Miracle-dz/UniFAR-FTUs huggingface dataset:
Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer’s disease

Semorinemab shows beneficial effects in preclinical models and engages tau in a phase 1 study of patients with Alzheimer’s disease. Developing an immunotherapy for AD Hyperphosphorylated TAU aggregates contribute to neurodegeneration in patients with Alzheimer’s disease (AD), and reducing TAU accumulation had therapeutic effects in preclinical models. Here, Ayalon et al. generated and characterized a humanized anti-TAU monoclonal antibody, called semorinemab, and tested it in mice, nonhuman primates, and in a phase 1 clinical trial in humans. Semorinemab was able to bind all six human tau isoforms and had therapeutic effects in vivo in AD mice, by reducing TAU accumulation. In patients with AD, semorinemab crossed the blood-brain barrier and showed evidence of target engagement, without evident side effects. The results support the idea that immunotherapies targeting TAU might be effective in reducing TAU pathology in AD. Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer’s disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month.
A portable magnetofluidic platform for detecting sexually transmitted infections and antimicrobial susceptibility

A portable magnetofluidic platform integrates nucleic acid purification and PCR to rapidly detect the pathogen causing gonorrhea in clinical samples. A rapid point-of-care test for gonorrhea Rapid diagnosis of sexually transmitted infections in the clinic ensures treatment with the appropriate antibiotic. Trick et al. developed a cartridge-based magnetofluidic polymerase chain reaction platform that detects Neisseria gonorrhoeae, the pathogen causing gonorrhea, in urethral swabs from patients within 15 min. This test simultaneously reported whether the strains detected are resistant to the antimicrobial drug ciprofloxacin. Testing of urethral swab samples was performed at sexual health clinics in Baltimore and in Kampala, Uganda. This study demonstrates that this rapid assay can detect gonorrhea at the point of care and determine ciprofloxacin resistance of the pathogen. Effective treatment of sexually transmitted infections (STIs) is limited by diagnostics that cannot deliver results rapidly while the patient is still in the clinic. The gold standard methods for identification of STIs are nucleic acid amplification tests (NAATs), which are too expensive for widespread use and have lengthy turnaround times. To address the need for fast and affordable diagnostics, we have developed a portable, rapid, on-cartridge magnetofluidic purification and testing (PROMPT) polymerase chain reaction (PCR) test. We show that it can detect Neisseria gonorrhoeae, the pathogen causing gonorrhea, with simultaneous genotyping of the pathogen for resistance to the antimicrobial drug ciprofloxacin in <15 min. The duplex test was integrated into a low-cost thermoplastic cartridge with automated processing of penile swab samples from patients using magnetic beads. A compact instrument conducted DNA extraction, PCR, and analysis of results while relaying data to the user via a smartphone app. This platform was tested on penile swab samples from sexual health clinics in Baltimore, MD, USA (n = 66) and Kampala, Uganda (n = 151) with an overall sensitivity and specificity of 97.7% (95% CI, 94.7 to 100%) and 97.6% (95% CI, 94.1 to 100%), respectively, for N. gonorrhoeae detection and 100% concordance with culture results for ciprofloxacin resistance. This study paves the way for delivering accessible PCR diagnostics for rapidly detecting STIs at the point of care, helping to guide treatment decisions and combat the rise of antimicrobial resistant pathogens.
STRUCTURAL AND PROTEIN PRESERVATION IN FOSSIL WHALE BONES FROM THE PISCO FORMATION (MIDDLE-UPPER MIOCENE), PERU

