Browse Articles

Comparative assessment of vegetable yield with and without biochar derived from locally sourced apricot shells

Nongenetic adaptation by collective migration

Cell populations must adjust their phenotypic composition to adapt to changing environments. One adaptation strategy is to maintain distinct phenotypic subsets within the population and to modulate their relative abundances via gene regulation. Another strategy involves genetic mutations, which can be augmented by stress-response pathways. Here, we studied how a migrating bacterial population regulates its phenotypic distribution to traverse diverse environments. We generated isogenic Escherichia coli populations with varying distributions of swimming behaviors and observed their phenotype distributions during migration in liquid and porous environments. We found that the migrating populations became enriched with high-performing swimming phenotypes in each environment, allowing the populations to adapt without requiring mutations or gene regulation. This adaptation is dynamic and rapid, reversing in a few doubling times when migration ceases. By measuring the chemoreceptor abundance distributions during migration toward different attractants, we demonstrated that adaptation acts on multiple chemotaxis-related traits simultaneously. These measurements are consistent with a general mechanism in which adaptation results from a balance between cell growth generating diversity and collective migration eliminating underperforming phenotypes. Thus, collective migration enables cell populations with continuous, multidimensional phenotypes to flexibly and rapidly adapt their phenotypic composition to diverse environmental conditions.

Development and validation of a deep reinforcement learning algorithm for auto-delineation of organs at risk in cervical cancer radiotherapy

Integrative analysis of KCNQ1 variants reveals molecular mechanisms of type 1 long QT syndrome pathogenesis

Loss-of-function (LOF) pathogenic variants in KCNQ1 encoding a cardiac potassium channel predispose to sudden cardiac death in type 1 congenital long QT syndrome (LQT1). To determine the spectrum of molecular mechanisms responsible for this life-threatening condition, we used an integrative approach to determine the biophysical, functional, and trafficking properties of 61 KCNQ1 variants distributed throughout all domains of the channel. Impaired trafficking to the plasma membrane was the most common cause of LOF across all channel domains, often but not always coinciding with protein instability. However, many LOF variants, particularly in transmembrane domains, trafficked normally, but when coexpressed with KCNE1 exhibited impaired conductance, altered voltage dependence, or abnormal gating kinetics, highlighting diverse pathogenic mechanisms. This indicates a need for personalized treatment approaches for LQT1. Use of our data to benchmark variant pathogenicity prediction methods demonstrated that prediction accuracy depends on the exact mechanism of pathogenicity associated with a given variant.

The relationship between expression level and gene polymorphism of inflammatory factors and sepsis risk

A binary trait model reveals the fitness effects of HIV-1 escape from T cell responses

Natural selection often acts on multiple traits simultaneously. For example, the virus HIV-1 faces pressure to evade host immunity while also preserving replicative fitness. While past work has studied selection during HIV-1 evolution, as in other examples where selection acts on multiple traits, it is challenging to quantitatively separate different contributions to fitness. This task is made more difficult because a single mutation can affect both immune escape and replication. Here, we develop an evolutionary model that disentangles the effects of escaping CD8 + T cell–mediated immunity, which we model as a binary trait, from other contributions to fitness. After validation in simulations, we applied this model to study within-host HIV-1 evolution in a clinical dataset. We observed strong selection for immune escape, sometimes greatly exceeding past estimates, especially early in infection. Conservative estimates suggest that roughly half of HIV-1 fitness gains during the first months to years of infection can be attributed to T cell escape. Our approach is not limited to HIV-1 or viruses and could be adapted to study the evolution of quantitative traits in other contexts.

CDK4/6 inhibitors upregulate cIAP1/2, and Smac mimetic LCL161 enhances their antitumor effects in cholangiocarcinoma cells

Cell-based glycoengineering for production of homogeneous and specific glycoform-enriched antibodies with improved effector functions

Glycosylation of humanized antibody at Fc-Asn297 significantly affects the Fc-mediated killing of target cells through effector functions, especially antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent vaccinal effect (ADVE). Previous studies showed that therapeutic immunoglobulin G (IgG) antibodies with α2,6-sialyl complex type (SCT) glycan attached to Fc-Asn297 exhibited optimal binding to the Fc receptors on effector cells associated with ADCC, ADCP, and ADVE. However, the production of antibodies with homogeneous Fc-SCT glycan requires multiple in vitro enzymatic and purification steps. In this study, we report two cell-based methods to produce Fc-GlcNAc antibody and Fc-SCT-enriched antibodies with improved effector functions. First, we expressed endoglycosidase S2 in Expi293F GnT1- cells to trim all N-glycans to Fc-GlcNAc antibody for in vitro transglycosylation to generate homogeneous antibodies with well-defined Fc glycan. Second, we engineered the glycosylation pathway of HEK293T cells through knock-out of undesired glycosyltransferases and knock-in of desired glycosyltransferases to produce Fc-SCT-enriched antibodies and evaluated their binding to Fc receptors, and we found that the Fc-SCT-enriched antibody is like or better than the homogeneous Fc-SCT antibody in binding to the Fc receptors associated with ADCC, ADCP, and ADVE.

