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International approvals of cilta-cel: a lens on CAR T cell regulation

Most Christian American religious leaders silently believe in climate change, and informing their congregation can help open dialogue

Religious leaders shape the attitudes and beliefs of their congregations. In a nationally representative sample of U.S. religious leaders ( N = 1,600), the majority of which were of a Christian faith, we find that nearly 90% believe in anthropogenic climate change to some degree. From this 90%, a total of 60% believe humans play a major role and an additional 30% believe they play a role, but a more minor one. Yet roughly half have never discussed it with their congregation, and only a quarter have mentioned it more than once or twice. In a sample of Christian Americans representative of the proportions of major national denominations ( N = 987), we find that Christians underestimate the prevalence of their leaders who believe in climate change by 39 to 45 percentage points. Conversely, having a religious leader who talks about climate change predicts greater willingness to discuss it with fellow churchgoers and attend climate events. In an experimental intervention on another sample matching major Christian American denomination ( N = 959), we find that providing the actual consensus level of religious leaders’ belief in climate change reduces congregants’ misperception of religious leaders, increases their perception that other church members believe in and are open to discussing climate change, and leads Christians to believe that taking climate action is consistent with their church’s values while voting for politicians who will not take climate action is not.

Experimental study of pore-scale flow mechanism of immiscible CO2 flooding under in-situ temperature-pressure coupling conditions

The flow mechanism of CO2 flooding serves as the theoretical foundation for examining the synergic integration of oil recovery and CO2 storage. Immiscible CO2 flooding has attracted considerable research attention due to its simplicity and cost-efficiency. However, minimal studies are available regarding the flow characteristics and EOR mechanism of immiscible CO2 flooding in in-situ temperature-pressure coupling conditions at the pore scale. Therefore, this study employed a modified high-temperature, high-pressure microfluidic system to simulate the in-situ CO2 and water injection processes in a combined temperature-pressure environment and analyze the multiphase flow characteristics in the pores. The injection rate, displacement pressure difference, displacement efficiency, and residual oil distribution were quantitatively analyzed at different pressures. The results indicated higher residual oil clustering after water flooding at the same injection rate. CO2 flooding significantly reduced residual oil clustering and enhanced the oil flooding effect. The multiphase flow dynamics, type of remaining oil in different injection conditions, and flow characteristics of immiscible CO2 flooding were determined. A higher confining pressure interrupted the CO2 flow, which destabilized the displacement front increased the recovery efficiency by 12.9%. Furthermore, a higher injection rate and displacement pressure increased the recovery efficiency by 24.9% and 6.1%, respectively.

Author Correction: Association between ACTN3 (R577X), BDKRB2 (−9/+9) and AGT (M235T) polymorphisms and physical performance in Brazilian junior handball players

Hiding in plain sight: NUT carcinoma is an unrecognized subtype of squamous cell carcinoma of the lungs and head and neck

Acute TREM2 inhibition depletes MAFB-high microglia and hinders remyelination

We investigated the role of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) in myelin regeneration in the brain. TREM2 is a receptor that activates microglia, which are crucial for clearing myelin debris and promoting remyelination. Previous studies in a mouse model of demyelination induced by the copper-chelating agent Cuprizone (CPZ) have shown that stimulation of TREM2 with a monoclonal antibody reduces demyelination, while deleting the Trem2 gene in mice impairs remyelination. Here, we blocked TREM2 function acutely with an antibody during both the demyelination and remyelination phases of the CPZ model and analyzed the impact of the antibody treatment on myelination and gene expression in single cells. We found that blocking TREM2 depleted a distinct population of microglia with high expression of the transcription factor MAFB during remyelination. The loss of these MAFB-high microglia was linked to impaired generation of myelinating oligodendrocytes. Importantly, we identified MAFB + microglia in acute and acute-chronic brain lesions from individuals with multiple sclerosis (MS), but not in inactive lesions. We conclude that TREM2 is essential for maintaining a population of MAFB-high microglia that is associated with myelin repair. This finding has significant implications for understanding demyelinating diseases like MS and suggests that stimulating TREM2 could be a promising therapeutic approach for myelin repair.

Correction: Biomechanical effects of saddle height changes in leisure cycling with unilateral transtibial prostheses: A simulated study

Optimizing sintering air volume for enhanced lean gas recovery and environmental performance

Perioperative chemotherapy superior to preoperative chemoradiotherapy for locally advanced EAC

De novo discovery of a molecular glue–like macrocyclic peptide that induces MCL1 homodimerization

Macrocyclic peptides have emerged as promising drug candidates, filling the gap between small molecules and large biomolecules in drug discovery. The antiapoptotic protein myeloid cell leukemia 1 (MCL1) is crucial for numerous cancers, yet it presents challenges for selective targeting by traditional inhibitors. In this study, we identified a macrocyclic peptide, 5L1, that strongly binds to MCL1, with a dissociation constant ( K D ) of 7.1 nM. This peptide shows the potential to specifically inhibit the function of MCL1, and demonstrates effective antitumor activity against several blood tumor cell lines with the half maximal inhibitory concentration (IC 50 ) values for cell-penetrating peptide-conjugated 5L1 in the range of 0.6 to 3 μM. Structural analysis revealed that it functions similarly to molecular glue, capable of binding to two MCL1 molecules simultaneously and inducing their homodimerization. This unique mechanism of action distinguishes it from traditional small-molecule MCL1 inhibitors, underscoring the potential of macrocyclic peptides functioning as molecular glues. Moreover, it inspires the development of highly selective inhibitors targeting MCL1 and other related targets with this glue-like mechanism.

