Miracle-dz/UniFAR-FTUs huggingface dataset:
In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL

Combining synthetic biology with adoptive T-cell transfer has led to promising advances in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Chimeric antigen receptors (CARs) are synthetic receptors that redirect T-cell specificity against cancer. CARs include “built-in” signaling domains that reprogram T-cell metabolism, enhance effector function, and support long-term persistence. Despite their success in blood-based malignancies, relapse can occur in CD19-redirected CAR T-cell therapies for several reasons, including poor engraftment, impaired in vivo proliferation, and T-cell senescence. Herein, we explain how subtle alterations in CAR design may overcome barriers to effective adoptive immunotherapy. We also discuss how the physiochemical properties of the single-chain variable fragment (scFv) affect differentiation and persistence. Moreover, we describe innovative advances in CAR engineering and provide insight into the development of humanized scFvs whose proposed benefits include increased persistence and improved clinical outcomes. Tumor cells can evade CAR T-cell–mediated detection and elimination due to the emergence or presence of CD19-negative leukemic cell subpopulations. We also discuss the opportunities and challenges in targeting other B-ALL–associated antigens. Identifying alternate targets is fundamentally necessary to restore the success of CAR T-cell therapies in CD19-negative patients with B-ALL.
Validity and reliability of the Spanish version of the “Wijma Delivery Expectancy/Experience Questionnaire” (W-DEQ-B)

The Wijma Delivery Expectancy/Experience Questionnaire (W-DEQ-B) is an instrument that allows the experiences around fear of childbirth to be examined after the birth. It is currently the most widely used to measure different aspects related to the fear of childbirth and enables healthcare and additional assistance to women after birth to be adapted according to their needs. The objective of this study was to translate the W-DEQ-B into Spanish and analyse its reliability and validity. The study was carried out in two phases: (1) transcultural adaption of the questionnaire to Spanish and (2) a transversal study in a sample of 190 postpartum women from Sexual and Reproductive Health Clinics in the province of Barcelona (Spain). The psychometric properties were examined in terms of reliability (internal consistency and temporal stability) and construct validity (confirmatory factorial analysis [CFA] and exploratory factorial analysis [EFA]). The results of the CFA did not confirm unidimensionality of the W-DEQ-B questionnaire. The EFA suggested four very similar, but not identical, dimensions to those obtained in other studies in which the W-DEQ-B has been evaluated. Both the Cronbach’s alpha and the omega coefficient were adequate for the total questionnaire and for each of the four dimensions. The results of this study confirm that the W-DEQ-B is multi-dimensional. In the Spanish version of the W-DEQ-B-Sp four dimensions have been identified that allow the experiences around fear of childbirth to be examined after the birth. The Spanish version of the WDEQ-B (WDEQ-B-Sp) is reliable and valid for the measurement of fear of childbirth in clinical practice and for use in future research.
Ovarian Hyperandrogenism and Response to Gonadotropin-releasing Hormone Analogues in Primary Severe Insulin Resistance

Abstract Context Insulin resistance (IR) is associated with polycystic ovaries and hyperandrogenism, but underpinning mechanisms are poorly understood and therapeutic options are limited. Objective To characterize hyperandrogenemia and ovarian pathology in primary severe IR (SIR), using IR of defined molecular etiology to interrogate disease mechanism. To extend evaluation of gonadotropin-releasing hormone (GnRH) analogue therapy in SIR. Methods Retrospective case note review in 2 SIR national referral centers. Female patients with SIR with documented serum total testosterone (TT) concentration. Results Among 185 patients with lipodystrophy, 65 with primary insulin signaling disorders, and 29 with idiopathic SIR, serum TT ranged from undetectable to 1562 ng/dL (54.2 nmol/L; median 40.3 ng/dL [1.40 nmol/L]; n = 279) and free testosterone (FT) from undetectable to 18.0 ng/dL (0.625 nmol/L; median 0.705 ng/dL [0.0244 nmol/L]; n = 233). Higher TT but not FT in the insulin signaling subgroup was attributable to higher serum sex hormone–binding globulin (SHBG) concentration. Insulin correlated positively with SHBG in the insulin signaling subgroup, but negatively in lipodystrophy. In 8/9 patients with available ovarian tissue, histology was consistent with polycystic ovary syndrome (PCOS). In 6/6 patients treated with GnRH analogue therapy, gonadotropin suppression improved hyperandrogenic symptoms and reduced serum TT irrespective of SIR etiology. Conclusion SIR causes severe hyperandrogenemia and PCOS-like ovarian changes whether due to proximal insulin signaling or adipose development defects. A distinct relationship between IR and FT between the groups is mediated by SHBG. GnRH analogues are beneficial in a range of SIR subphenotypes.
5-Aminolevulinic acid improves chicken sperm motility

