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Osteoporosis affects over 200 million women worldwide, one-third of whom are predicted to suffer from an osteoporotic fracture in their lifetime. The most promising anabolic drugs involve administration of expensive antibodies. Because mechanical loading stimulates bone formation, our current data, using a mouse model, replicates the anabolic effects of loading in humans and may identify novel pathways amenable to oral treatment. Murine tibial compression produces axially varying deformations along the cortical bone, inducing highest strains at the mid-diaphysis and lowest at the metaphyseal shell. To test the hypothesis that load-induced transcriptomic responses at different axial locations of cortical bone would vary as a function of strain magnitude, we loaded the left tibias of 10-week-old female C57Bl/6 mice in vivo in compression, with contralateral limbs as controls. Animals were euthanized at 1, 3, or 24 hours post-loading or loaded for 1 week (n = 4-5/group). Bone marrow and cancellous bone were removed, cortical bone was segmented into the metaphyseal shell, proximal diaphysis, and mid-diaphysis, and load-induced differential gene expression and enriched biological processes were examined for the three segments. At each time point, the mid-diaphysis (highest strain) had the greatest transcriptomic response. Similarly, biological processes regulating bone formation and turnover increased earlier and to the greatest extent at the mid-diaphysis. Higher strain induced greater levels of osteoblast and osteocyte genes, whereas expression was lower in osteoclasts. Among the top differentially expressed genes at 24-hours post-loading, 17 had known functions in bone biology, of which 12 were present only in osteoblasts, 3 exclusively in osteoclasts, and 2 were present in both cell types. Based on these results, we conclude that murine tibial loading induces spatially unique transcriptomic responses correlating with strain magnitude in cortical bone. © 2022 American Society for Bone and Mineral Research (ASBMR).

Purpose: We conducted genome-wide miRNA-sequencing (miRNA-seq) in primary cancer tissue from patients of lung adenocarcinoma to identify markers for the presence of lymph node metastasis.Experimental Design: Markers for lymph node metastasis identified by sequencing were validated in a separate cohort using quantitative PCR. After additional validation in the The Cancer Genome Atlas (TCGA) dataset, functional characterization studies were conducted in vitro.Results: MiR-31 was upregulated in lung adenocarcinoma tissues from patients with lymph node metastases compared with those without lymph node metastases. We confirmed miR-31 to be upregulated in lymph node-positive patients in a separate patient cohort (P = 0.009, t test), and to be expressed at higher levels in adenocarcinoma tissue than in matched normal adjacent lung tissues (P < 0.0001, paired t test). MiR-31 was then validated as a marker for lymph node metastasis in an external validation cohort of 233 lung adenocarcinoma cases of the TCGA (P = 0.031, t test). In vitro functional assays showed that miR-31 increases cell migration, invasion, and proliferation in an ERK1/2 signaling-dependent manner. Notably, miR-31 was a significant predictor of survival in a multivariate cox regression model even when controlling for cancer staging. Exploratory in silico analysis showed that low expression of miR-31 is associated with excellent survival for T2N0 patients.Conclusions: We applied miRNA-seq to study microRNomes in lung adenocarcinoma tissue samples for the first time and potentially identified a miRNA predicting the presence of lymph node metastasis and survival outcomes in patients of lung adenocarcinoma. Clin Cancer Res; 19(19); 5423–33. ©2013 AACR.

PDF file, 34K, Supplementary Table 1. Clinical demographic information of 43 lung ADC cases. NAT is normal adjacent tissue. Supplementary Table 2. Clinical demographic information of lung adenocarcinoma TCGA patients. Supplementary Table 3. IPA analysis for the downstream targets for miR-31. Supplementary Table 4. Genetic alteration overview of the cell lines used in this study. Supplementary Table 5. Correlation coefficient between EMT-related genes and miR-31 expression.