Acute effects of high-intensity interval training and moderate-intensity continuous training on executive functions in healthy older adults

Abstract Numerous studies have demonstrated that executive functions benefit from high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). However, the immediate effects of HIIT and MICT on these functions in older adults have not been compared. This study aimed to examine the acute impact of HIIT and MICT on executive function components in this demographic. Twenty-five healthy community-dwelling older adults (15 females; average age 67.1 ± 4.5 years) participated. The study involved three sessions: an initial session with cognitive assessments (Stroop Task: Naming, Inhibition, and Switching) and a maximal continuous graded exercise test, followed by two sessions involving HIIT (15s at 100% peak power output, 15s rest, 2 × 20 min) or MICT (34 min at 60% peak power output) training protocols in random order. Cognitive tests were administered immediately after and 45 min post-training. The results showed a significant difference in Switching reaction times between MICT and HIIT, with HIIT showing a greater reduction in Switching times after 45 min (p = 0.019). In conclusion, our study indicates that HIIT’s beneficial effects on executive functions demonstrated a larger effect size than those of MICT. This suggests that brief, high-intensity exercise could be more effective in enhancing executive functions among older adults.

Stepwise activation of SARM1 for cell death and axon degeneration revealed by a biosynthetic NMN mimic

Axon degeneration, driven by the NAD + hydrolyzing enzyme SARM1, is an early pathological hallmark of numerous neurodegenerative diseases. SARM1 exists in an inactive form and is activated following nerve injury. However, the precise molecular mechanism underlying SARM1 activation remains to be fully elucidated. In this study, we report the identification of a potent proactivator of SARM1, G10, which is converted into a direct activator (M1) by the enzyme nicotinamide phosphoribosyltransferase. Cryoelectron microscopy structures of SARM1 bound to M1, as well as to M1 and a nonhydrolyzable NAD + analog (1AD), captured two intermediate activation states and the fully active state, revealing a stepwise mechanism of SARM1 activation. Further, introducing a disulfide bond to prevent conformational transitions between the two intermediate states mediated by M1 stabilized SARM1 in its inactive form and blocked M1-induced cell death. Together, these findings propose a sequential, stepwise activation model for SARM1 and offer a framework for developing potential SARM1 inhibitors for the treatment of neurodegenerative diseases.

Author Correction: Gradual chromosomal lagging drive programmed genome elimination in hemiclonal fishes from the genus Hypseleotris

pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies

Anti-CTLA-4 Abs (ACAs) are a breakthrough for cancer therapy, but their potential is limited by immunotherapy-related adverse events (irAE). We previously reported that ACAs with acidic pH-sensitive binding to CTLA-4 exhibit higher antitumor activity with fewer irAE. We now test a panel of variants of Ipilimumab (Ipi), the first ACA cancer therapeutic, for tumoricidal efficacy and irAE. Surprisingly, not all pH-sensitive Ipi variants exhibited an enhanced therapeutic index. Ipi13, which retained binding to CTLA-4 at pH 6.0 but dissociated at lower pH, showed no enhancement. By contrast, Ipi25, which dissociates from CTLA-4 at pH 6.0, the pH of the early endosome (EE), showed greater tumor regression and less severe irAE. Confocal microscopy showed that Ipi13 maintained colocalization with CTLA-4 at the late endosomes (LE) and lysosomes resulting in lysosomal degradation of CTLA-4. Conversely, Ipi25 did not colocalize with CTLA-4 in LE or lysosomes after endocytosis but allowed both proteins to transfer to recycling endosomes. EE dissociation was also characteristic of variants of Tremelimumab (Treme), another clinical ACA, that showed better efficacy and fewer side effects. Thus, our data reveal the significance of early intracellular dissociation from CTLA-4 to improve ACAs for safer and more effective cancer immunotherapy.

Separation of pups from their mother mice enhances odor associative learning at the late lactation stage

ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep

Metabolism plays a key role in the maintenance of sleep/wake states. Brain lactate fluctuations are a biomarker of sleep/wake transitions, where increased interstitial fluid (ISF) lactate levels are associated with wakefulness and decreased ISF lactate is required for sleep. ATP-sensitive potassium (K ATP ) channels couple glucose-lactate metabolism with excitability. Using mice lacking K ATP channel activity (e.g., Kir6.2 −/− mice), we explored how changes in glucose utilization affect cortical electroencephalography (EEG) activity and sleep/wake homeostasis. In the brain, Kir6.2 −/− mice shunt glucose toward glycolysis, reducing neurotransmitter biosynthesis and dampening cortical EEG activity. Kir6.2 −/− mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-K ATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of sleep/wake states and providing the metabolic flexibility to transition between states.