Abstract: Microstructural and biomolecular preservation is reported in fossils as old as the Triassic. Such preservation suggests unusual taphonomic conditions. We collected fragments of fossil whale bone from silty, tuffaceous, and diatomaceous rocks of the middle-upper Miocene portion of the Pisco Formation. The whale fossils within the region are generally well-preserved and mostly articulated, including some specimens with in situ baleen. Due to the depositional setting associated with the preservation of these fossils, they could be expected to be favorable candidates for the preservation of cellular microstructures and/or original biomolecules. To test this hypothesis, fossil whale bone fragments were subjected to microscopic analysis and EDTA-mediated demineralization to release extractable materials. Microscopy of partially demineralized fossil bones revealed quartz-permineralized osteocyte-like and vessel-like structures. Protein assay (micro-Bicinchoninic Acid Assay) of the supernatants obtained from demineralized fossils yielded 12 to 19.5 µg of protein per gram of bone. MALDI-TOF analysis of the extracted protein demonstrated the presence of approximately 5 kD molecules in one fossil sample, consistent with the presence of highly fragmented polypeptides. An LC-MS/MS analysis of the fragmentation pattern of the tryptic digest of extracted protein was performed. However, attempted protein identification was unsuccessful. Nevertheless, this study first documents the microstructural preservation with some silicification of the fossil whale bones of the Pisco Formation, and then quantifies extractable protein from these bones. It adds to the growing body of reports of microstructural and organic preservation in fossils.
Genetics of physiological and agronomical traits linked to salinity tolerance in tomato

Abstract. Improvement of tomato (Lycopersicon esculentum L.) for growth in saline soils is a major goal of tomato breeders. The aim of this study was to identify the genetic combining ability and genetics of salinity tolerance in tomato. Plant materials were grown under normal (NG) and salinity stress (SSG) conditions. Results showed that the genetic controlling mechanism of salinity-related traits and fruit weight is complex and that all genetic components of additive, non-additive and maternal are involved. The nature of gene action for fruit weight and salinity-related traits was significantly affected by salinity stress. Dominance and additive gene action were predominant under NG and SSG, respectively. Under NG, the best general combiner parent for fruit weight was P3 (salt-tolerant with moderate fruit yield). Under SSG, P1 (highly salt-tolerant with low fruit yield) was the best general combiner parent for fruit weight and exhibited high genetic combining ability for K+/Na+, lipoxygenase activity, proline, relative water content, total carbohydrate and cell membrane stability. With the high frequency of genes effective in salt tolerance, the P1 parent appeared as the best specific mating partner with other parents under SSG. Simultaneous selection for fruit weight and surrogate traits (cell membrane stability, proline and relative water content) in a population derived from the P1 × P5 (susceptible with high fruit yield) cross could result in a salt-tolerant tomato genotype.
An oral antisense oligonucleotide for PCSK9 inhibition

A highly potent, chemically modified PCSK9 antisense oligonucleotide formulated with a permeation enhancer was developed for oral administration. An oral ASO to lower LDL Strategies to decrease low-density lipoprotein (LDL) cholesterol could help treat atherosclerosis. Here, Gennemark et al. developed an antisense oligonucleotide (ASO) that can be delivered orally, is taken up by the liver, and targets PCSK9, which regulates the LDL receptor. Subcutaneous administration of the ASO showed high potency in mice overexpressing PCSK9, a liver half-life of 18 days in monkeys, and reduced circulating PCSK9 in humans. The oral formulation showed 5 to 7% liver bioavailability compared to subcutaneous administration in rats and dogs, and it reduced LDL cholesterol in healthy monkeys. Results support the potential of this ASO for PCSK9 inhibition while avoiding the need for injections. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
CD4+ T cells are essential for the development of destructive thyroiditis induced by anti–PD-1 antibody in thyroglobulin-immunized mice