PDF file, 450K, Supplementary Figure 1. The length distribution of reads for ten miR-seq samples Supplementary Figure 2. Flow diagram illustrating microRNA quantification techniques used and sample sizes of each step of the analysis. NAT: normal adjacent tissue. Supplemental Figure 3. Identification of differentially expressed miRNAs between N0 and N1+ groups of patients. Supplementary Figure 4. The receiver operator characteristic (ROC) curve as well as area under curve (AUC) was determined using CART. The results show that AUC is 0.79 in 43 lung ADC samples (cohort 1 +2). Supplementary Figure 5. Higher miR-31 expression is associated with adverse outcome in T2N0 patients (n=75, log-rank p=0.0194) Supplementary Figure 6. IPA showing the top five canonical pathways for miR-31 target genes is the CDK5 (A), PTEN (B), p70S6K (C) , ERK/MAPK (D) and PI3K/AKT (E)signaling. Supplementary Figure 7. Ectopic expression of miR-31 increases migration/invasion capabilities of H2228 cells. (A) Expression of miR-31 following infection with Lenti-miR vector containing miR-31 precursor was confirmed by TaqMan real-time PCR. (B) Cell invasion assay for miR-31 overexpressing H2228 cells. (C) Cell migration assay for miR-31 overexpressing H2228 cells using transwell membranes (upper panel, representative pictures of migration chambers; bottom panel, average counts from 10 random microscopic fields). The average counts were derived from ten random microscopic fields. (D) Cell proliferation assay for miR-31 overexpressing H2228 cells. Data are presented as mean plus-minus S.D. *P

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Parathyroid hormone (PTH) is an anabolic osteoporosis treatment that increases bone mass and reduces fracture risk. Clinically, the effects of PTH are site-specific, increasing bone mass more at the spine than the hip and not increasing bone mass at the radius. Differences in local loading environment between the spine, hip, and radius may help explain the variation in efficacy, as PTH and mechanical loading have been shown to synergistically increase bone mass. We hypothesized that differences in loading mode might further explain these variations. Owing to the curvature of the mouse tibia, cyclic compression of the hindlimb causes bending at the tibial midshaft, placing the anterior surface under tension and the posterior surface under compression. We investigated the combination of PTH treatment and tibial loading in an osteoblast-specific estrogen receptor-alpha knockout mouse model of low bone mass (pOC-ERαKO) and their littermate controls (LCs) and analyzed bone morphology in the tensile, compressive, and neutral regions of the tibial midshaft. We also hypothesized that pretreating wild-type C57Bl/6J (WT) mice with PTH prior to mechanical loading would enhance the synergistic anabolic effects. Compression was more anabolic than tension, and PTH enhanced the effect of loading, particularly under compression. PTH pretreatment maintained the synergistic anabolic effect for longer durations than concurrent treatment and loading alone. Together these data provide insights into more effective physical therapy and exercise regimens for patients receiving PTH treatment. © 2022 American Society for Bone and Mineral Research (ASBMR).

β-glucans are polymers of glucose that have been isolated from a variety of organisms. Isolated β-glucans have been used for medical purposes for centuries; however, efforts to define the biological activities of β-glucans experimentally were initiated in the 1940's. The diversity of structure associated with isolated β-glucans has impeded said investigations, and efforts to leverage the biological activity of β-glucans for clinical applications. In recognition of the need for defined β-glucans that retain the biological activity of isolated β-glucans, considerable investment has been made to facilitate the synthesis of structurally defined β-glucans. Here, we review the different approaches that have been applied to prepare β-glucans. In addition, we summarize the approaches that have been utilized to conjugate β-glucans to proteins.

