Miracle-dz/UniFAR-FTUs huggingface dataset:
Discovery and engineering of an anti-TREM2 antibody to promote amyloid plaque clearance by microglia in 5XFAD mice

ABSTRACT Triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in regulating microglial functions and removal of amyloid plaques in Alzheimer’s disease (AD). However, therapeutics based on this knowledge have not been developed due to the low antibody brain penetration and weak TREM2 activation. In this study, we engineered a TREM2 bispecific antibody to potently activate TREM2 and enter the brain. To boost TREM2 activation, we increased the valency of bivalent anti-TREM2 Ab2 IgG to tetra-variable domain immunoglobulin (TVD-Ig), thus improving the EC50 of amyloid-β oligomer (oAβ)-lipid microglial phagocytosis by more than 100-fold. Ab2 TVD-Ig treatment also augmented both microglia migration toward oAβ and microglia survival by 100-fold over the bivalent IgG antibody. By targeting the transferrin receptor (TfR), the brain-penetrating Ab2 TVD-Ig/αTfR bispecific antibody realized broad brain parenchyma distribution with a 10-fold increase in brain antibody concentration. Ab2 TVD-Ig/αTfR treatment of 5-month-old 5XFAD mice significantly boosted microglia-plaque interactions and enhanced amyloid plaque phagocytosis by microglia. Thus, potent TREM2 activation by a multivalent agonist antibody coupled with TfR-mediated brain entry can boost microglia clearance of amyloid plaques, which suggests the antibody has potential as an AD treatment. List of abbreviations AD: Alzheimer’s disease; Ab: antibody; APOE: apolipoprotein E; Aβ: amyloid beta; BBB: blood–brain barrier; BLI: bio-layer interferometry; CNS: central nervous system; CSF: colony-stimulating factor; CytoD: cytochalasin d; DAM: microglia type associated with neurodegenerative diseases; DAP12: DNAX-activation protein 12; TVD-Ig: tetra-variable domain immunoglobulin; ECD: extracellular domain; ELISA: enzyme-linked immunoassay; ESC: embryonic stem cell; hMGLs: human embryonic stem cell-derived microglia-like lines; IBA1: ionized calcium-binding adaptor molecule 1; ITAM: immunoreceptor tyrosine-based activation motif; KiH: knob-into-hole; NFAT: nuclear factor of activated t-cells; PC: phosphatidylcholine; PK: pharmacokinetics; PS: phosphatidylserine; pSYK: phosphorylated spleen tyrosine kinase; scFv: single-chain variable fragment; SEC: size-exclusion chromatography; sTREM2: soluble triggering receptor expressed on myeloid cells 2; SYK: spleen tyrosine kinase; TfR: transferrin receptor; TREM2: triggering receptor expressed on myeloid cells 2.
Mouse model of NASH that replicates key features of the human disease and progresses to fibrosis stage 3

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and the world; with no Food and Drug Administration–approved pharmacological treatment available, it remains an area of unmet medical need. In nonalcoholic steatohepatitis (NASH), the most important predictor of clinical outcome is the fibrosis stage. Moreover, the Food and Drug Administration recommends that clinical trials for drugs to treat this disease include patients with fibrosis stage 2 or greater. Therefore, when using animal models for investigating the pathophysiology of NAFLD and for the preclinical evaluation of new drugs, it is important that the animals develop substantial fibrosis. The aim of this study was to develop a mouse model of NAFLD that replicated the disease in humans, including obesity and progressive liver fibrosis. Agouti yellow mutant mice, which have hyperphagia, were fed a Western diet and water containing high‐fructose corn syrup for 16 weeks. Mice became obese and developed glucose intolerance. Their gut microbiota showed dysbiosis with changes that replicate some of the changes described in humans with NASH. They developed NASH with activity scores of 5–6 and fibrosis, which was stage 1 after 16 weeks, and stage 3 after 12 months. Changes in liver gene expression assessed by gene‐set enrichment analysis showed 90% similarity with changes in human patients with NASH. Conclusion: Ay mice, when fed a Western diet similar to that consumed by humans, develop obesity and NASH with liver histology, including fibrosis, and gene expression changes that are highly similar to the disease in humans.
Live‐fast‐die‐young: Carryover effects of heatwave‐exposed adult urchins on the development of the next generation

