Miracle-dz/UniFAR-FTUs huggingface dataset:
Knockout studies using CD34+ hematopoietic cells suggest that CD44 is a physiological human neutrophil E-selectin ligand

The recruitment of peripheral blood neutrophils at sites of inflammation involves a multistep cascade, starting with E- and P-selectin expressed on the inflamed vascular endothelium binding sialofucosylated glycans on leukocytes. As the glycoconjugate biosynthesis pathways in different cells are distinct, the precise carbohydrate ligands of selectins varies both across species, and between different immune cell populations in a given species. To study this aspect in human neutrophils, we developed a protocol to perform CRISPR/Cas9 gene-editing on CD34+ hHSCs (human hematopoietic stem/progenitor cells) as they are differentiated towards neutrophil lineage. This protocol initially uses a cocktail of SCF (stem-cell factor), IL-3 (interleukin-3) and FLT-3L (FMS-like tyrosine kinase 3 ligand) to expand the stem/progenitor cells followed by directed differentiation to neutrophils using G-CSF (granulocyte colony-stimulating factor). Microfluidics based assays were performed on a confocal microscope platform to characterize the rolling phenotype of each edited cell type in mixed populations. These studies demonstrated that CD44, but not CD43, is a major E-selectin ligand on human neutrophils. The loss of function results were validated by developing sialofucosylated recombinant CD44. This glycosylated protein supported both robust E-selectin binding in a cell-free assay, and it competitively blocked neutrophil adhesion to E-selectin on inflamed endothelial cells. Together, the study establishes important methods to study human neutrophil biology and determines that sialoflucosylated-CD44 is a physiological human E-selectin ligand. KEY POINTS A CRISPR-Cas9 based protocol was optimized to knockout genes in primary human neutrophils derived from CD34+ hHSCs Under physiological fluid shear conditions, a sialofucosylated form of CD44 expressed on human neutrophils is a major E-selectin ligand VISUAL ABSTRACT
Targeting CD19-positive lymphomas with the antibody-drug conjugate (ADC) loncastuximab tesirine: preclinical evidence as single agent and as combinatorial approach

Purpose Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. Experimental Design We assessed the activity of loncastuximab tesirine in in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels and identified combination partners providing synergy with loncastuximab tesirine. Results Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine has strong cytotoxic activity in B-cell lymphoma cell lines and the in vitro activity is correlated with CD19 expression level and with intrinsic sensitivity of cell lines to the ADC’s warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Conclusions Our data support the further development of loncastuximab tesirine as single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression, and the existence of lymphoma populations characterized by resistance to multiple therapies.
Chromatin-associated cohesin turns over extensively and forms new cohesive linkages during meiotic prophase

In dividing cells, accurate chromosome segregation depends on sister chromatid cohesion, protein linkages that are established during DNA replication. Faithful chromosome segregation in oocytes requires that cohesion, first established in S phase, remain intact for days to decades, depending on the organism. Premature loss of meiotic cohesion in oocytes leads to the production of aneuploid gametes and contributes to the increased incidence of meiotic segregation errors as women age (maternal age effect). The prevailing model is that cohesive linkages do not turn over in mammalian oocytes. However, we have previously reported that cohesion-related defects arise in Drosophila oocytes when individual cohesin subunits or cohesin regulators are knocked down after meiotic S phase. Here we use two strategies to express a tagged cohesin subunit exclusively during mid-prophase in Drosophila oocytes and demonstrate that newly expressed cohesin is used to form de novo linkages after meiotic S phase. Moreover, nearly complete turnover of chromosome-associated cohesin occurs during meiotic prophase, with faster replacement on the arms than at the centromeres. Unlike S-phase cohesion establishment, the formation of new cohesive linkages during meiotic prophase does not require acetylation of conserved lysines within the Smc3 head. Our findings indicate that maintenance of cohesion between S phase and chromosome segregation in Drosophila oocytes requires an active cohesion rejuvenation program that generates new cohesive linkages during meiotic prophase.
Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells

Aging of the hematopoietic system promotes various blood, immune and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction (1). Autophagy is central for the benefits associated with activation of longevity signaling programs (2), and for HSC function and response to nutrient stress (3,4). With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional (4). However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown. Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche (5). We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement preserves functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity. One-Sentence Summary Autophagy compensates for chronic inflammation-induced metabolic deregulation in old HSCs, and its transient modulation can reset old HSC glycolytic and regenerative capacity.
SSDs Striking Back: The Storage Jungle and Its Implications to Persistent Indexes

