Miracle-dz/UniFAR-FTUs huggingface dataset:
SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models

SynNotch CAR circuits targeting specific solid tumor antigens enhance specificity and improve therapeutic efficacy by regulating T cell exhaustion. Short circuiting solid tumors Two major hurdles in chimeric antigen receptor (CAR) T cell therapy for solid tumors are ensuring specificity to tumor cells without affecting healthy cells and avoiding tumor escape due to antigen loss. To address these challenges, Hyrenius-Wittsten et al. and Choe et al. developed synthetic Notch (synNotch)–CAR T cells targeting solid tumor antigens and used them to treat mouse models of mesothelioma, ovarian cancer, and glioblastoma. In both studies, the authors demonstrated that synNotch-CAR T cells were better at controlling tumors than traditional CAR T cells and did not result in toxicity or damage to healthy tissue. These results suggest that synNotch-CAR T cells may be an effective treatment strategy for solid tumors. The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening “on-target/off-tumor” toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic T cells with synthetic Notch (synNotch) CAR circuits. We identify alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma and ovarian cancer. ALPPL2 can act as a sole target for CAR therapy or be combined with tumor-associated antigens such as melanoma cell adhesion molecule (MCAM), mesothelin, or human epidermal growth factor receptor 2 (HER2) in synNotch CAR combinatorial antigen circuits. SynNotch CAR T cells display superior control of tumor burden when compared to T cells constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer. This was achieved by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable cell therapy target for multiple solid tumors and demonstrate the multifaceted therapeutic benefits of synNotch CAR T cells.
Voxelated three-dimensional miniature magnetic soft machines via multimaterial heterogeneous assembly

Complex 3D miniature wireless soft machines for biomedical applications were fabricated with a 3D heterogeneous integration approach. Small-scale soft-bodied machines that respond to externally applied magnetic field have attracted wide research interest because of their unique capabilities and promising potential in a variety of fields, especially for biomedical applications. When the size of such machines approach the sub-millimeter scale, their designs and functionalities are severely constrained by the available fabrication methods, which only work with limited materials, geometries, and magnetization profiles. To free such constraints, here, we propose a bottom-up assembly-based 3D microfabrication approach to create complex 3D miniature wireless magnetic soft machines at the milli- and sub-millimeter scale with arbitrary multimaterial compositions, arbitrary 3D geometries, and arbitrary programmable 3D magnetization profiles at high spatial resolution. This approach helps us concurrently realize diverse characteristics on the machines, including programmable shape morphing, negative Poisson’s ratio, complex stiffness distribution, directional joint bending, and remagnetization for shape reconfiguration. It enlarges the design space and enables biomedical device-related functionalities that are previously difficult to achieve, including peristaltic pumping of biological fluids and transport of solid objects, active targeted cargo transport and delivery, liquid biopsy, and reversible surface anchoring in tortuous tubular environments withstanding fluid flows, all at the sub-millimeter scale. This work improves the achievable complexity of 3D magnetic soft machines and boosts their future capabilities for applications in robotics and biomedical engineering.
SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma

SynNotch-CAR T cells durably clear glioblastoma xenografts, overcoming dual challenges of antigen heterogeneity and specificity common to solid tumors. Short circuiting solid tumors Two major hurdles in chimeric antigen receptor (CAR) T cell therapy for solid tumors are ensuring specificity to tumor cells without affecting healthy cells and avoiding tumor escape due to antigen loss. To address these challenges, Hyrenius-Wittsten et al. and Choe et al. developed synthetic notch (synNotch)–CAR T cells targeting solid tumor antigens and used them to treat mouse models of mesothelioma, ovarian cancer, and glioblastoma. In both studies, the authors demonstrated that synNotch-CAR T cells were better at controlling tumors than traditional CAR T cells and did not result in toxicity or damage to healthy tissue. These results suggest that synNotch-CAR T cells may be an effective treatment strategy for solid tumors. Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack of ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show that multi-antigen prime-and-kill recognition circuits provide flexibility and precision to overcome these challenges in the context of glioblastoma. A synNotch receptor that recognizes a specific priming antigen, such as the heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor receptor splice variant III (EGFRvIII) or the central nervous system (CNS) tissue-specific antigen myelin oligodendrocyte glycoprotein (MOG), can be used to locally induce expression of a CAR. This enables thorough but controlled tumor cell killing by targeting antigens that are homogeneous but not absolutely tumor specific. Moreover, synNotch-regulated CAR expression averts tonic signaling and exhaustion, maintaining a higher fraction of the T cells in a naïve/stem cell memory state. In immunodeficient mice bearing intracerebral patient-derived xenografts (PDXs) with heterogeneous expression of EGFRvIII, a single intravenous infusion of EGFRvIII synNotch-CAR T cells demonstrated higher antitumor efficacy and T cell durability than conventional constitutively expressed CAR T cells, without off-tumor killing. T cells transduced with a synNotch-CAR circuit primed by the CNS-specific antigen MOG also exhibited precise and potent control of intracerebral PDX without evidence of priming outside of the brain. In summary, by using circuits that integrate recognition of multiple imperfect but complementary antigens, we improve the specificity, completeness, and persistence of T cells directed against glioblastoma, providing a general recognition strategy applicable to other solid tumors.
Examining Racial Discrimination’s Association With Depressive Symptoms Through Metadehumanization Among African Americans: Does Racial Identity Matter?

Though considerable empirical work has documented the ways in which African Americans are dehumanized by other racial groups, there is no research examining how perceiving dehumanization (i.e., metadehumanization) is associated with the mental health of African Americans. In this study, we examined the indirect effect of racial discrimination on depressive symptoms through metadehumanization and explored whether this indirect effect was contingent on racial identity (i.e., centrality, private regard). African American students completed measures in a university lab located in the Midwestern region of the United States (N = 326; Mage = 19.7, 72.4% women). We found that the degree to which racial discrimination was indirectly associated with depressive symptoms through metadehumanization was contingent on racial identity dimensions. Specifically, the indirect effect of racial discrimination on depressive symptoms through metadehumanization was only significant for individuals who were relatively higher on centrality and private regard. This research suggests that the role of metadehumanization is stronger among African Americans who strongly identify with and have positive views of their racial group. We discuss these results in the context of social cognitive theories.
A Large-Scale Analysis of the Semantic Password Model and Linguistic Patterns in Passwords

In this article, we present a thorough evaluation of semantic password grammars. We report multifactorial experiments that test the impact of sample size, probability smoothing, and linguistic information on password cracking. The semantic grammars are compared with state-of-the-art probabilistic context-free grammar (PCFG) and neural network models, and tested in cross-validation and A vs. B scenarios. We present results that reveal the contributions of part-of-speech (syntactic) and semantic patterns, and suggest that the former are more consequential to the security of passwords. Our results show that in many cases PCFGs are still competitive models compared to their latest neural network counterparts. In addition, we show that there is little performance gain in training PCFGs with more than 1 million passwords. We present qualitative analyses of four password leaks (Mate1, 000webhost, Comcast, and RockYou) based on trained semantic grammars, and derive graphical models that capture high-level dependencies between token classes. Finally, we confirm the similarity inferences from our qualitative analysis by examining the effectiveness of grammars trained and tested on all pairs of leaks.
Privacy Maintenance in Self-Digitization