With rising ocean temperatures, extreme weather events such as marine heatwaves (MHWs) are increasing in frequency and duration, pushing marine life beyond their physiological limits. The potential to respond to extreme conditions through physiological acclimatization, and pass on resistance to the next generation, fundamentally depends on the capacity of an organism to cope within their thermal tolerance limits. To elucidate whether heat conditioning of parents could benefit offspring development, we exposed adult sea urchins (Heliocidaris erythrogramma) to ambient summer (23°C), moderate (25°C) or strong (26°C) MHW conditions for 10 days. Offspring were then reared at constant temperature along a thermal gradient (22–28°C) and development was tracked to the 14‐day juvenile stage. Progeny from the MHW‐conditioned adults developed through to metamorphosis faster than those of ambient conditioned parents, with most individuals from the moderate and strong heatwaves developing to the larval stage across all temperatures. In contrast, the majority of offspring from the control summer temperature died before metamorphosis at temperatures above 25°C (moderate MHW). Juveniles produced from the strong MHW‐conditioned adults were also larger across all temperatures, with the largest juveniles in the 26°C treatment. In contrast, the smallest juveniles were from control (current‐day summer) parents (and reared at 22 and 25°C). Surprisingly, initial survival was higher in the progeny of MHW exposed parents, even at temperatures hotter than predicted MHWs (28°C). Importantly, however, there was substantial mortality of juveniles from the strong MHW parents by day 14. Therefore, while carryover effects of parental conditioning to MHWs resulted in faster growing, larger progeny, this benefit will only persist beyond the more sensitive juvenile stage and enhance survival if conditions return promptly to normal seasonal temperatures within current thermal tolerance limits.
Improving power in functional magnetic resonance imaging by moving beyond cluster-level inference

Significance Localizing cognitive function to distinct brain areas has been a mainstay of human brain research since early reports that focal injuries produce changes in behavior. Yet, accumulating evidence shows that areas do not act in isolation. Here, we evaluate the practical implications of the localizationist perspective by comparing the performance of localizing versus broad-scale statistical procedures in real connectome data (1,000 subjects performing 7 tasks). We find that popular localizing procedures miss substantially more true effects than simple broad-scale procedures. By highlighting the power of simple alternatives, we argue that moving beyond localization is viable and can help unlock opportunities for human neuroscience discovery.
Phytochemical characterization and antimicrobial activity of Nigella sativa seeds

Nigella sativa is one of the medicinal plant species that gained popularity for a wide range of medicinal applications due to its seeds which are rich in phytoconstituents. Continuous scientific investigations on N. sativa seeds are needed to better understand its many medicinal potentials. This will also form a composition-based foundation that support several old and/or new case beneficial histories of its seeds. In this study, the antimicrobial activity of N. sativa seeds was phytochemically characterized and evaluated. Different extracts of N. sativa seeds were obtained by maceration and soxhlet extraction methods using different extraction solvents. The obtained extracts were tested using UV-Vis, FTIR, TLC, and GC-MS techniques. Antimicrobial analysis against pathogenic bacterial strains (E. coli, P. aeruginosa, S. aureus and B. subtilis) was carried out by disc diffusion method using different preparations of N. sativa seeds. The screening analysis revealed the presence of all the tested phytochemicals. FT-IR analysis of N. sativa seeds oil extracted with absolute ethanol revealed functional groups that are associated with active ingredients of medicinal value. The GC-MS chromatograms revealed different chemical constituents whose known bioactivities and/or applications are essential in the management of life-threatening infections. Different extracts of N. sativa seeds showed antimicrobial activity with different efficacy against the tested pathogenic bacterial strains. Therefore, this study shows that extracts of N. sativa seeds contain a variety of chemical components and functional groups linked to their antimicrobial properties, and they might be natural precursors of nutraceuticals.
Chronic Leptin Deficiency Improves Tolerance of Physiological Damage and Host-Pathogen Cooperation during Yersinia pseudotuberculosis Infection

