Soluble pre-fibrillar tau and β-amyloid species emerge in early human Alzheimer’s disease and track disease progression and cognitive decline

Acknowledgments We would like to gratefully acknowledge all donors and their families for the tissue provided for this study. Human tissue samples were supplied by the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK, the Alzheimer’s Society and the Medical Research Council, and sourced from the MRC London Neurodegenerative Diseases Brain Bank, the Manchester Brain Bank, the South West Dementia Brain Bank (SWDBB), the Newcastle Brain Tissue Resource and the Oxford Brain Bank. The Newcastle Brain Tissue Resource and Oxford Brain Bank are also supported by the National Institute for Health Research (NIHR) Units. The South West Dementia Brain Bank (SWDBB) receives additional support from BRACE (Bristol Research into Alzheimer’s and Care of the Elderly). Alz-50, CP13, MC-1 and PHF-1 antibodies were gifted from Dr. Peter Davies and brain lystates from BACE1−/−mice were obtained from Prof Mike Ashford. The work presented here was funded by Alzheimer’s Research UK (Grant refs: ARUKPPG2014A-21 and ARUK-NSG2015-1 to BP and DK and NIH/NIA grants NIH/NINDS R01 NS082730 and R01 AG044372 to NK)Peer reviewedPublisher PD

Short- and Long-Term Complications of Free Anterolateral Thigh Flap Reconstructions: A Single-Centre Experience of 92 Consecutive Cases.

Background The anterolateral thigh (ALT) flap has been amongst the most versatile components of the reconstructive surgeon's armamentarium. The authors utilise these flaps for a variety of reconstructive procedures including lower limb reconstruction; postsarcoma excision; and open fractures. Few studies have discussed the extent of recipient site morbidity and subsequent revisional procedures. We will report our experience of the ALT flap in 92 consecutive reconstructions with focus on recipient site complications and revisional procedures. Methods Retrospective data collection was done from 92 patients who underwent ALT flap reconstruction-for various large soft tissue defects-at our unit at the Royal Free Hospital, London. We evaluated primary recipient site complications and the requirements for secondary operations after flap transfer. Results All flaps survived with the exception of 3 cases (97% survival rate) in which irreversible venous thrombosis was encountered. 16 of 92 patients (17%) required a second recipient site operation for the following: 7 patients experienced major recipient site complications that warranted early return to theatre and 9 patients required a secondary revision thinning procedure(s). 8 of the 16 patients (50%) requiring second operations had construction on their lower leg/ankle/feet (p value = 0.10). Conclusions Our data demonstrated effective use of the ALT flap in the management of soft tissue reconstructive surgery. Partial flap necrosis was the main complication at the recipient site. In future work, secondary thinning procedures, particularly at the ankle/foot, should be separated from flap-specific complications. Furthermore, we demonstrate tailoring ALT thickness can be performed safely without compromising flap viability

Association between Pitch Break on the 4-Seam Fastball and Slider and Shoulder Injury in Major League Baseball Pitchers: A Case-Control Study

Background: Few specific risk factors are known for shoulder injury in professional pitchers. New pitch-tracking data allow for risk stratification based on advanced metrics. Purpose/Hypothesis: The purpose of this study was to determine the association between shoulder injury, pitch frequency, and pitch metrics (velocity, total break, break angle, and spin rate) for the 4-seam fastball, curveball, and slider. We hypothesized that more frequent use of the 4-seam fastball would be associated with shoulder injury. Study Design: Case-control study; Level of evidence, 3. Methods: The Major League Baseball (MLB) database was queried for pitchers who had been placed on the injury list (IL) with a shoulder injury between 2015 and 2019. Injured pitchers were matched 1:1 with controls (pitchers not on the IL with a shoulder injury during the study period), based on age (±1 year), history of ulnar collateral ligament reconstruction, position (starter vs reliever), and pitches thrown during the injury season (±500). Pitch frequency, velocity, horizontal break, vertical break, total break, and spin rate for the season were collected from the Baseball Savant website for the 4-seam fastball, curveball, and slider. Univariate analysis was used to determine group differences for individual variables. Multiple logistic regression was performed to determine odds ratios (ORs) for shoulder injury associated with pitch frequency, velocity, total break, break angle, and spin rate. Covariates included age, position, ulnar collateral ligament reconstruction status, expected weighted on-base average, and total pitches thrown. Results: Overall, 233 injured pitchers were evaluated. The most common reason for IL placement was inflammation (78/233; 33.5%) followed by strain or sprain (61/233; 26.2%). Increased total pitch break was associated with an increased risk of shoulder injury for the 4-seam fastball (OR, 1.340 [95% confidence interval (CI), 1.199-1.509]; P \u3c .001) and slider (OR, 1.360 [95% CI, 1.206-1.554]; P \u3c .001). For the slider, a decreased spin rate (OR = 0.998 [95% CI, 0.997-0.999]; P = .026) and a more vertical break angle (OR = 1.170 [95% CI: 1.073-1.278]; P = .004) were associated with increased risk of injury. Conclusion: Increased pitch break of the 4-seam fastball and slider was associated positively with shoulder injury in MLB pitchers. These findings add to the understanding of throwing injury and ability to detect risk using ball-tracking technology