Individuals are increasingly using personal Internet of Things (IoT) devices that digitize their day-to-day lives. Those devices, however, often require substantial personal information to generate their intended benefits. For example, fitness technologies collect health, sleep, personal, and a vast array of other information ubiquitously, creating possible privacy issues for the users when fitness technology platform providers store or share their information, whether users know this or not. To explore the role of privacy perceptions in the context of continued use of fitness technologies, this study collected data from 212 fitness tracker users. We find empirical support for the importance of privacy perceptions in a user's intention to continue to use their fitness tracker. More specifically, consistent with privacy calculus research, privacy concern is negatively related to willingness to disclose information while perceived benefit is positively related to it. As an extension to calculus variables, users' expectations towards the data sharing practices of organizations also influences their willingness to disclose information. Importantly, willingness to disclose information has a direct effect on continued use intentions but also moderates the relationship between perceived benefit and users' intentions to continue using a fitness tracker. We discuss the implications of these findings for research and practice.
Stabilizing nickel-rich layered cathode materials by a high-charge cation doping strategy: zirconium-doped LiNi0.6Co0.2Mn0.2O2

Ni-rich layered lithiated transition metal oxides Li[NixCoyMnz]O2 (x + y + z = 1) are the most promising materials for positive electrodes for advanced Li-ion batteries. However, one of the drawbacks of these materials is their low intrinsic stability during prolonged cycling. In this work, we present lattice doping as a strategy to improve the structural stability and voltage fade on prolonged cycling of LiNi0.6Co0. 2Mn0.2O2 (NCM-622) doped with zirconium (+4). It was found that LiNi0.56Zr0. 04Co0.2Mn0.2O2 is stable upon galvanostatic cycling, in contrast to the undoped material, which undergoes partial structural layered-to-spinel transformation during cycling. The current study provides sub-nanoscale insight into the role of Zr4+ doping on such a transformation in Ni-rich Li[NixCoyMnz]O2 materials by adopting a combined experimental and first-principles theory approach. A possible mechanism for a Ni-mediated layered-to-spinel transformation in Ni-rich NCMs is also proposed.
Memory stem T cells modified with a redesigned CD30‐chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma

Adoptive cell therapy (ACT) with mature T cells modified with a chimeric antigen receptor has demonstrated improved outcome for B‐cell malignancies. However, its application for others such as Hodgkin lymphoma remains a clinical challenge. CD30 antigen, expressed in Hodgkin lymphoma cells, is absent in most healthy tissues, representing an ideal target of ACT for this disease. Despite that, efficacy of CD30‐chimeric antigen receptor (CAR) T cells for Hodgkin lymphoma remains modest. Here, we have developed and tested a novel CD30‐CAR T to improve efficacy of CD30‐CAR therapy, using a targeting epitope within the non‐cleavable part of CD30 receptor, and memory stem T cells (TSCM) to improve engraftment, persistence and antitumor activity.
Categorisation of patients based on immune profiles: a new approach to identifying candidates for response to checkpoint inhibitors

Inhibitors to the checkpoint proteins cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) and programmed cell death protein 1 (PD‐1) are becoming widely used in cancer treatment. However, a lack of understanding of the patient response to treatment limits accurate identification of potential responders to immunotherapy.
Acute Effects of Resistance Training with Blood Flow Restriction on Achilles Tendon Thickness

Abstract The Achilles tendon is one of the strongest and thickest tendons of the human body. Several studies have reported an immediate decrease in Achilles tendon thickness after a single bout of resistance training. However, the effects of blood flow restriction training on Achilles tendon thickness have not been investigated. The purpose of this study was to investigate the acute effects of different regimens of resistance training on Achilles tendon thickness. Fiftytwo participants (27.3 ± 7 years; 177.6 ± 11 cm; 72.2 ± 13.7 kg) were randomly allocated into one of the three groups: low-intensity exercise without (LI, n = 13) and with blood flow restriction (LI-BFR, n = 24), and high-intensity exercise (HI, n = 15). Participants from LI and LI-BFR groups performed four sets (1 x 30 + 3 x 15 reps) at 30% 1RM, while the HI group performed four sets (1 x 30 with 30% 1RM + 3 x 10 reps with 75% 1RM). All groups performed a plantar flexion exercise. For the LI-BFR group, a blood pressure cuff was placed on the dominant calf and inflated at 30% of the individual´s occlusion pressure (47.6 ± 19.8 mmHg). Sonographic images of Achilles tendon thickness were taken at pre, immediately after, 60 min and 24 h following acute bouts of exercise. Achilles tendon thickness was significantly reduced immediately after, 60 min and 24 h post-LI-BFR exercise (pre: 4.4 ± 0.4 mm vs. IA: 3.8 ± 0.4 mm vs. 60 min: 3.7 ± 0.3 mm vs. 24 h: 4.1 ± 0.3 mm; p < 0.001), whereas Achilles tendon thickness was unchanged for HI and LI groups (p > 0.05). These results suggest that blood flow restriction training may be an effective strategy to stimulate a positive response in Achilles tendon thickness.
Post-Activation Potentiation in Strength Training: A Systematic Review of the Scientific Literature

