Nebraska Settlements: Status, Trends, and Policy Choices

This chapter looks at historical and contemporary trends in Nebraska\u27s system of incorporated places. Particular attention is given to changes in the number and proportion of places in different population size categories, the movement of places between different size categories, and what Nebraska\u27s settlement system is likely to look like in the future. A review of past and recent trends, together with forecasts about the future, indicates a likely increase in the number of very small places, major shifts for middle-sized places, and continued growth in the number of places over 5,000 population. Based upon these trends, three separate needs tied to each community type are identified. These include managing decline, strategic economic planning assistance, and growth center promotion. The chapter concludes with a discussion of criteria that might guide choices about which categories of places in Nebraska to assist and how to provide help to those places identified for assistance

Microbiota functional activity biosensors for characterizing nutrient metabolism in vivo

Methods for measuring gut microbiota biochemical activities in vivo are needed to characterize its functional states in health and disease. To illustrate one approach, an arabinan-containing polysaccharide was isolated from pea fiber, its structure defined, and forward genetic and proteomic analyses used to compare its effects, versus unfractionated pea fiber and sugar beet arabinan, on a human gut bacterial strain consortium in gnotobiotic mice. We produced \u27Microbiota Functional Activity Biosensors\u27 (MFABs) consisting of glycans covalently linked to the surface of fluorescent paramagnetic microscopic glass beads. Three MFABs, each containing a unique glycan/fluorophore combination, were simultaneously orally gavaged into gnotobiotic mice, recovered from their intestines, and analyzed to directly quantify bacterial metabolism of structurally distinct arabinans in different human diet contexts. Colocalizing pea-fiber arabinan and another polysaccharide (glucomannan) on the bead surface enhanced in vivo degradation of glucomannan. MFABs represent a potentially versatile platform for developing new prebiotics and more nutritious foods

In situ solid-liquid extraction enhances recovery of taxadiene from engineered Saccharomyces cerevisiae cell factories

Microbial cell factories express diverse heterologous pathways for the production of a wide range of valuable natural products. However, the recovery and purification of such compounds is a major bottleneck in commercialization. In this study, a novel in situ solid phase adsorption strategy was investigated for enhanced recovery of taxadiene, a precursor to the blockbuster anticancer drug, paclitaxel, from engineered Saccharomyces cerevisiae. A synthetic adsorbent resin (HP-20) was employed to efficiently sequester taxadiene as it was secreted during growth and a carefully optimized desorption solvent was applied following cultivation to maximize recovery of both secreted and intracellular taxadiene, across a range of scales (2 – 250 mL). Resin concentration was found to have an impact on cellular growth, with the high concentration of 12 % (w/v) resulting in fragmentation of the resin beads, which was detrimental to growth. The optimal resin concentration and desorption solvent combination elucidated at microscale (2 mL) resulted in a two-fold improvement in taxadiene titer to 61 ± 8 mg/L, compared to the traditional liquid-liquid extraction approach (dodecane overlay). Taxadiene was found to be distributed evenly between resin beads and biomass. Performance of the optimal process was subsequently investigated through scale-up using controlled mini-bioreactors (250 mL). Here, a comparable taxadiene titer of 76 ± 19 mg/L was achieved despite a 125-fold scale-up in cultivation volume. This represented a 1.4-fold improvement in taxadiene recovery compared to previous mini-bioreactor scale cultivations using the dodecane overlay extraction approach

Expanding phenotype of schimke immuno-osseous dysplasia: Congenital anomalies of the kidneys and of the urinary tract and alteration of nk cells

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype\u2013genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD\u2014both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7R\u3b1 expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies

A Multilevel Mhealth intervention Boosts adherence to Hydroxyurea in individuals With Sickle Cell Disease