The recent exciting development of persistent memory (PM) has led to many new proposals that directly operate and persist indexes on the memory bus, potentially removing the need for the storage stack. However, next-generation SSDs are quickly catching up with performance that overlaps with PM, effectively turning the storage hierarchy into a storage jungle . It is unclear how future persistent indexes (and data structures in general) should be designed, and more importantly, how their performance/cost would change given PM’s unconventional installation requirements compared to SSDs. This paper takes a first step to revisit the overall system cost and performance characteristics of the storage jungle, in the context of persistent indexes. We do so by experimentally evaluating PM and SSD indexes under real-world hardware constraints. We find that although PM has its own set of advantages, traditional DRAM-SSD hierarchies continue to be more cost-effective, and there is much to be further unleashed. Through careful analysis, we distill a series of observations, implications, and outlook on future index designs to navigate through the storage jungle.
“Important enough to show the world”: Using Authentic Research Opportunities and Micropublications to Build Students’ Science Identities

Primarily undergraduate institutions (PUIs) often struggle to provide authentic research opportunities that culminate in peer-reviewed publications due to “recipe-driven” lab courses and the comprehensive body of work necessary for traditional scientific publication. However, the advent of short-form, single-figure “micropublications” has created novel opportunities for early-career scientists to make and publish authentic scientific contributions on a scale and in a timespan compatible with their training periods. The purpose of this qualitative case study is to explore the benefits accrued by eight undergraduate and master’s students who participated in authentic, small-scale research projects and disseminated their work as coauthors of peer-reviewed micropublications at a PUI. In these interviews, students reported that through the process of conducting and publishing their research, they developed specific competencies: reading scientific literature, proposing experiments, and collecting/interpreting publication-worthy data. Further, they reported this process enabled them to identify as contributing members of the greater scientific community.
AI Forensics: Did the Artificial Intelligence System Do It? Why?

In an increasingly autonomous manner AI systems make decisions impacting our daily life. Their actions might cause accidents, harm or, more generally, violate regulations -- either intentionally or not. Thus, AI systems might be considered suspects for various events. Therefore, it is essential to relate particular events to an AI, its owner and its creator. Given a multitude of AI systems from multiple manufactures, potentially, altered by their owner or changing through self-learning, this seems non-trivial. This paper discusses how to identify AI systems responsible for incidents as well as their motives that might be "malicious by design". In addition to a conceptualization, we conduct two case studies based on reinforcement learning and convolutional neural networks to illustrate our proposed methods and challenges. Our cases illustrate that "catching AI systems" seems often far from trivial and requires extensive expertise in machine learning. Legislative measures that enforce mandatory information to be collected during operation of AI systems as well as means to uniquely identify systems might facilitate the problem.
T OWARDS A SOFT FLUIDIC ELASTOMER TONGUE FOR A MECHANICAL VOCAL TRACT

: Most mechanical vocal tract models use rigid-bodied robotic components to represent soft articulators such as the tongue and the velum. However, such rigid articulators have limited capabilities to deform realistically during contact with the vocal tract walls, to generate ﬂow-induced vibrations for trill conso-nants, or to dampen the acoustic resonances of the vocal tract. Here we present the ﬁrst prototype of a soft ﬂuidic elastomer tongue based on the ideas of soft robotics. The tongue was designed as a soft silicone structure with three water-ﬁlled chambers for the anterior, middle, and posterior parts of the tongue. The tongue shape is controlled by the volumes of water in the three chambers. Integrated into a simpli-ﬁed vocal tract model, we explored the potential of this design to reproduce human tongue shapes for vowels, and synthesized the corresponding speech sounds using a vibrating reed source at the glottis. While it was possible to create plausible tongue shapes for the vowels /a, i, e, E/ , the vowels /o/ and /u/ could not be reproduced. The F1-F2 formant space of the synthesized sounds was considerably smaller than the human formant space. Consequently, follow-up designs of this type of tongue would beneﬁt from ﬁnite-element simulations to optimize the possible variations in shape.
The Anxiety Situation of Older People Living in Residential Care Facilities