Correction: From tradition to progressiveness: Analyzing Thailand’s image on youtube amid post-cannabis legalization

Performance of vertical steel plate anchor in layered cohesionless soil

Prediction of phase-separation propensities of disordered proteins from sequence

Phase separation is one possible mechanism governing the selective cellular enrichment of biomolecular constituents for processes such as transcriptional activation, mRNA regulation, and immune signaling. Phase separation is mediated by multivalent interactions of macromolecules including intrinsically disordered proteins and regions (IDRs). Despite considerable advances in experiments, theory, and simulations, the prediction of the thermodynamics of IDR phase behavior remains challenging. We combined coarse-grained molecular dynamics simulations and active learning to develop a fast and accurate machine learning model to predict the free energy and saturation concentration for phase separation directly from sequence. We validate the model using computational and previously measured experimental data, as well as new experimental data for six proteins. We apply our model to all 27,663 IDRs of chain length up to 800 residues in the human proteome and find that 1,420 of these (5%) are predicted to undergo homotypic phase separation with transfer free energies < −2 k B T . We use our model to understand the relationship between single-chain compaction and phase separation and find that changes from charge- to hydrophobicity-mediated interactions can break the symmetry between intra- and intermolecular interactions. We also provide proof of principle for how the model can be used in force field refinement. Our work refines and quantifies the established rules governing the connection between sequence features and phase-separation propensities, and our prediction models will be useful for interpreting and designing cellular experiments on the role of phase separation, and for the design of IDRs with specific phase-separation propensities.

Correction: Novel deep reinforcement learning based collision avoidance approach for path planning of robots in unknown environment

Advanced design of 3D knitted padding for wearable cushioning in knee protector

The visuomotor transformations underlying target-directed behavior

The visual system can process diverse stimuli and make the decision to execute appropriate behaviors, but it remains unclear where and how this transformation takes place. Innate visually evoked behaviors such as hunting, freezing, and escape are thought to be deeply conserved, and have been described in a range of species from insects to humans. We found that zebrafish larvae would respond to predator-like visual stimuli with immobility and bradycardia, both hallmarks of freezing, in a head-fixed behavioral paradigm. We then imaged the zebrafish visual system while larvae responded to different visual stimuli with hunting, freezing, and escape behaviors and systematically identified visually driven neurons and behaviorally correlated sensorimotor neurons. Our analyses indicate that within the optic tectum, broadly tuned sensory neurons are functionally correlated with sensorimotor neurons which respond specifically during one behavior, indicating that it contains suitable information for sensorimotor transformation. We also identified sensorimotor neurons in four other areas downstream of the tectum, and these neurons are also specific for one behavior, indicating that the segregation of the pathways continues in other areas. While our findings shed light on how sensorimotor neurons may integrate visual inputs, further investigation will be required to determine how sensorimotor neurons in different regions interact and where the decision to behave is made.

Trends of inequities in healthcare seeking behavior for diarrhea, fever, and ARI symptoms among women in reproductive age groups for their under-five children in Ethiopian: A multilevel Analysis of EDHS Surveys from 2000 to 2016