Kifunensine is a known inhibitor of type I α-mannosidase enzymes and has been shown to have therapeutic potential for a variety of diseases and application in the expression of high-mannose N-glycan bearing glycoproteins; however, the compound's hydrophilic nature limits its efficacy. We previously synthesized two hydrophobic acylated derivatives of kifunensine, namely, JDW-II-004 and JDW-II-010, and found that these compounds were over 75-fold more potent than kifunensine. Here we explored the effects of these compounds on different mice and human B cells, and we demonstrate that they affected the cells in a similar fashion to kifunensine, further demonstrating their functional equivalence to kifunensine in assays utilizing primary cells. Specifically, a dose-dependent increase in the formation of high-mannose N-glycans decorated glycoproteins were observed upon treatment with kifunensine, JDW-II-004, and JDW-II-010, but greater potency was observed with the acylated derivatives. Treatment with kifunensine or the acylated derivatives also resulted in impaired B-cell receptor (BCR) signaling of the primary mouse B cells; however, primary human B cells treated with kifunensine or JDW-II-004 did not affect BCR signaling, while a modest increase in BCR signaling was observed upon treatment with JDW-010. Nevertheless, these findings demonstrate that the hydrophobic acylated derivatives of kifunensine can help overcome the mass-transfer limitations of the parent compound, and they may have applications for the treatment of ERAD-related diseases or prove to be more cost-effective alternatives for the generation and production of high-mannose N-glycan bearing glycoproteins.

Cancer-associated alterations to glycosylation have been shown to aid cancer development and progression. An increased abundance of high mannose N-glycans has been observed in several cancers. Here, we describe the preparation of lectin drug conjugates (LDCs) that permit toxin delivery to cancer cells presenting high mannose N-glycans. Additionally, we demonstrate that cancer cells presenting low levels of high mannose N-glycans can be rendered sensitive to the LDCs by co-treatment with a type I mannosidase inhibitor. Our findings establish that an increased abundance of high mannose N-glycans in the glycocalyx of cancer cells can be leveraged to enable toxin delivery.

Madagascar is a threatened global biodiversity hotspot and conservation priority, yet we lack broad-scale surveys to assess biodiversity across space and time. To fill this gap, we collated camera trap surveys, capturing species occurrences within Madagascar into a single standardized database. This data set includes nine distinct protected areas of Madagascar and encompasses 13 subprojects, 38 camera arrays, and 1156 sampling units (independent camera site per survey) within two important biodiversity eco-regions: western dry deciduous forest and eastern humid rainforest. Camera surveys were conducted from June 2007 to January 2021. The final data set includes 17 unique families of mammals (Bovidae, Canidae, Cheirogaleidae, Daubentoniidae, Equidae, Eupleridae, Felidae, Hominidae, Indriidae, Lemuridae, Lepilemuridae, Muridae, Nesomyidae, Pteropodidae, Soricidae, Suidae, Tenrecidae) comprising 45 species and 27 unique families of birds (Accipitridae, Acrocephalidae, Alcedinidae, Bernieridae, Brachypteraciidae, Caprimulgidae, Cisticolidae, Columbidae, Coraciidae, Corvidae, Cuculidae, Dicruridae, Mesitornithidae, Monarchidae, Motacillidae, Muscicapidae, Numididae, Phasianidae, Rallidae, Sarothruridae, Strigidae, Sturnidae, Sulidae, Threskiornithidae, Upupidae, Vangidae, Zosteropidae) comprising 58 species. Images were processed and verified by individual project data set creators and camera operation and species tables were then collated. The final product represents the first broad-scale freely available standardized formal faunal database for Madagascar. Data are available through this publication and at DOI: 10.5281/zenodo.5801806. These data will be useful for examining species-level and community-level trends in occurrence across space or time within Madagascar and globally, evaluating native and invasive species dynamics, and will aid in determining species conservation status and planning for at-risk species. There are no copyright restrictions; please cite this paper when using the data for publication.