CD4+ T cells are essential for development of thyroiditis induced by anti–PD-1 antibody treatment in thyroglobulin-immunized mice. Adverse events in the thyroid Anti–programmed cell death–1 (PD-1) antibody blockade has revolutionized cancer treatment by enhancing immune responses against tumors. However, anti–PD-1 treatment can also induce immune-related adverse events by promoting autoreactive immune responses. In this study, Yasuda et al. investigated the immune cell type responsible for promoting destructive thyroiditis, a common adverse event observed in patients treated with anti–PD-1 antibody. The authors found that CD4+ T cells are required for the onset of destructive thyroiditis in a mouse model, which was supported by analysis of circulating CD4+ T cells isolated from patients. These results suggest that CD4+ T cells may mediate destructive thyroiditis in patients with cancer after anti–PD-1 treatment. Immune-related adverse events induced by anti–programmed cell death–1 antibodies (PD-1-Ab), including destructive thyroiditis (thyroid-irAE), are thought to be caused by activated T cells. However, the T cell subsets that are directly responsible for damaging self-organs remain unclear. To clarify which T cell subsets are involved in the development of thyroid-irAE, a mouse model of thyroid-irAE was analyzed. PD-1-Ab administration 2.5 months after immunization with thyroglobulin caused destructive thyroiditis. Thyroiditis was completely prevented by previous depletion of CD4+ T cells and partially prevented by depleting CD8+ T cells. The frequencies of central and effector memory CD4+ T cell subsets and the secretion of interferon-γ after stimulation with thyroglobulin were increased in the cervical lymph nodes of mice with thyroid-irAE compared with controls. Histopathological analysis revealed infiltration of CD4+ T cells expressing granzyme B in thyroid glands and major histocompatibility complex class II expression on thyrocytes in mice with thyroid-irAE. Adoptive transfer of CD4+ T cells from cervical lymph nodes in mice with thyroid-irAE caused destruction of thyroid follicular architecture in the irradiated recipient mice. Flow cytometric analyses showed that the frequencies of central and effector memory CD4+ T cells expressing the cytotoxic marker CD27 were higher in peripheral blood mononuclear cells collected from patients with thyroid-irAE induced by PD-1-Ab versus those without. These data suggest a critical role for cytotoxic memory CD4+ T cells activated by PD-1-Ab in the pathogenesis of thyroid-irAE.
Gender Differences in Affective and Evaluative Responses to Experimentally Induced Body Checking of Positively and Negatively Valenced Body Parts

Body checking (BC) is defined as behavior aimed at gaining information on body shape, size, or weight. Besides its occurrence as a transdiagnostic symptom in eating disorders (EDs), BC is widespread in non-clinical populations. It is associated with body dissatisfaction and the development of body image disturbances and ED. Males and females differ in terms of body dissatisfaction and associated BC strategies. However, the question of a gender-related intensity of negative affect and state body satisfaction as reactions to BC remains open. Therefore, the present experimental study aimed to examine gender differences in affective and evaluative responses to BC. We tested n = 60 women and n = 60 men in a crossover design, implementing two experimental conditions and one control condition. In the negative body checking condition (NBC), participants received standardized instructions to check negatively valenced body parts. In the positive body checking condition (PBC), by contrast, participants were asked to check positively valenced body parts. The control condition (CBC) consisted of playing a computer game. Before and after checking of one’s own body, participants rated negative body-related affect, i.e., guilt, shame, and disgust, and state body satisfaction. The results indicate that both NBC and PBC led to an increase in negative affect for men and women. Eating pathology predicted negative affect after checking in NBC for both genders. Men reported a significantly higher state body satisfaction in all conditions, whereas only women showed decreased body satisfaction in NBC. These findings suggest that BC of any body part (i.e., positively or negatively valenced) leads to increased negative affect for both genders. Eating pathology significantly influences the affective responses to BC for both genders. Changes in state body satisfaction, however, only occur in females. An explanation might be that men generally report higher body satisfaction, resulting in a more stable body image. Females and males with pathological eating behavior seem to be more vulnerable to changes in negative affect. As negative affect is equally increased after NBC and PBC for both genders, BC might play a central role in the maintenance of body image disturbances in males and females.
Electrical Transport in Solids

K C Mao and W Hwang 1981 Oxford: Pergamon xvi + 663 pp price £50 This seven-chapter book reviews charge transport, carrier injection, photoelectronic processes and luminescence in semiconductors and insulators. The subtitle reference to organic semiconductors applies to the first chapter on charge transport and the final two chapters on photoelectronic and luminescence topics.
Thermal expansion of .GAMMA.-Mg2SiO4.

Thermal expansion of γ-Mg2SiO4 was measured with X-ray powder diffraction method up to 750°C at atmospheric pressure. The data are analyzed in terms of Gruneisen's theory of thermal expansion and Gruneisen's parameter is obtained to be 1.27. Volume thermal expansion coefficient is 19 at 20°C and 27 at 500°C in unit of 10-6/K. These values are compared with those of γ-Fe2SiO4, MgAl2O4 and other spinel type compounds, and it is suggested that the anharmonic properties of γ-(Mg, Fe)2SiO4 may be very close to those of MgAl2O4.
Migrant Remittances and Violent Responses to Crime in Latin America and the Caribbean