Hydroxyurea reduces sickle cell disease (SCD) complications, but medication adherence is low. We tested 2 mobile health (mHealth) interventions targeting determinants of low adherence among patients (InCharge Health) and low prescribing among providers (HU toolbox) in a multi-center, non-randomized trial of individuals with SCD ages 15-45. We compared the percentage of days covered (PDC), labs, healthcare utilization, and self-reported pain over 24 weeks of intervention and 12 weeks post-study with a 24-week preintervention interval. We enrolled 293 patients (51% male; median age 27.5 years, 86.8% HbSS/HbSβ0-thalassemia). The mean change in PDC among 235 evaluable subjects increased (39.7% to 56.0%; P \u3c 0.001) and sustained (39.7% to 51.4%, P \u3c 0.001). Mean HbF increased (10.95% to 12.78%; P = 0.03). Self-reported pain frequency reduced (3.54 to 3.35 events/year; P = 0.041). InCharge Health was used ≥1 day by 199 of 235 participants (84.7% implementation; median usage: 17% study days; IQR: 4.8-45.8%). For individuals with ≥1 baseline admission for pain, admissions per 24 weeks declined from baseline through 24 weeks (1.97 to 1.48 events/patient, P = 0.0045) and weeks 25-36 (1.25 events/patient, P = 0.0015). PDC increased with app use (P \u3c 0.001), with the greatest effect in those with private insurance (P = 0.0078), older subjects (P = 0.033), and those with lower pain interference (P = 0.0012). Of the 89 providers (49 hematologists, 36 advanced care providers, 4 unreported), only 11.2% used HU toolbox ≥1/month on average. This use did not affect change in PDC. Tailoring mHealth solutions to address barriers to hydroxyurea adherence can potentially improve adherence and provide clinical benefits. A definitive randomized study is warranted. This trial was registered at www.clinicaltrials.gov as #NCT04080167

Blind trials of computer-assisted structure elucidation software

<p>Abstract</p> <p>Background</p> <p>One of the largest challenges in chemistry today remains that of efficiently mining through vast amounts of data in order to elucidate the chemical structure for an unknown compound. The elucidated candidate compound must be fully consistent with the data and any other competing candidates efficiently eliminated without doubt by using additional data if necessary. It has become increasingly necessary to incorporate an <it>in silico </it>structure generation and verification tool to facilitate this elucidation process. An effective structure elucidation software technology aims to mimic the skills of a human in interpreting the complex nature of spectral data while producing a solution within a reasonable amount of time. This type of software is known as computer-assisted structure elucidation or CASE software. A systematic trial of the ACD/Structure Elucidator CASE software was conducted over an extended period of time by analysing a set of single and double-blind trials submitted by a global audience of scientists. The purpose of the blind trials was to reduce subjective bias. Double-blind trials comprised of data where the candidate compound was unknown to both the submitting scientist and the analyst. The level of expertise of the submitting scientist ranged from novice to expert structure elucidation specialists with experience in pharmaceutical, industrial, government and academic environments.</p> <p>Results</p> <p>Beginning in 2003, and for the following nine years, the algorithms and software technology contained within ACD/Structure Elucidator have been tested against 112 data sets; many of these were unique challenges. Of these challenges 9% were double-blind trials. The results of eighteen of the single-blind trials were investigated in detail and included problems of a diverse nature with many of the specific challenges associated with algorithmic structure elucidation such as deficiency in protons, structure symmetry, a large number of heteroatoms and poor quality spectral data.</p> <p>Conclusion</p> <p>When applied to a complex set of blind trials, ACD/Structure Elucidator was shown to be a very useful tool in advancing the computer's contribution to elucidating a candidate structure from a set of spectral data (NMR and MS) for an unknown. The synergistic interaction between humans and computers can be highly beneficial in terms of less biased approaches to elucidation as well as dramatic improvements in speed and throughput. In those cases where multiple candidate structures exist, ACD/Structure Elucidator is equipped to validate the correct structure and eliminate inconsistent candidates. Full elucidation can generally be performed in less than two hours; this includes the average spectral data processing time and data input.</p

Fabrication and Repair of Ion Source Components in the 80 keV Neutral Beam Lines for DIII-D