OBJECTIVE The aim of this study was to analyze outcomes of open lobectomy (OL), video-assisted thoracoscopic lobectomy (VATS) and robotic-assisted lobectomy (RL). SUMMARY BACKGROUND DATA Robotic-assisted lobectomy has seen increasing adoption for treatment of early-stage lung cancer. Comparative data regarding these approaches is largely from single-institution case series or administrative datasets. METHODS Retrospective data was collected from 21 institutions from 2013-2019. All consecutive cases performed for clinical stage IA-IIIA lung cancer were included. Neoadjuvant cases were excluded. Propensity-score matching (1:1) was based on age, gender, race, smoking-status, FEV1%, Zubrod score, ASA score, tumor size and clinical T and N stage. RESULTS A total of 2,391 RL, 2,174 VATS, and 1,156 OL cases were included. After propensity-score matching there were 885 pairs of RL vs. OL, 1,711 pairs of RL vs. VATS, and 952 pairs of VATS vs. OL. Operative time for RL was shorter than VATS (p < 0.0001) and OL (p = 0.0004). Compared to OL, RL and VATS had less overall postoperative complications, shorter hospital stay (LOS), and lower transfusion rates (all p < 0.02). Compared to VATS, RL had lower conversion rate (p < 0.0001), shorter hospital stay (p < 0.0001) and a lower postoperative transfusion rate (p = 0.01). RL and VATS cohorts had comparable postoperative complication rates. In-hospital mortality was comparable between all groups. CONCLUSIONS RL and VATS approaches were associated with favorable perioperative outcomes compared to OL. Robotic-assisted lobectomy was also associated with a reduced length of stay and decreased conversion rate when compared to VATS.

There is considerable interest in syphilis preexposure (44.1%) and postexposure (60.1%) prophylaxis among gay, bisexual, and other men who have sex with men attending Toronto/Vancouver sexual health clinics., Background We assessed the acceptability of doxycycline-based syphilis pre-exposure and post-exposure prophylaxis (PrEP/PEP) as well as human immunodeficiency virus (HIV) PrEP/PEP in gay, bisexual, and other men who have sex with men (gbMSM). Methods We recruited gbMSM from Toronto and Vancouver sexually transmitted infection (STI) clinics during routine visits from June 2018 to August 2018. We analyzed data using descriptive statistics and constructed multivariable logistic regression models for willingness to use syphilis and HIV PrEP and PEP respectively. Results Among 424 participants (56.4% Toronto, 43.6% Vancouver), median (interquartile range [IQR]) age was 31.0 years (26.0–39.0 years), 61.7% had completed postsecondary education and 54.4% were white. Median (IQR) number of male partners in the past 6 months was 6.0 (3.0–13.0), and 18.2% had 1 or more prior syphilis diagnosis. 60.1%/44.1% indicated willingness to use syphilis PEP/PrEP; 36.6% were unwilling to use either. Among HIV-negative participants, 74.0% and 75.2% were willing to use HIV PrEP and PEP, respectively. Most participants were familiar with antibiotic resistance (89.0%) and agreed that syphilis rates are rising in Canada (68.2%), but only 55.4% believed they were at risk for syphilis. Agreement with the latter statement was associated with willingness to use syphilis PrEP (adjusted odds ratio [aOR], 1.6; 95% confidence interval [95%CI], 1.0–2.5), as was previous/existing HIV PrEP use (aOR, 2.2; 95% CI, 1.1–4.3) and being “very concerned” about STI acquisition (aOR, 1.9; 95% CI, 1.0–3.4). Odds of being willing to use syphilis PEP were higher in Toronto versus Vancouver (aOR, 2.0; 95% CI, 1.2–3.4) and increased with the number of different STIs previously diagnosed (aOR, 1.4; 95% CI, 1.2,1.7). Conclusions There is considerable interest in syphilis PrEP/PEP in gbMSM attending Toronto/Vancouver STI clinics.

Estrogen receptor-alpha (ERα) regulates bone mass and is implicated in bone tissue's response to mechanical loading. The effects of ERα deletion in mice depend on sex, anatomical location, and the cellular stage at which ERα is removed. Few studies have investigated the effect of age on the role of ERα in skeletal maintenance and functional adaptation. We previously demonstrated that bone mass and adaptation to loading were altered in growing 10-week-old female and male mice lacking ERα in mature osteoblasts and osteocytes (pOC-ERαKO). Here our goal was to determine the effects of ERα and mechanical loading in skeletally-mature adult mice. We subjected 26-week-old skeletally-mature adult pOC-ERαKO and littermate control (LC) mice of both sexes to two weeks of in vivo cyclic tibial loading. ERα deletion in male mice did not alter bone mass or the response to loading. Adult female pOC-ERαKO mice had reduced cancellous and cortical bone mass and increased adaptation to high-magnitude mechanical loading compared to LC mice. Thus, ERα deletion from mature osteoblasts reduced the bone mass and increased the mechanoadaptation of adult female but not male mice. Additionally, compared to our previous work in young mice, adult female mice had greatly reduced mechanoadaptation and adult male mice retained most of their mechanoadaptation with age.