Abstract Anxiety is one of the most common psychological problems in older people and older people staying in geriatric centers are more vulnerable. This study aims to explore Anxiety and associated factors of older people staying in care facilities in Nepal. This is a descriptive cross-sectional study. A total of 216 older people were recruited from geriatric centers of Kathmandu Valley, Nepal. Anxiety was assessed using Beck Anxiety Scale. Statistical software SPSS23.0 was used for data entry and analysis. The mean of Anxiety was 13.23±6.84. The prevalence of anxiety disorder in the study population was 8.8 %, where 5.6 % of respondents had mild and 3.2% had moderate Anxiety. Results show gender, marital status, religion, type of previous family, chronic illness, stress, and type of living facilities were statistically significantly associated with anxiety. The difference was statistically significant (p<0.05). Depression and anxiety were also significantly positively correlated (r=0.232, p< 0.01).
Local topography is more important than climate as a determinant of regional alpine plant diversity in southwestern British Columbia

Supervisory Committee Dr. Brian M. Starzomski, (School of Environmental Studies). Supervisor Dr. John P. Volpe, (School of Environmental Studies). Departmental Member Mountain ecosystems are considered highly sensitive to the impacts of climate change, and are experiencing a magnitude of change that far exceeds global averages, particularly with respect to increases in average temperature and precipitation. As such, scientists are predicting a rapid habitat reduction or even the loss of the coolest climatic alpine zones, thus threatening the continued survival of high elevation specialists. However, many of these ‘doomsday’ predictions are based primarily on models with coarse-resolution changes to atmospheric climate parameters, and do not take into account the potential buffering effects of other environmental gradients known to structure alpine plant communities, related to topography and soils. To assess the accuracy of predictions regarding the state of vulnerability of alpine plant communities to climate change, this thesis examined the relative importance of climate, topography and soils as determinants of regional alpine plant diversity for all species, as well as for forbs, graminoids and woody species separately, in alpine meadows of southwestern British Columbia. Through redundancy analyses and variation partitioning, results show that topography and soils are more important than climate as determinants of regional alpine plant diversity. Within these groups, elevation, slope, soil moisture and mean summer temperature were most
IEEE 802.11 AD HOC Networks: Protocols, Performance, and Open Issues

The aim of this chapter is triple: an in-depth investigation of the ad hoc features of the IEEE 802.11 standard; an analysis of the performance of 802.11-based ad hoc networks; and an investigation of the major problems arising when using the 802.11 technology for ad hoc networks, and possible directions for enhancing this technology for a better support of the ad hoc networking paradigm. We briefly describe the architecture and protocols of IEEE 802.11 WLANs and later introduce the terminology and present the concepts that are relevant throughout the chapter.
Confidence Intervals for the Coefficient Alpha Difference from Two Independent Samples (Groups)

Four different bootstrap methods for estimating conﬁdence intervals (CIs) for a coefﬁ-cient alpha difference from two independent samples (groups) were examined. These four CIs were compared to the most promising non-bootstrap CI alternatives in the literature. All CIs were assessed with a Monte Carlo simulation with conditions similar to previous research. The results indicate that there is a clear order in coverage performance of the CIs. The bootstrapped highest density interval had the best coverage performance across all simulation conditions. Yet, it was impacted by unequal sample sizes when one of the groups had the smallest sample size investigated of 50, or when items came from a compound symmetric correlation matrix with ρ = 0 . 64 . Regardless of the simulation condition, the percentile bootstrap is a good alternative as long as both group sample sizes were 200 or more.
A systematic review and meta-analysis of KRAS status as the determinant of response to anti-EGFR antibodies and the impact of partner chemotherapy in metastatic colorectal cancer