To combat infections, hosts employ a combination of antagonistic and cooperative defense strategies. The former refers to pathogen killing mediated by resistance mechanisms, while the latter refers to physiological defense mechanisms that promote host health during infection independent of pathogen killing, leading to an apparent cooperation between the host and the pathogen. ABSTRACT To combat infections, hosts employ a combination of antagonistic and cooperative defense strategies. The former refers to pathogen killing mediated by resistance mechanisms, while the latter refers to physiological defense mechanisms that promote host health during infection independent of pathogen killing, leading to an apparent cooperation between the host and the pathogen. Previous work has shown that Leptin, a pleiotropic hormone that plays a central role in regulating appetite and energy metabolism, is indispensable for resistance mechanisms, while a role for Leptin signaling in cooperative host-pathogen interactions remains unknown. Using a mouse model of Yersinia pseudotuberculosis (Yptb) infection, an emerging pathogen that causes fever, diarrhea, and mesenteric lymphadenitis in humans, we found that the physiological effects of chronic Leptin-signaling deficiency conferred protection from Yptb infection due to increased host-pathogen cooperation rather than greater resistance defenses. The protection against Yptb infection was independent of differences in food consumption, lipolysis, or fat mass. Instead, we found that the chronic absence of Leptin signaling protects from a shift to lipid utilization during infection that contributes to Yptb lethality. Furthermore, we found that the survival advantage conferred by Leptin deficiency was associated with increased liver and kidney damage. Our work reveals an additional level of complexity for the role of Leptin in infection defense and demonstrates that in some contexts, in addition to tolerating the pathogen, tolerating organ damage is more beneficial for survival than preventing the damage.
SURVEY AND SUMMARY Quantiﬁcation of radiation-induced DNA double strand break repair foci to evaluate and predict biological responses to ionizing radiation

Radiation-induced foci (RIF) are nuclear puncta vi-sualized by immunostaining of proteins that regulate DNA double-strand break (DSB) repair after exposure to ionizing radiation. RIF are a standard metric for measuring DSB formation and repair in clinical, envi-ronmental and space radiobiology. The time course and dose dependence of their formation has great potential to predict invivoresponses to ionizing radiation, predisposition to cancer and probability of adverse reactions to radiotherapy. However, increasing complexity of experimentally and therapeutically setups (charged particle, FLASH . . . ) is associated with several confounding factors that must be taken into account when interpreting RIF values. In this review, we discuss the spatiotemporal characteristics of RIF development after irradiation, addressing the common confounding factors, including cell proliferation and foci merging. We also describe the relevant endpoints and mathematical models that enable accurate biological interpretation of RIF formation and resolution. Finally, we discuss the use of RIF
Between routine and moral obligation: Exploring family consumption, emotions and sustainable lifestyles

: Consumption and production are crucial areas for reducing societies’ impact on the climate and environment and this is also one of the United Nations’ global goals for sustainable development. Despite that the risks of climate change and environmental degradation is well-known, lifestyle changes where it is needed have not reached sufficient scales. This study focuses on the emotional aspects of sustainable choices to highlight the ambiguousness of consumption. The purpose is to explore possibilities and barriers for sustainable consumption by investigating the family as one unit of consumption, as well as families’ emotional orientation and reasoning about consumption and sustainability as a way of living. It does so by conducting interviews with six middle-class families in Gothenburg, Sweden, that to some extend try to make sustainable choices in everyday consumption. The results indicate that changing consumption patterns are intertwined with changing emotional attachments to consumption practices, re-negotiating relationships connected to these practices, and develop-ing an emotional obligation to sustainability or environmentalism. Emotions also inform and express barriers to sustainable living, in that even the interested have to balance sustainable consumption with conventional consumption to manage everyday family life.
DESIGNING A ZERO-WASTE MASS-TIMBER HIGH-RISE LOAD-BEARING STRUCTURE