Abstract This review aimed to determine the ideal combination of post activation potentiation (PAP) strategies for an improved strength performance. After analysing 202 articles, 15 studies met the inclusion criteria. The findings of this review suggest that a potentiation effect exists as long as a minimum intensity and enough rest are provided. Although intensities of 65% 1RM are sufficient to elicit a potentiation effect, higher effects can be achieved with 85 - 90% 1RM intensities. Similarly, we found that experienced athletes will benefit more from a higher volume bout (1-3 sets), as long as 7-8 minutes of rest are allowed to avoid fatigue.
The Second‐to‐Fourth Digit (2D:4D) Ratio of Male Combat Athletes is Associated with the Choice of Sport

Abstract The second-to-fourth-digit (2D:4D) ratio has been widely used as a putative marker of prenatal exposure to testosterone in health, behavioral and sport sciences, but it has only been used few times regarding combat athletes. This study involved 200 male elite combat athletes (Olympic wrestling, kickboxing, judo, taekwondo and karate) and 179 males not participating in any sports. The lengths of the index finger (2D) and ring (4D) finger were measured using computer-assisted image analysis (AutoMetric 2.2 software). The 2D:4D ratio of combat athletes was significantly lower than that of the controls. Moreover, a lower 2D:4D ratio was found among wrestlers, judo athletes and kickboxers than in the control group, and a higher 2D:4D ratio was found, but with borderline significance, among karate and taekwondo athletes. Moreover, multivariate analysis adjusted for age showed that judo, Olympic wrestling and kickboxing athletes combined had 2D:4D ratios significantly lower (by 0.035 on average) than those of the rest of the subjects and that karate and taekwondo athletes together had 2D:4D ratios significantly higher (by 0.014 on average) than those of the rest of the subjects. The research results and literature review indicate that knowledge about the functional meaning of the 2D:4D ratio is still too fragmentary and it is too early to use the 2D:4D ratio in the selection of sport talent; however, it may be a useful criteria when screening prospective athletes to be recruited to a team. That is why 2D:4D reference values should be defined for particular sports.
Analyses of Countermovement Jump Performance in Time and Frequency Domains

Abstract This study aimed to analyze counter-movement jump (CMJ) performance in time and frequency domains. Fortyfour Division I American football players participated in the study. Kinetic variables were collected from both dominant and non-dominant legs using two force plates. Normalized peak power, normalized net impulse, and normalized peak force significantly correlated with jump height (r = .960, r = .998, r = .725, respectively with p < .05). The mean frequency component was significantly correlated with CMJ performance (r = .355 with p < .05). The reliability of the frequency variables was higher than the time domain variables. Frequency domain variables showed weaker correlations with jump height compared with time domain variables. Frequency domain analysis provides frequency components, which represent the rate of energy transmission from the eccentric phase to the end of the push-off phase. Frequency component information may provide additional information for the analyses of CMJ performance for athletes.
The Effects of Avoiding Instructions Under Pressure: An Examination of the Volleyball Serving Task