Regulation of nucleosome positioning by a CHD Type III chromatin remodeler and its relationship to developmental gene expression in Dictyostelium

Nucleosome placement and repositioning can direct transcription of individual genes; however, the precise interactions of these events are complex and largely unresolved at the whole-genome level. The Chromodomain-Helicase-DNA binding (CHD) Type III proteins are a subfamily of SWI2/SNF2 proteins that control nucleosome positioning and are associated with several complex human disorders, including CHARGE syndrome and autism. Type III CHDs are required for multicellular development of animals and Dictyostelium but are absent in plants and yeast. These CHDs can mediate nucleosome translocation in vitro, but their in vivo mechanism is unknown. Here, we use genome-wide analysis of nucleosome positioning and transcription profiling to investigate the in vivo relationship between nucleosome positioning and gene expression during development of wild-type (WT) Dictyostelium and mutant cells lacking ChdC, a Type III CHD protein ortholog. We demonstrate major nucleosome positional changes associated with developmental gene regulation in WT. Loss of chdC caused an increase of intragenic nucleosome spacing and misregulation of gene expression, affecting ∼50% of the genes that are repositioned during WT development. These analyses demonstrate active nucleosome repositioning during Dictyostelium multicellular development, establish an in vivo function of CHD Type III chromatin remodeling proteins in this process, and reveal the detailed relationship between nucleosome positioning and gene regulation, as cells transition between developmental states

Porcine iGb3s gene silencing provides minimal benefit for clinical xenotransplantation

Background The Galα(1,3)Gal epitope (α-GAL), created by α-1,3-glycosyltransferase-1 (GGTA1), is a major xenoantigen causing hyperacute rejection in pig-to-primate and pig-to-human xenotransplantation. In response, GGTA1 gene-deleted pigs have been generated. However, it is unclear whether there is a residual small amount of α-Gal epitope expressed in GGTA1−/− pigs. Isoglobotrihexosylceramide synthase (iGb3s), another member of the glycosyltransferase family, catalyzes the synthesis of isoglobo-series glycosphingolipids with an α-GAL-terminal disaccharide (iGb3), creating the possibility that iGb3s may be a source of α-GAL epitopes in GGTA1−/− animals. The objective of this study was to examine the impact of silencing the iGb3s gene (A3GalT2) on pig-to-primate and pig-to-human immune cross-reactivity by creating and comparing GGTA1−/− pigs to GGTA1−/−- and A3GalT2−/−-double-knockout pigs. Methods We used the CRISPR/Cas 9 system to target the GGTA1 and A3GalT2 genes in pigs. Both GGTA1 and A3GalT2 genes are functionally inactive in humans and baboons. CRISPR-treated cells used directly for somatic cell nuclear transfer produced single- and double-gene-knockout piglets in a single pregnancy. Once grown to maturity, the glycosphingolipid profile (including iGb3) was assayed in renal tissue by normal-phase liquid chromatography. In addition, peripheral blood mononuclear cells (PBMCs) were subjected to (i) comparative cross-match cytotoxicity analysis against human and baboon serum and (ii) IB4 staining for α-GAL/iGb3. Results Silencing of the iGb3s gene significantly modulated the renal glycosphingolipid profile and iGb3 was not detected. Moreover, the human and baboon serum PBMC cytotoxicity and α-GAL/iGb3 staining were unchanged by iGb3s silencing. Conclusions Our data suggest that iGb3s is not a contributor to antibody-mediated rejection in pig-to-primate or pig-to-human xenotransplantation. Although iGb3s gene silencing significantly changed the renal glycosphingolipid profile, the effect on Galα3Gal levels, antibody binding, and cytotoxic profiles of baboon and human sera on porcine PBMCs was neutral

Unfolding Humanity: Cross-Disciplinary Sculpture Design

Unfolding Humanity is a 12 foot tall, 30 foot wide, 2 ton interactive metal sculpture that calls attention to the tension between technology and humanity. This sculpture was conceived, designed, and built by a large group (80+) of faculty, students, and community volunteers at the University of San Diego (USD). The piece is a dodecahedron whose pentagonal walls unfold under human power, an engineered design that alludes to Albrecht Dürer\u27s 500-year-old unsolved math problem on unfolding polyhedra. When closed, the mirrored interior of the sculpture makes visitors feel as though they are at the center of the universe. The idea for the sculpture began with two USD mathematics professors, they recount their journey elsewhere (Devadoss & Hoffoss, 2019). This narrative focuses on the story of bringing their vision to a reality

Comparing the effects of medical cannabis for chronic pain patients with and without co-morbid anxiety: A cohort study.