Objective This study investigated the effects of 5-aminolevulinic acid (5-ALA) on the motility parameters, mitochondrial membrane depolarization, and ATP levels in chicken sperm. Methods The pooled semen from Barred Plymouth Rock males was used. In the first experiment, the semen was diluted 4-times with phosphate-buffered saline (PBS (−)) containing various concentrations (0, 0.01, 0.05, and 0.1 mM) of 5-ALA, and then the sperm motility parameters after incubation were evaluated by computer-assisted sperm analysis (CASA). In the second experiment, the semen was diluted 4-times with PBS (−) containing 0.05 mM 5-ALA, and then sperm mitochondrial membrane depolarization and ATP levels after 1.5 h of incubation were analyzed with the MitoPT® JC-1 Assay and ATP Assay kits, respectively. In the third experiment, the semen was removed from the seminal plasma and resuspended with the mediums of PBS (−), PBS (−) supplemented with CaCl2 and MgCl2 (PBS (+)) + 5-ALA, PBS (+) + caffeine, and PBS (+) + caffeine + 5-ALA. Then, the sperm motility parameters after incubation were evaluated by CASA. In the last experiment, the semen was treated with the mediums of PBS (−), PBS (−) + 5-ALA, 5.7% glucose, 5.7% glucose + 5-ALA after removing the seminal plasma, and then the sperm motility parameters were evaluated by CASA. Results The addition of 0.05 mM 5-ALA significantly increased the chicken sperm motility, progressive motility, linearity, average path velocity, curvilinear velocity, straight-line velocity, and the wobble. The sperm mitochondrial membrane depolarization was also increased by the 5-ALA treatment. The 5-ALA treatment decreased the sperm ATP levels. Both the caffeine treatment and glucose treatment decreased the sperm motility during incubation period. Conclusion 5-ALA might increase sperm mitochondrial membrane depolarization to utilize the ATP for enhancing sperm movement.
Quantitative Magnetic Resonance-Derived Biomarkers as Predictors of Function and Histotype in Adenohypophyseal Tumours

Introduction: Magnetic resonance imaging (MRI) is the main modality to diagnose adenohypophyseal tumours, while biochemical assessment of pituitary hormones allows for their functional classification. In this retrospective exploratory cohort study, we investigated if quantitative differences in tumour MR signal intensity (SI) could be utilized to predict the function and histotype. Methods: Clinically acquired pretreatment MRI images were retrospectively analysed in 67 clinically non-functioning gonadotropinomas (NFG), 38 somatotropinomas, and 16 medically treated giant macroprolactinomas. Mean T1- and T2-weighted SI values were determined for each tumour and normalized against either centrum semiovale white matter or CSF to derive relative T1W and T2W SI values and the relative tumour T2/T1 SI ratio. Inter-group differences in quantitative MR parameters were compared, and the power of each parameter to discriminate tumour type and subtype was assessed using the area under the receiver operator characteristic curve (AUROC). In resected somatotropinomas, the relationship between tumour granulation status, relative MR SI values, and biochemical data was also compared. Results: Compared to somatotropinomas, NFG and macroprolactinomas displayed higher relative T2W SI (p < 0.001) and higher relative tumour T2/T1 SI ratio values (p < 0.001, ANOVA). Compared to intermediate/densely granulated tumours, sparsely granulated somatotropinomas were larger (p = 0.006, Mann-Whitney U test), had higher relative T2W SI (p ≤ 0.005), and higher relative tumour T2/T1 SI ratios (p ≤ 0.001, 2-tailed t test). Relative tumour T2W SI values and relative tumour T2/T1 ratio values demonstrated good discriminatory power in differentiating NFG from somatotropinoma (AUROC = 0.87–0.94) and predicting somatotropinoma subtypes (AUROC = 0.87–0.95). Conclusion: Quantitative SI-based MR parameters derived using clinical acquisition MRI protocols may help non-invasively discriminate the functional status of adenohypophyseal tumours and the histological subtype of somatotropinomas.
MRI-based quantification of ophthalmic changes in healthy volunteers during acute 15° head-down tilt as an analogue to microgravity

