emergency. Following the water emergency, investigators conducted a household survey. Logistic regression models were used to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) for self-reported AGI and ARI by water exposures. AGI was higher in households that lost water service for ⩾7 days (aPR 2·4, 95% CI 1·1–5·2) and experienced low water pressure for ⩾7 days (aPR 3·6, 95% CI 1·4–9·0) compared to households that experienced normal service and pressure; prevalence of AGI increased with increasing duration of water service interruptions. Investments in the ageing drinking water infrastructure are needed to prevent future low-pressure events and to maintain uninterrupted access to the fundamental public health protection provided by safe water supplies. Households and communities need to increase their awareness of and preparedness for water emergencies to mitigate adverse health impacts.
Previous studies have identified a close relationship between the monospecific Masonhalea richardsonii and Tuckermannopsis inermis. However, formal taxonomic changes were postponed until existing sequence data could be confirmed. Here we validate these data and discuss the transfer of T. inermis to Masonhalea (made by Lumbsch et al. in Thell & Moberg 2011), consider the morphological, anatomical and biogeographic similarities and differences between these two taxa. The two Masonhalea species both produce lateral apothecia, marginal pycnidia, a layer of cortical tissue beneath the pycnidial wall and bacillariform conidia.
Fix an elliptic curve
and assume the Riemann Hypothesis for the
for every quadratic twist
. We combine Weil's explicit formula with techniques of Heath-Brown to derive an asymptotic upper bound for the weighted moments of the analytic rank of
. We derive from this an upper bound for the density of low-lying zeros of
that is compatible with the randommatrixmodels of Katz and Sarnak. We also show that for any unbounded increasing function
, the analytic rank and (assuming in addition the Birch and Swinnerton-Dyer conjecture) the number of integral points of
are less than
for almost all