S100P is a core gene for diagnosing and predicting the prognosis of sepsis

Fungal-derived methyldeoxaphomins target <i>Plasmodium falciparum</i> segregation through the inhibition of PfActin1

Herein we report the finding and structure determination of a natural product based on the methyldeoxaphomin scaffold family from the fungus Trichocladium asperum that shows promising antiplasmodial activity and selectivity against host cells. In vitro evolution and whole genome analysis in Plasmodium falciparum with the most potent member, NPDG-F (EC 50 of 550 nM in Dd2; 290 nM in 3D7), shows that parasite resistance to methyldeoxaphomins is strongly associated with mutations in PfActin1 (PF3D7_1246200), a critically essential ATPase needed for all stages of parasite development. Molecular docking study with available PfActin1 crystal structure shows NPDG-F occupies the same allosteric binding pocket as the known actin inhibitor cytochalasin D. The direct PfActin1 target engagement in the allosteric site was supported by cross-resistance studies, isobologram analysis with other PfActin1 inhibitors, and the structure–activity relationships for the methyldeoxaphomin family. When added to in vitro culture, NPDG-F induced morphological abnormalities in merozoite cellularization during schizogony in both the Plasmodium blood and liver stages. Our data provide chemical validation that PfActin1 is an attractive, pan-lifecycle target and inform strategies for the design of more selective inhibitors.

Combined cerebrospinal fluid sCD163, MMP-9, with serum NCAM1 protein levels for predicting the prognosis of patients with tuberculous meningitis

PCSK9 potentiates innate immune response to RNA viruses by preventing AIP4-mediated polyubiquitination and degradation of VISA/MAVS

Upon viral infection, retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) detect viral RNA to initiate antiviral innate immune response, which is mediated by the mitochondrial adaptor protein VISA virus-induced signaling adaptor; also known as mitochondiral antiviral-signaling protein (MAVS). The stability and activity of VISA are tightly regulated by various posttranslational modifications, among which polyubiquitination plays important roles. Various E3 ubiquitin ligases, including atrophin interacting protein 4 (AIP4), mediate polyubiquitination of VISA and result in its degradation. However, how polyubiquitination of VISA is regulated remains unclear. Here, we uncovered a dual function for proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis and a well-known therapeutic target in cardiovascular diseases, modulating host responses to RNA viruses both extracellularly and intracellularly. Secreted PCSK9 inhibited sendai virus (SeV) and vesicular stomatitis virus (VSV) infection, while the intracellular PCSK9 potentiated RLRs-mediated interferons (IFNs) induction by stabilizing VISA on mitochondria. Viral infection induced the translocation of PCSK9 to mitochondria where it competed with AIP4 for VISA, thereby inhibiting its polyubiquitination and degradation. Consequently, overexpression of PCSK9 enhanced VISA-mediated innate immune response against RNA viral infection, whereas its deficiency had the opposite effects and resulted in more robust replication of the virus. Pcsk9 −/− mice produced lower levels of type I IFNs and proinflammatory cytokines, rendering the increased sensitivity to VSV and influenza A virus infection. Altogether, our findings uncovered an important and unexpected role of PCSK9 in virus–host interaction and contribute to the understanding of the sophisticated mechanism governing the proper and efficient immune response to viral infection.

Evaluation of future land use change impacts on soil erosion for holota watershed, Ethiopia

Fluoride-based hydrogen bond chemistry in a layered double hydroxide cathode toward high-performance aqueous NH ₄ ⁺ storage

In aqueous ammonium-ion storage, hydrogen bonds play a pivotal role in the reversible insertion/extraction of NH 4 + within transition metal oxides/hydroxides. Although fluorine (F) is known for its strong electronegativity and potential to form robust hydrogen bonds with NH 4 + , its specific influence on NH 4 + storage remains unexplored. Herein, we systematically investigate the effects of F-based hydrogen bond chemistry within a layered double hydroxide matrix, where F species are introduced and subsequently partially removed via an electrochemical method. Our findings demonstrate that while increasing F doping content accelerates NH 4 + diffusion due to F’s strong electronegativity, it also triggers crystal shrinkage and depresses storage capacity. To this end, controlled partial removal of F, employing a lye-assistant electrochemical strategy, induces expanded interlayer spacing and distinct edge lattice tearing, thereby facilitating improved NH 4 + accommodation. The retained F sites couple with emerging exposed O sites maintain a high hydrogen bonding capability, which is further enhanced by the formation of highly active, curved hydroxyl groups centered around F sites. These manipulations significantly boost the NH 4 + storage performance of the electrode, providing insights into leveraging the strongest F-based hydrogen bond chemistry in developing high-performance ammonium-ion energy storage devices.