Type 1 diabetes (T1D) occurs when autoreactive T cells destroy insulin-producing beta cells. Anti-insulin B cells promote this disease, acting as essential antigen-presenting cells. Rituximab, which globally depletes B cells, provided temporary preservation of insulin production in early onset T1D, but increases susceptibility to infection. Antigen-specific immune therapy (ASIT) may be a viable option for treating T1D by targeting anti-insulin B cells for removal from the B cell repertoire. In this study we investigate the efficacy of soluble antigen arrays containing insulin (SAgAins) developed by the Berkland lab. These constructs consist of a polyethylene glycol (PEG) backbone with four linker arms for bioconjugation. We conducted in vitro experiments to investigate the effects of constructs containing insulin and a trisaccharide ligand (CD22L) for inhibitory B cell receptor CD22 on transgenic anti-insulin B cells. We found that incubating insulin-PEG with anti-insulin B cells stimulates proliferation and CD86 upregulation. However, when CD22L is added (CD22L-PEG-insulin) the expression of CD86 is dampened. This suggests that this novel construct harnesses the regulatory power of CD22 to dampen activation of B cells in an autoantigen-specific manner.

This study examines the various factors that contribute to the changes in starting teacher salaries in the state of Indiana from 2015 to 2019. In 2009, the funding formula was changed so that locally assessed property values will not contribute to inequitable funding between wealthy districts and less wealthy districts (Hirth & Eiler, 2012).This study examines the relationship between district wealth, Total Tuition Support per student and starting teacher salaries for each of the 289 public school districts in Indiana from 2015-2019. Additionally, the 50 wealthiest districts were compared to the 50 least wealthy districts to determine if there is a statistically significant difference in starting teacher salaries between the two samples. Finally, starting teacher salaries were compared between school districts that have passed a referendum to those districts that attempted, but failed to pass a referendum. Three equity principles were selected to measure the equity within a school funding system, as related to starting teacher salary: fiscal neutrality, horizontal equity, and vertical equity (Berne & Stiefel, 1984). A review of the literature explores the history of school funding in the United States and specifically examines Indiana’s funding history. The sample comprised quantitative data from each of Indiana’s 289 public school districts and used statistical analysis to determine if changes in the state funding formula, high or low assessed valuation or passing a referendum contributed to differences in starting teacher salaries for the years 2015-2019. The purpose of this quantitative study is to examine the variables that contribute to a range of $17,464.00 for starting teacher salaries in the 2019-2020 school year. Superintendents are challenged with recruiting and retaining the most effective teachers in the market. A main factor for teachers in deciding which district to work is the salary schedule (Imazeki, 2005). Additionally, this study will provide insights to the legislature on how money is, or is not spent, after a change in the funding formula.

A rapid increase in the capabilities of machine learning and artificial intelligence (AI) has focused attention on their potential applications in the health care setting. As health care providers begin to explore these opportunities, organizations must develop an understanding of how implementing AI tools will impact patient safety. This article reviews some of the challenges in development and implementation that may create barriers to the safe utilization of these technologies and prevent quality care for patients.

A modular protection system was developed for DC radial microgrids. The novelty of the realised protection system is based on the combination of different fault detection, characterisation and localisation criteria. The protection system was developed based on real-time monitoring of voltages and currents at different positions within smart modular switches in the DC system. Intelligent modular DC switches were developed for the setup. On the basis of fault detection criteria, protective measures are initiated and appropriate switching signals are sent to the appropriate switches in order to isolate the faulty part. Different fault locations and types have been tested in the laboratory for a 24 V DC test setup. Hence, the selectivity of the new protection concept has been verified.