Spaceflight is known to cause ophthalmic changes in a condition known as spaceflight-associated neuro-ocular syndrome (SANS). It is hypothesized that SANS is caused by cephalad fluid shifts and potentially mild elevation of intracranial pressure (ICP) in microgravity. Head-down tilt (HDT) studies are a ground-based spaceflight analogue to create cephalad fluid shifts. Here, we developed non-invasive magnetic resonance imaging (MRI)-based techniques to quantify ophthalmic structural changes under acute 15° HDT. We specifically quantified: (i) change in optic nerve sheath (ONS) and optic nerve (ON) cross-sectional area, (ii) change in ON deviation, an indicator of ON tortuosity, (iii) change in vitreous chamber depth, and (iv) an estimated ONS Young's modulus. Under acute HDT, ONS cross-sectional area increased by 4.04 mm2 (95% CI 2.88–5.21 mm2, p < 0. 000), while ON cross-sectional area remained nearly unchanged (95% CI −0.12 to 0.43 mm2, p = 0.271). ON deviation increased under HDT by 0.20 mm (95% CI 0.08–0.33 mm, p = 0.002). Vitreous chamber depth decreased under HDT by −0.11 mm (95% CI −0.21 to −0.03 mm, p = 0.009). ONS Young's modulus was estimated to be 85.0 kPa. We observed a significant effect of sex and BMI on ONS parameters, of interest since they are known risk factors for idiopathic intracranial hypertension. The tools developed herein will be useful for future analyses of ON changes in various conditions.
A novel capsule-based smell test fabricated via coaxial dripping

In this paper, we demonstrate that aromatic oil capsules, produced by dripping droplets, can offer a simple, yet effective, testing tool to aid in the diagnosis of various diseases, in which the loss of smell is a key symptom. These include chronic neurological conditions such as Parkinson's and Alzheimer's diseases, and acute respiratory infections such as that caused by COVID-19. The capsules were fabricated by concentrically dripping oil/alginate droplets, from a coaxial nozzle, into an oppositely charged ionic liquid. This fabrication technique enables full control over the capsule size, the shell thickness and the volume of the encapsulated oil. After formation, liquid capsules were left to dry and form a solid crust surrounding the oil. The prototype test consists of placing a standardized number of capsules between adhesive strips that users crush and pull apart to release the smell. In addition to the fabrication method, a simple mathematical model was developed to predict the volume of encapsulated oil within the capsule in terms of the flow rate ratio and the nozzle size. Tensile tests show that capsule strength is inversely proportional to its size owing to an increase in the shell thickness. By increasing the alginate concentration, the load required to rupture the capsule increases, to the point where capsules are too stiff to be broken by a fingertip grip. Results from a preliminary screening test, within a group of patients with Parkinson's disease, found that smells were detectable using a ‘forced choice’ paradigm.
Habitat loss on the breeding grounds is a major contributor to population declines in a long-distance migratory songbird

Many migratory species are declining and for most, the proximate causes of their declines remain unknown. For many long-distance Neotropical migratory songbirds, it is assumed that habitat loss on breeding or non-breeding grounds is a primary driver of population declines. We integrated data collected from tracking technology, community science and remote sensing data to quantify migratory connectivity (MC), population trends and habitat loss. We quantified the correlation between forest change throughout the annual cycle and population declines of a long-distance migratory songbird, the Connecticut warbler (Oporornis agilis, observed decline: −8.99% yr−1). MC, the geographic link between populations during two or more phases of the annual cycle, was stronger between breeding and autumn migration routes (MC = 0.24 ± 0.23) than between breeding and non-breeding locations (MC = −0.2 ± 0.14). Different Connecticut warbler populations tended to have population-specific fall migration routes but overlapped almost completely within the northern Gran Chaco ecoregion in South America. Cumulative forest loss within 50 km of breeding locations and the resulting decline in the largest forested patch index was correlated more strongly with population declines than forest loss on migratory stopover regions or on wintering locations in South America, suggesting that habitat loss during the breeding season is a driver of observed population declines for the Connecticut warbler. Land-use practices that retain large, forested patches within landscapes will likely benefit breeding populations of this declining songbird, but further research is needed to help inform land-use practices across the full annual cycle to minimize the impacts to migratory songbirds and abate ongoing population declines.
Inclusive data visualization for people with disabilities