ABSTRACT High levels of crime are a key driver of emigration from Latin America and the Caribbean. But can emigration change public opinion about how best to respond to crime? Focusing on the political economy of remittances—the money migrants send to their families and communities—this study argues that emigration can increase support for violent responses to crime. Migrants’ families often spend remittances on investment goods, which makes them more vulnerable to crime and more supportive of violence to protect themselves. An analysis of AmericasBarometer data finds that remittance recipients are more likely both to fear crime and to be victims of crime than nonrecipients. They are also more approving of vigilantism, more tolerant of police bending the law to apprehend criminals, and more supportive of deploying the military in crime fighting. These findings contribute to our knowledge of the consequences of international migration for political development in migrant-sending countries.
Nudging openly – An experimental analysis of nudge transparency in a public goods setting

Abstract Around the world, policy makers and public authorities are increasingly turning to behaviorally informed interventions (“nudges”) in order to help tackle important contexts of public policy. Despite their impressive merit record, these policy tools have been heavily criticized as being obscure and manipulative, thus facing challenges for their legitimate assertion in the regulatory toolkit. In this study, we seek to assess whether transparency over the use of such interventions may constitute a viable way of addressing these ethical concerns, and focus particularly on the potentially moderating role of something we call “status quo experience”, i. e. subjects’ understanding of the behavioral consequences of different choice architectures. We conduct a laboratory experiment, whereby subjects play three rounds of a public good game, the first of which defaults them towards a fully non-cooperative contribution, while the rest default them towards a fully cooperative one. Subjects in our treatment groups further receive an “informational shock” at varying points in time, disclosing how and why a fully cooperative default contribution is being used. We find that providing subjects with informational disclosure about the nudge intervention did not result in significantly different aggregate behavioral measurements between control and treatment groups. This seems to be independent of status quo experience and of the timing of transparency provision. We nonetheless find some indication that the latter could help sustain cooperation over time.
Bayesian Additive Regression Trees for Genotype by Environment Interaction Models

We propose a new class of models for the estimation of genotype by environment (GxE) interactions in plant-based genetics. Our approach, named AMBARTI, uses semi-parametric Bayesian additive regression trees to accurately capture marginal genotypic and environment effects along with their interaction in a cut Bayesian framework. We demonstrate that our approach is competitive or superior to similar models widely used in the literature via both simulation and a real world dataset. Furthermore, we introduce new types of visualisation to properly assess both the marginal and interactive predictions from the model. An R package that implements our approach is available at https://github.com/ebprado/ambarti.
Short-interval fires and vegetation change in southern California

Questions In southern California, shortened fire return intervals may contribute to a decrease in native chaparral shrub presence and an increase in non-native annual grass presence. To test the hypothesis that short-fire return intervals promote a loss in shrub cover, we examined the contribution of single short-interval fires and abiotic conditions on the change of shrub cover within Ventura and Los Angeles counties. Through evaluating pre- and post-fire historical aerial images, we answered the following questions, 1) How has vegetation type cover changed after repeat fires? and 2) What landscape variables contribute the most to the observed change? Location Ventura County and Los Angeles County, California, USA. Methods We assessed the impact of a single short-interval fire by comparing vegetation recovery in adjacent once- and twice-burned fire burn polygons (long- and short-interval respectively). Pixel plots were examined within each polygon and vegetation cover was classified to vegetation type. We determined the best predictor of vegetation type cover with a linear mixed effects model comparison using Akaike Information Criterion. Results Pre-fire and post-fire community type cover was highly correlated. Burn interval was the best predictor of tree cover change (lower cover in twice-burned pixel plots). Aspect was the best predictor of sage scrub cover change (greater cover on north-facing aspects). Years since fire was the best predictor of chaparral cover change (positive correlation) and sage scrub cover change (negative correlation). Conversion of chaparral to sage scrub cover was more likely to occur than conversion of chaparral to annual grass cover. Conclusions Our study did not find extensive evidence of a decrease in chaparral shrub cover due to a single short-interval fire. Instead, post-fire cover was highly correlated with pre-fire cover. Chaparral recovery, however, was dynamic suggesting that stand recovery may be strongly influenced by local scale conditions and processes.