Background Ethiopia is one of the developing countries with the highest inequity in the healthcare seeking behavior for under-five children. Despite this fact, not much is known about the trend of inequity, in healthcare seeking-behavior for symptoms of diarrhea, fever and acute respiratory infections (ARIs) among under-five children. Objective This study aimed to measure trends of inequity in healthcare seeking -behavior for diarrhea, fever, and ARI symptoms and its determinant factors among under-five children in Ethiopia. Methods Data from 2000, 2005, 2011, and 2016 Ethiopian Demographic and Health Surveys (EDHSs) were analyzed using the 2019 updated version of the WHO’s Health Equity Assessment Toolkit (HEAT) software. Five equity dimensions were used to disaggregate datasets on healthcare seeking behavior for diarrhea, fever, and ARI symptoms: Based on wealth status, education, place of residence, sex of the child and administrative regions. Second, summary measures such as: equity gaps, equity ratios, population attributable fraction (PAF), population attributable Risk (PAR), absolute concentration index (ACI) and relative concentration index (RCI), was used. The concentration curve and horizontal inequity indices were used to evaluate the wealth-related disparities. To measure the determinants a multilevel logistic regression with 95% confidence interval was employed. Result This study showed remarkable improvement in healthcare seeking behavior for symptoms of diarrhea, fever and ARI among under-five children between 2000 and 2016. The increases are more, from the poorest subgroups compared to the wealthiest. The absolute percentage point changes (or healthcare seeking rate changes) between 2000 and 2016 among the poorest quintile of households are at least twice that of the wealthiest quintile for symptoms of diarrhea. However, significant disparities between the rich and the poor persist for the majority of the indicators examined for the three childhood morbidities. Moreover, horizontal inequity indices and the concentration curve both point out to the existence of pro-rich inequity in healthcare seeking behavior for under five children. In the multilevel analysis various demographic, parental and household characteristic show an association with healthcare seeking behavior for symptoms of diarrhea, fever and ARIs. Conclusion A promising trend is observed in healthcare seeking behavior for diarrhea, fever and ARI symptoms among under-five children. Faster progress in use of healthcare services among the poor than the wealthy in Ethiopia would potentially result in elimination of inequities and rapid improvement in health among the poor. Intervention programs that focused on the underprivileged, while also taking into account the wealthier sub-groups.

Structural changes in vortex vein ampullae in eyes with pachychoroid-spectrum disorder

Neural basis for individual differences in the attention-enhancing effects of methylphenidate

Stimulant drugs that boost dopamine, like methylphenidate (MP), enhance attention and are effective treatments for attention-deficit hyperactivity disorder (ADHD). Yet there is large individual variation in attentional capacity and response to MP. It is unclear whether this variation is driven by individual differences in relative density of dopamine receptor subtypes, magnitude of dopamine increases induced by MP, or both. Here, we extensively characterized the brain dopamine system with positron emission tomography (PET) imaging (including striatal dopamine D1 and D2/3 receptor availability and MP-induced dopamine increases) and measured attention task-evoked fMRI brain activity in two separate sessions (placebo and 60 mg oral MP; single-blind, counterbalanced) in 37 healthy adults. A network of lateral frontoparietal and visual cortices was sensitive to increasing attentional (and working memory) load, whose activity positively correlated with performance across individuals (partial r = 0.474, P = 0.008; controlling for age). MP-induced change in activity within this network correlated with MP-induced change in performance (partial r = 0.686, P < 0.001). The ratio of D1-to-D2/3 receptors in dorsomedial caudate positively correlated with baseline attentional network activity and negatively correlated with MP-induced changes in activity (all pFWE < 0.02). MP-induced changes in attentional load network activity mediated the association between D1-to-D2/3 ratio and MP-induced improvements in performance (mediation estimate = 23.20 [95%CI: −153.67 −81.79], P = 0.004). MP attention-boosting effects were not linked to the magnitude of striatal dopamine increases, but rather showed dependence on an individual’s baseline receptor density. Individuals with lower D1-to-D2/3 ratios tended to have lower frontoparietal activity during sustained attention and experienced greater improvement in brain function and task performance with MP.

Intraoperative phrenic nerve stimulation to prevent diaphragm fiber weakness during thoracic surgery

Thoracic surgery rapidly induces weakness in human diaphragm fibers. The dysfunction is thought to arise from combined effects of the surgical procedures and inactivity. This project tested whether brief bouts of intraoperative hemidiaphragm stimulation would mitigate slow and fast fiber loss of force in the human diaphragm. We reasoned that maintenance of diaphragm activity with brief bouts of intraoperative phrenic stimulation would mitigate diaphragm fiber weakness and myofilament protein derangements caused by thoracic surgery. Nineteen adults (9 females, age 59 ± 12 years) with normal inspiratory strength or spirometry consented to participate. Unilateral phrenic twitch stimulation (twitch duration 1.5 ms, frequency 0.5 Hz, current 2x the motor threshold, max 25 mA) was applied for one minute, every 30 minutes during cardiothoracic surgery. Thirty minutes following the last stimulation bout, biopsies were obtained from the hemidiaphragms for single fiber force mechanics and quantitation of myofilament proteins (abundance and phosphorylation) and compared by a linear mixed model and paired t-test, respectively. Subjects underwent 6 ±  2 hemidiaphragm stimulations at 17 ±  6 mA, during 278 ±  68 minutes of surgery. Longer-duration surgeries were associated with a progressive decline in diaphragm fiber force (p < 0.001). In slow-twitch fibers, phrenic stimulation increased absolute force (+25%, p <  0.0001), cross-sectional area (+16%, p < 0.0001) and specific force (+7%, p < 0.0005). Stimulation did not alter contractile function of fast-twitch fibers, calcium-sensitivity in either fiber type, and abundance and phosphorylation of myofilament proteins. In adults without preoperative weakness or lung dysfunction, unilateral phrenic stimulation mitigated diaphragm slow fiber weakness caused by thoracic surgery, but had no effect on myofilament protein abundance or phosphorylation.