driven communication by business, government, and science. Furthermore, the use and need for visualizations is not just confined to data experts: Data visualizations are becoming ubiquitous in textbooks, presentations, and reports, as well as in popular media, both online and in print. The design of these visualizations, however, is premised on implicit assumptions about the reader's sensory, cognitive, and motor abilities. People without these abilities are ultimately disenfranchised, and access to the benefits of data visualization and to the underlying information is limited. Data visualizations, such as statistical charts, diagrams, and maps, are an effective means to represent, analyze, and explore data as well as identify and communicate insights. They take advantage of the human visual system’s high bandwidth, parallel processing, and ability to quickly recognize patterns. For instance, a table of numbers may be hard to understand, while those same numbers shown in a graphic form (such as a line chart) will immediately reveal a steadily increasing trend. For these reasons, interactive data visualization is central to both exploratory data analysis and dataD Insights → Lack of accessible access to data visualizations is a significant equity issue. → It's not only visual impairments that can restrict access but also other kinds of disabilities including cognitive and learning disabilities, and motor disabilities. → Overcoming this challenge requires visualization practitioners, visualization and accessibility researchers, and the relevant disability communities to work together.
Antiviral Resistance and Phage Counter Adaptation to Antibiotic-Resistant Extraintestinal Pathogenic Escherichia coli

Extraintestinal pathogenic Escherichia coli (ExPEC), often multidrug resistant (MDR), is a leading cause of urinary tract and systemic infections. The crisis of emergent MDR pathogens has led some to propose bacteriophages as a therapeutic. ABSTRACT Extraintestinal pathogenic Escherichia coli (ExPEC), often multidrug resistant (MDR), is a leading cause of urinary tract and systemic infections. The crisis of emergent MDR pathogens has led some to propose bacteriophages as a therapeutic. However, bacterial resistance to phage is a concerning issue that threatens to undermine phage therapy. Here, we demonstrate that E. coli sequence type 131, a circulating pandemic strain of ExPEC, rapidly develops resistance to a well-studied and therapeutically active phage (ϕHP3). Whole-genome sequencing of the resisters revealed truncations in genes involved in lipopolysaccharide (LPS) biosynthesis, the outer membrane transporter ompA, or both, implicating them as phage receptors. We found ExPEC resistance to phage is associated with a loss of fitness in host microenvironments and attenuation in a murine model of systemic infection. Furthermore, we constructed a novel phage-bacterium bioreactor to generate an evolved phage isolate with restored infectivity to all LPS-truncated ExPEC resisters. This study suggests that although the resistance of pandemic E. coli to phage is frequent, it is associated with attenuation of virulence and susceptibility to new phage variants that arise by directed evolution. IMPORTANCE In response to the rising crisis of antimicrobial resistance, bacteriophage (phage) therapy has gained traction. In the United States, there have been over 10 cases of largely successful compassionate-use phage therapy to date. The resilience of pathogens allowing their broad antibiotic resistance means we must also consider resistance to therapeutic phages. This work fills gaps in knowledge regarding development of phage resisters in a model of infection and finds critical fitness losses in those resisters. We also found that the phage was able to rapidly readapt to these resisters.
ColdZyme Maintains Integrity in SARS-CoV-2-Infected Airway Epithelia