Abstract Wegner predicts that under pressure self-avoiding instructions not to perform in a certain manner will break down precisely where it is least desired that is the hypothesis of the present study. Specifically, the aim was to test the hypothesis that when instructed not to serve into a certain zone, ironic error would be more prevalent under pressure. Our sample comprised 43 female participants between the age of 13 and 16 (Mage = 14.51, SD = 1.35) who were active volleyball players (Mtraining years = 5.40, SD = 2.38). We measured the participants’ psychophysiological indications of anxiety via the heart rate, heart rate variability as well as the self-reported Mental Readiness Form-3. To measure performance, we counted the number of target and non-target serving zones under different anxiety conditions. Participants scored +5 points for serving into the target zone, scored -5 points for serving to the out or hitting the net and 1 point for serving into the court except the target zone. A 2 (anxiety) × 3 (serving zone) fully repeated measures ANOVA revealed a significant anxiety x serving zone interaction F (2, 84) = 36.52, p < . 001. When instructed not to serve in a certain zone, players’ overall performance did not change across anxiety conditions t (42) = . 68, p =. 50. Results did not provide support for the Wegner’s theory as expected, but instead revealed evidence for the Woodman et al.’s (2015) differentiation of ironic performance error. The results demonstrate that the theory of ironic processes may account for practical instruction-based solution for reducing the susceptibility to ironic errors in the serving type of task in volleyball.
Atrazine Degradation in Two Soil Profiles

Degradation of 2-chloro-4-ethylamino-6-isopropyl-s-triazine (atrazine) was studied in the 0 to 9, 14 to 24, and 36 to 48-inch depths of Sharpsburg silty clay loam and Keith silt loam soils. The effects of moisture, temperature, and microorganisms on degradation were observed. Atrazine was degraded two to three times faster in the topsoils than in the subsoils. Each 10 C temperature increase from 15 to 35 C caused the degradation rate to increase two to three times in these soils. Increasing the moisture content of the soils from 0.4 to 0.8 field capacity caused 14CO2 evolution from chain-labeled atrazine-14C treated soils to increase zero to six times. At 25 C and 0.8 field capacity, 100 to 194 atrazine molecules were detoxified for each molecule evolved as 14CO2 from chain-labeled atrazine. Solution culture studies showed cleavage of the side chain and ring of atrazine-14C except in the 14 to 24 and 36 to 48-inch depths of Keith silt loam.
Influence of Biological Maturity on the Muscular Strength of Young Male and Female Swimmers

Abstract The present study compared the evolution of strength and muscle mass in swimmers of both sexes across different chronological and biological ages. Seventy-six swimmers (55 males and 21 females) from 10 to 20 years of age underwent evaluations of sexual maturation using the developmental stage of the genitals (G1, G2, G3 G4 and G5) and pubic hair (P1, P2, P3, P4 and P5) (Tanner criteria), lean mass using the dual-energy X-ray absorptiometry method, and isokinetic strength of the knee extensor muscles. Boys did not present a significant difference in strength among G1, G2, and G3 (p > 0.05) nor between 10 and 13 years of age (p > 0.05), although significant differences in strength of the extensor (p = 0.038) muscles of the knee were found between G3 and G4 and between athletes of 10 and 14 years of age (extensor muscles, p = 0.033). Muscle mass was different between G3 and G4 (p = 0.003) and between 10 and 14 years of age (p = 0.020). The mean age of boys in the G4 pubertal stage was 13.7 ± 2.0 years, although from 12 to 16 years of age, boys are typically in the G4 stage. Girls showed no significant differences in strength nor muscle mass among the pubertal stages (p > 0.05). We conclude that by equating boys by chronological age, individuals with different pubertal development levels, muscle mass, and strength levels can be grouped. Therefore, the relationship between the level of pubertal deve-lopment and chronological age seems to be a useful strategy for grouping boys, while grouping girls by chronological age seems adequate for training and competition.