OAK-B135 After 8 years of operation, leaks began to develop in critical components of the ion sources of the 80 keV neutral beam lines in DIII-D. Operational adjustments were made that seemed to remedy the problems, but five years later leaks began occurring again, this time with greater frequency. Failures occurred in the stainless steel bellows and molybdenum rails of the grid rail modules as well as in the Langmuir probes. Failure analyses identified several root causes of the leaks and operational adjustments were again made to mitigate the problems, but the rash of failures depleted the program's supply of spare grid rail modules and probes and removed one of the ion sources from regular operation. Fifteen years after their original fabrication, the ion source components were no longer commercially available. In 2001, a program was initiated to fabricate new grid rail modules, including new molybdenum grid rails, bellows, and stainless steel grid rail holders, as well as new Langmuir probes. In parallel, components removed from service due to leaks were to be repaired with new rails and bellows and returned to service. An overview of the root causes of the service failures is offered, details of the repair processes are described, and a summary and evaluation of the fabrication procedures for the new molybdenum rails, grid modules, and Langmuir probes are given

Predicting Crystallization of Amorphous Drugs with Terahertz Spectroscopy.

There is a controversy about the extent to which the primary and secondary dielectric relaxations influence the crystallization of amorphous organic compounds below the glass transition temperature. Recent studies also point to the importance of fast molecular dynamics on picosecond-to-nanosecond time scales with respect to the glass stability. In the present study we provide terahertz spectroscopy evidence on the crystallization of amorphous naproxen well below its glass transition temperature and confirm the direct role of Johari-Goldstein (JG) secondary relaxation as a facilitator of the crystallization. We determine the onset temperature Tβ above which the JG relaxation contributes to the fast molecular dynamics and analytically quantify the level of this contribution. We then show there is a strong correlation between the increase in the fast molecular dynamics and onset of crystallization in several chosen amorphous drugs. We believe that this technique has immediate applications to quantify the stability of amorphous drug materials.JS and JAZ would like to acknowledge the UK Engineering and Physical Sciences Research Council for funding (EP/J007803/1).This is the final version of the article. It first appeared from ACS at http://dx.doi.org/10.1021/acs.molpharmaceut.5b0033

FATTORI AMBIENTALI DI RISCHIO DELLA SCLEROSI LATERALE AMIOTROFICA: UNO STUDIO CASO-CONTROLLO DI POPOLAZIONE BASATO SU QUESTIONARI ANAMNESTICI

Introduzione: La sclerosi laterale amiotrofica (SLA) \ue8 una malattia neurodegenerativa progressiva la cui eziologia \ue8 ancora sostanzialmente ignota, ad eccezione di alcune rare forme di origine genetica. Numerosi suoi possibili fattori di rischio ambientali sono attualmente oggetto di indagine. Metodi: Abbiamo realizzato uno studio caso-controllo di popolazione nelle province di Modena, Reggio Emilia e Catania, al fine di valutare il ruolo eziologico di alcuni possibili fattori ambientali di rischio. Abbiamo somministrato per via postale un questionario finalizzato alla raccolta di informazioni anamnestiche ai casi di SLA diagnosticati nel periodo 2008-2011 e ad un gruppo di controlli di popolazione appaiati per alcune variabili confondenti. Risultati: Il 35% (n=162, 61 casi e 101 controlli) dei questionari inviati \ue8 stato compilato e restituito. In un modello di regressione logistica, i pregressi traumatismi soggetti a valutazione medica sono risultati associati ad un odds ratio (OR) di SLA pari a 1.20 (intervalli di confidenza al 95% (IC 95%) 0.62-2.30), con un valore pi\uf9 elevato (3.04, 1.22-7.55) per traumi alla testa. Gli shock elettrici hanno evidenziato un OR di 2.25 (0.66-7.63). Con riferimento alla storia occupazionale, l\u2019OR associata all\u2019attivit\ue0 lavorativa in ambito agricolo o come saldatore \ue8 risultata rispettivamente pari a 2.44 (1.02-5.79) e 1.25 (0.27-5.80). Aver vissuto in zona agricola \ue8 stato associato ad un lieve aumento del rischio (OR=1.67, 0.87-3.20), a differenza della pratica sportiva e specificatamente del calcio (OR 0.84 (0.46-1.51) e 1.04 (0.44-2.47). Conclusioni: I risultati ottenuti appaiono di potenziale interesse eziologico e meritevoli di ulteriori approfondimenti, pur tenendo conto del rischio di distorsioni di selezione del campione o di informazione, specie nei pazienti

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families

Purpose: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. Methods: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. Results: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. Conclusion: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.Anne Guimier ... Liza K. Phillips ... et al