Although our understanding of COVID-19 continuously progresses, essential questions regarding prophylaxis and treatment remain open. A hallmark of severe SARS-CoV-2 infection is a hitherto-undescribed mechanism leading to excessive inflammation and tissue destruction associated with enhanced pathogenicity and mortality. ABSTRACT SARS-CoV-2 infection causing the COVID-19 pandemic calls for immediate interventions to avoid viral transmission, disease progression, and subsequent excessive inflammation and tissue destruction. Primary normal human bronchial epithelial cells are among the first targets of SARS-CoV-2 infection. Here, we show that ColdZyme medical device mouth spray efficiently protected against virus entry, excessive inflammation, and tissue damage. Applying ColdZyme to fully differentiated, polarized human epithelium cultured at an air-liquid interphase (ALI) completely blocked binding of SARS-CoV-2 and increased local complement activation mediated by the virus as well as productive infection of the tissue model. While SARS-CoV-2 infection resulted in exaggerated intracellular complement activation immediately following infection and a drop in transepithelial resistance, these parameters were bypassed by single pretreatment of the tissues with ColdZyme mouth spray. Crucially, our study highlights the importance of testing already evaluated and safe drugs such as ColdZyme mouth spray for maintaining epithelial integrity and hindering SARS-CoV-2 entry within standardized three-dimensional (3D) in vitro models mimicking the in vivo human airway epithelium. IMPORTANCE Although our understanding of COVID-19 continuously progresses, essential questions regarding prophylaxis and treatment remain open. A hallmark of severe SARS-CoV-2 infection is a hitherto-undescribed mechanism leading to excessive inflammation and tissue destruction associated with enhanced pathogenicity and mortality. To tackle the problem at the source, transfer of SARS-CoV-2, subsequent binding, infection, and inflammatory responses have to be avoided. In this study, we used fully differentiated, mucus-producing, and ciliated human airway epithelial cultures to test the efficacy of ColdZyme medical device mouth spray in terms of protection from SARS-CoV-2 infection. Importantly, we found that pretreatment of the in vitro airway cultures using ColdZyme mouth spray resulted in significantly shielding the epithelial integrity, hindering virus binding and infection, and blocking excessive intrinsic complement activation within the airway cultures. Our in vitro data suggest that ColdZyme mouth spray may have an impact in prevention of COVID-19.
Plural marking in the second language: Atomicity, definiteness, and transfer

Abstract This paper examines whether second language (L2)-English learners whose native languages (L1; Korean and Mandarin) lack obligatory plural marking transfer the properties of plural marking from their L1s, and whether transfer is manifested both offline (in a grammaticality judgment task) and online (in a self-paced reading task). The online task tests the predictions of the morphological congruency hypothesis (Jiang 2007), according to which L2 learners have particular difficulty automatically activating the meaning of L2 morphemes that are incongruent with their L1. Experiment 1 tests L2 learners’ sensitivity to errors of –s oversuppliance with mass nouns, while Experiment 2 tests their sensitivity to errors of –s omission with count nouns. The findings show that (a) L2 learners detect errors with nonatomic mass nouns (sunlights) but not atomic ones (furnitures), both offline and online; and (b) L1-Korean L2-English learners are more successful than L1-Mandarin L2-English learners in detecting missing –s with definite plurals (these boat), while the two groups behave similarly with indefinite plurals (many boat). Given that definite plurals require plural marking in Korean but not in Mandarin, the second finding is consistent with L1-transfer. Overall, the findings show that learners are able to overcome morphological incongruency and acquire novel uses of L2 morphemes.
Grammatical performance in children with dyslexia: the contributions of individual differences in phonological memory and statistical learning

Abstract Several studies have signaled grammatical difficulties in individuals with developmental dyslexia. These difficulties may stem from a phonological deficit, but may alternatively be explained through a domain-general deficit in statistical learning. This study investigates grammar in children with and without dyslexia, and whether phonological memory and/or statistical learning ability contribute to individual differences in grammatical performance. We administered the CELF “word structure” and “recalling sentences” subtests and measures of phonological memory (digit span, nonword repetition) and statistical learning (serial reaction time, nonadjacent dependency learning) among 8- to 11-year-old children with and without dyslexia (N = 50 per group). Consistent with previous findings, our results show subtle difficulties in grammar, as children with dyslexia achieved lower scores on the CELF (word structure: p = .0027, recalling sentences: p = .053). While the two phonological memory measures were found to contribute to individual differences in grammatical performance, no evidence for a relationship with statistical learning was found. An error analysis revealed errors in irregular morphology (e.g., plural and past tense), suggesting problems with lexical retrieval. These findings are discussed in light of theoretical accounts of the underlying deficit in dyslexia.