INTRODUCTION: There is growing evidence on the efficacy of cannabis-based medicinal products (CBMPs) for chronic pain (CP). Due to the interaction between CP and anxiety, and the potential impact of CBMPs on both anxiety and CP, this article aimed to compare the outcomes of CP patients with and without co-morbid anxiety following CBMP treatment. METHODS: Participants were prospectively enrolled and categorized by baseline General Anxiety Disorder-7(GAD-7) scores, into 'no anxiety'(GAD-7  0.050). The anxiety cohort reported greater improvements in EQ-5D-5L index values, SQS and GAD-7(p < 0.050), but there were no consistent differences in pain outcomes. CONCLUSION: A potential association between CBMPs and improvements in pain and health-related quality of life (HRQoL) in CP patients was identified. Those with co-morbid anxiety reported greater improvements in HRQoL

Comparison of greenhouse gas fluxes from tropical forests and oil palm plantations on mineral soil

In Southeast Asia, oil palm (OP) plantations have largely replaced tropical forests. The impact of this shift in land use on greenhouse gas (GHG) fluxes remains highly uncertain, mainly due to a relatively small pool of available data. The aim of this study is to quantify differences of nitrous oxide (N2O) and methane (CH4) fluxes as well as soil carbon dioxide (CO2) respiration rates from logged forests, oil palm plantations of different ages, and an adjacent small riparian area. Nitrous oxide fluxes are the focus of this study, as these emissions are expected to increase significantly due to the nitrogen (N) fertilizer application in the plantations. This study was conducted in the SAFE (Stability of Altered Forest Ecosystems) landscape in Malaysian Borneo (Sabah) with measurements every 2 months over a 2-year period. GHG fluxes were measured by static chambers together with key soil physicochemical parameters and microbial biodiversity. At all sites, N2O fluxes were spatially and temporally highly variable. On average the largest fluxes (incl. 95 % CI) were measured from OP plantations (45.1 (24.0–78.5) µg m−2 h−1 N2O-N), slightly smaller fluxes from the riparian area (29.4 (2.8–84.7) µg m−2 h−1 N2O-N), and the smallest fluxes from logged forests (16.0 (4.0–36.3) µg m−2 h−1 N2O-N). Methane fluxes were generally small (mean ± SD): −2.6 ± 17.2 µg CH4-C m−2 h−1 for OP and 1.3 ± 12.6 µg CH4-C m−2 h−1 for riparian, with the range of measured CH4 fluxes being largest in logged forests (2.2 ± 48.3 µg CH4-C m−2 h−1). Soil respiration rates were larger from riparian areas (157.7 ± 106 mg m−2 h−1 CO2-C) and logged forests (137.4 ± 95 mg m−2 h−1 CO2-C) than OP plantations (93.3 ± 70 mg m−2 h−1 CO2-C) as a result of larger amounts of decomposing leaf litter. Microbial communities were distinctly different between the different land-use types and sites. Bacterial communities were linked to soil pH, and fungal and eukaryotic communities were linked to land use. Despite measuring a large number of environmental parameters, mixed models could only explain up to 17 % of the variance of measured fluxes for N2O, 3 % of CH4, and 25 % of soil respiration. Scaling up measured N2O fluxes to Sabah using land areas for forest and OP resulted in emissions increasing from 7.6 Mt (95 % confidence interval, −3.0–22.3 Mt) yr−1 in 1973 to 11.4 Mt (0.2–28.6 Mt) yr−1 in 2015 due to the increasing area of forest converted to OP plantations over the last ∼ 40 years

Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital

Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient-individualized treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen-induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA-122 (miR-122; high liver specificity), high mobility group box-1 (HMGB1; marker of necrosis), full-length and caspase-cleaved keratin-18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR-122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR-122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision-making, both in the treatment of ALI and the design/execution of patient-individualized treatment strategies

A study of white mica microstructure and microchemistry in a low grade mylonite

A suite of mylonites rich in white mica, taken from the Betic Movement Zone (Sierra Alhamilla, Spain) shows progressive grain refinement involving a two-stage recrystallization history. Stage one is isochemical and possibly works by nucleation and growth of new crystals at sites of fracture and dilatancy. Stage two is nonisochemical and may be driven by differences in strain energy and chemical free energy between the two phases. Deformation is probably governed by brittle fracture and diffusional mass transfer along grain boundaries and cracks. The two stages of recrystallization are thought to represent a single progressive episode of deformation under changing metamorphic conditions