An increasing amount of people is living in urban areas and this is expected to increase till the end of this century. Sustainable solutions are required to prevent resource depletion and to reduce carbon emissions. Mass-timber can be used to extend existing buildings due to its lightweight properties, preventing demolition and waste, and to densify the city. Timber is a renewable resource with a negative carbon footprint in contrast to traditional building materials. This paper examines the possibilities for designing zero-waste mass-timber high-rise extensions using case studies of existing projects, literature study and a study into mass-timber products. Because of the lightweight nature of mass-timber the structure should be suitably designed for stability to prevent overturning of the structure. It is also shown that structural modifications can enable larger load bearing capacities in existing structures for extensions. All wood mass-timber products can be used as a zero-waste building material in combination with metals, although in the future bio-resins can enable the use of more timber products. In combination with demountable connections a zero-waste design can be achieved. This appendix contains the documentation of the studies complementary to the paper Designing a zero-waste mass-timber high-rise load-bearing structure. It contains the zero-waste requirements, case studies into mass-timber high-rises, case studies into high-rise extensions and a study into the different mass-timber products available.
HOW EMERGENT ROLES AND STRUCTURES CREATE TRUST How Emergent Roles and Structures Create Trust In Hastily Formed Inter-Organizational Teams

Many activities, from disaster response to project management, require cooperation among people from multiple organizations who initially lack interpersonal relationships and trust. Upon entering inter-organizational settings, pre-existing identities and expectations, along with emergent social roles and structures, may all influence trust between colleagues. To sort out these effects, we collected time-lagged data from three cohorts of military MBA students, representing 2,224 directed dyads, shortly after they entered graduate school. Dyads that shared organizational identity, boundary-spanning roles, and similar network positions (structural equivalence) were likely to have stronger professional ties and greater trust.
N A ] 1 1 D ec 2 00 8 GREEDY SIGNAL RECOVERY REVIEW

The two major approaches to sparse recovery are L 1 -minimization and greedy methods. Recently, Needell and Vershynin developed Regularized Orthogonal Matching Pursuit (ROMP) that has bridged the gap between these two approaches. ROMP is the ﬁrst stable greedy algorithm providing uniform guarantees. Even more recently, Needell and Tropp developed the stable greedy algorithm Compressive Sampling Matching Pursuit (CoSaMP). CoSaMP provides uniform guarantees and improves upon the stability bounds and RIC requirements of ROMP. CoSaMP oﬀers rigorous bounds on computational cost and storage. In many cases, the running time is just O ( N log N ), where N is the ambient dimension of the signal. This review summarizes these major advances.
Causes of Multivariate Significance in a Multivariate Analysis of Variance.

Differrnt ways that dependent variables can cause multivariate significance are illustrated. It is argued that univariate tests should not be used as follow-up procedures to identify the variables that can contribute to multivariate significance. Methods that can be used to determine the contributions individual variables make to multivariate significance are discussed. Two-group multivariate analysis of variance (MANOVA) with two dependent variables is described; a significant multivariate test under three conditions of univariate significance is considered: (1) with both dependent variables significant; (2) with one dependent variable significant; and (3) with both dependent variables not significant. The relationships among the variables in these conditions yield 11 different situations. The data illustrate: multivariate significance can be caused under a variety of relationships; it is improper to interpret univariate analysis of variance results to find the causes of multivariate significance. The use of discriminant analysis and stepwise discriminant analysis is demonstrated as a valuable tool in considering the contributions of dependent variables to multivariate significance. Three tables illustrate the 11 situations, and Appendix A details the process used to create each situation. (SLD) *********************************************************************** Reproductions supplied by EDRS are the best that can be made from the original document. ***********************************************************************
MYLK , CNN 1 , TAGLN and LMOD 1 identi � ed as potential prognostic biomarkers for bladder cancer using bioinformatics analysis

zhiyong tan (  tanzhiyong1@kmmu.edu.cn ) Kunming Medical University Second Hospital https://orcid.org/0000-0001-7542-3719 Xuhua Qiao Kunming Medical University Second Hospital Shi Fu Kunming Medical University Second Hospital Xianzhong Duan the second people's hospital of baoshan Yigang Zuo Kunming Medical University Second Hospital Xiaorui Zhu the second people's hospital of baoshan Haifeng Wang Kunming Medical University Second Hospital Jiansong Wang Kunming Medical University Second Hospital
TACG_A_319065 331..339

1Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Menoufia University, Shebin Elkom City, Egypt; 2Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makah City, Saudi Arabia; 3Dermatology, Andrology & Sexually Transmitted Diseases (STDs) Department, Faculty of Medicine, Menoufia University, Shebin Elkom City, Egypt; 4Clinical Pathology Department, Faculty of Medicine, Menoufia University, Shebin Elkom City, Egypt Background: Psoriasis is a complex autoimmune multifactorial disease induced by interaction of environmental and genetic factors. This research aimed to clarify the association of NLRP3 (rs10754558) and PTPN22 (1858C/T) (rs2476601) polymorphisms with susceptibility to psoriasis. Methods: This case–control study involved 150 patients diagnosed with psoriasis and 100 ageand gender-matched apparently healthy individuals. NLRP3 (rs10754558) polymorphism was done by real time PCR and PTPN22 1858C/T (rs2476601) genotype was identified by tetra-primer amplification refractory mutation system-polymerase chain reaction (PCR) method. Results: The genotypes distribution of NLRP3 (rs10754558) were significantly associated with psoriasis (p<0.0001). Whereas for PTPN22 (1858C/T) (rs2476601), no significance was found (p=0.09). NLRP3 (rs10754558) GC genotype revealed a significant association with psoriasis (p<0.0001), mainly among male (p=0.004) patients with mild psoriasis (p=0.001) and affected extremities (p=0.0001). Conclusion: We can conclude that the NLRP3 (rs10754558) GC genotype may play a role in psoriasis susceptibility among male Egyptian populations with affected extremities. Future studies must evaluate its role in the prevention or the treatment of psoriasis.
Internet addiction of the first-year students in a Technical University

— Internet addiction is the most important problem of our time, especially among young people. The article presents the results of investigation of Internet addiction of first-year students of one of Russia's leading technical universities. The study was conducted on the basis of K. Young techniques. According to the results, the problem is very serious. Symptoms of Internet addiction have been found in nearly one-third of students. Only 10 percent of students are ordinary internet users. It is necessary to organize the educational process in the electronic environment more actively and efficiently. As a result, the students while they are at the computer will spend time with benefits for their education, without any negative consequences.
A respiratory-de¢cient mutation associated with high salt sensitivity in Kluyveromyceslactis

A salt-sensitive mutant of Kluyveromyces lactis was isolated that was unable to grow in high-salt media. This mutant was also respiratory-deﬁcient and temperature-sensitive for growth. The mutation mapped in a single nuclear gene that is the ortholog of BCS1 of Saccharomyces cerevisiae . The BCS1 product is a mitochondrial protein required for the assembly of respiratory complex III. The bcs1 mutation of S. cerevisiae leads to a loss of respiration, but, unlike in K. lactis , it is not accompanied by salt sensitivity. All the respiratory-deﬁcient K. lactis mutants tested were found to be salt-sensitive compared to their isogenic wild-type strains. In the presence of the respiratory inhibitor antimycin A, the wild-type strain also became salt-sensitive. By contrast, none of the S. cerevisiae respiratory-deﬁcient mutants tested showed increased salt sensitivity. The salt sensitivity of the Klbcs1 mutant, but not its respiratory deﬁciency, was suppressed by the multicopy KlVMA13 gene, a homolog of the S. cerevisiae VMA13 gene encoding a subunit of the vacuolar H 1 -ATPase. These results suggest that cellular salt homeostasis in K. lactis is strongly dependent on mitochondrial respiratory activity, and/or that the ion homeostasis of mitochondria themselves could be a primary target of salt stress.