Background: In the setting of metastatic colorectal cancer (CRC), anti-EGFR antibodies are not currently recommended for individuals with KRAS mutant tumours. This is based on subgroup analyses of individual clinical trials rather than a formal synthesis of evidence for KRAS status as a predictive biomarker, while newer trials report no benefit for anti-EGFR antibodies irrespective of KRAS status. This study systematically reviewed the evidence for KRAS mutation status as a treatment effect modifier of response to anti-EGFR antibodies and the influence of partner chemotherapy. Methods: Medline (1966–2010), EMBASE and American and European oncology meeting abstracts were searched for randomised controlled trials reporting the influence of KRAS status on effectiveness of anti-EGFR antibodies in metastatic CRC. The treatment efficacy was summarised by KRAS status using hazard ratios (HR) for progression-free survival (PFS) and risk differences (RD) for objective response. For each study, a measure of effect modification was calculated, and aggregated using random effects meta-analysis to assess the interaction between KRAS and treatment effect. Findings: Eleven studies (8924 patients) were selected from 198 reports. Two studies assessed anti-EGFR antibodies as monotherapy and nine their use with chemotherapy. KRAS status was reported in 7555 cases. In subgroup analysis, the progression HR for KRAS wild patients assigned to anti-EGFR antibodies was 0.80 (4436 patients 95%CI: 0.64, 0.99) and for mutant cases 1.11 (3119 patients, 95%CI: 0.97, 1.27). A significant treatment effect interaction between KRAS status and addition of anti-EGFR antibodies to standard treatment was found for PFS (ratio of HRs 0.71, 95%CI: 0.57, 0.90 p = 0.005) and response rate difference (difference in RDs 15%, 95%CI: 8, 22%, p < 0.001). There was no evidence that the extent of effect modification differed between chemotherapeutic partners for both PFS (p = 0.3) and response rate (p = 0.6). Interpretation: KRAS mutation status is a treatment effect modifier for anti-EGFR antibodies in metastatic CRC. Further evidence is needed to determine whether this is true for all chemotherapy partners and all clinical circumstances. 2011 Elsevier Ltd. All rights reserved. er Ltd. All rights reserved. fax: +61 293828885. Ward). 1344 E U R O P E A N J O U R N A L O F C A N C E R 4 7 ( 2 0 1 1 ) 1 3 4 3 – 1 3 5 4
Working Beyond Retirement Age: A Systematic Review

Introduction: Population ageing brings along various crucial implications, with working beyond retirement age is one of the economics implications of ageing. Realizing the increasing demand and concern to accommodate older adults into the workforce, this review was conducted to develop better understanding on the factors associated with post-retirement employment among older adults aged 50 years and older. Methods: Using Scopus, ScienceDirect and PubMed databases, related articles between January 2017 and June 2021 were thoroughly searched using combination of keywords and screened according to the predetermined eligibility criteria. Post-retirement employment was defined as employment of older adults aged 50 years old and above beyond retirement age or re-employment of retired older adults, either from compulsory or voluntary retirement. All observational, qualitative, mixed methods and experimental studies were included in the screening process. The Crowe Critical Appraisal Tool (CCAT) was used to assess the quality of included articles. Results: A total of 12 articles included for review, with seven articles rated as high-quality. The review had successfully identified 10 factors associated with working beyond retirement age among older adults. Having good health status and being male gender were the commonest factors influencing the decision to work beyond retirement age, followed by level of education, financial commitment/ reasons, and work characteristics. Conclusion: The findings of this review provide a crucial insight and foundation towards addressing the unique needs of older workers in the employment policy.
Performance Enhancement of a Low-Pressure Ratio Centrifugal Compressor Stage with a Rotating Vaneless Diffuser by Impeller Disk Extended Shrouds

Numerical simulations have been carried out to examine the performance and flow parameters of forced rotating vaneless diffuser obtained by the extension of impeller disks of a low-pressure ratio shrouded type centrifugal compressor stage with diffuser diameter ratio 1.40. Four different levels of shroud extensions (i.e., impeller disks alone) forming the rotating vaneless diffusers are analyzed at four different flow coefficients. The extension of impeller disks alone by 40% of impeller exit diameter leads to a fully forced rotating vaneless diffuser thereby replacing the existing stationary vaneless diffuser. The comparative studies are performed using the same impeller with a stationary vaneless diffuser also having a diffuser diameter ratio of 1.40. Static pressure rise in ES40 is found to be higher than SVD by around 9.84% at design flow coefficient and also at above off-design flow rates. Energy coefficient is highest for ES40, followed by ES30 compared to SVD. For ES40, the static pressure recovery coefficient also is higher compared to SVD. The efficiency of ES40 is lesser by around 5.40% to 3.43% compared to SVD, at design as well as at above off-design flow coefficients. The stagnation pressure losses for ES40 drastically reduced compared to SVD. The comparison of stagnation pressure contours and absolute velocity contours near the hub and shroud walls of ES40 and SVD configurations shows that the rotating diffuser walls as in ES40 causes further addition of energy to the fluid. This adds up the kinetic energy level of the fluid which due to better diffusion, results in gain of static pressure rise. Moreover, there is a net increase in stagnation pressure distribution at the exit of diffuser due to rotating vaneless diffuser. Also, the presence of a fully rotating vaneless diffuser (ES40) smooth out the distorted entry flow profiles, thereby improving the performance of the centrifugal compressor stage.