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The accurate simulation of regional-scale winter wheat yield is important for national food security and the balance of grain supply and demand in China. Presently, most remote sensing process models use the “biomass×harvest index (HI)” method to simulate regional-scale winter wheat yield. However, spatiotemporal differences in HI contribute to inaccuracies in yield simulation at the regional scale. Time-series dry matter partition coefficients (Fr) can dynamically reflect the dry matter partition of winter wheat. In this study, Fr equations were fitted for each organ of winter wheat using site-scale data. These equations were then coupled into a process-based and remote sensing-driven crop yield model for wheat (PRYM-Wheat) to improve the regional simulation of winter wheat yield over the North China Plain (NCP). The improved PRYM-Wheat model integrated with the fitted Fr equations (PRYM-Wheat-Fr) was validated using data obtained from provincial yearbooks. A 3-year (2000–2002) averaged validation showed that PRYM-Wheat-Fr had a higher coefficient of determination (R²=0.55) and lower root mean square error (RMSE=0.94 t ha–1) than PRYM-Wheat with a stable HI (abbreviated as PRYM-Wheat-HI), which had R² and RMSE values of 0.30 and 1.62 t ha–1, respectively. The PRYM-Wheat-Fr model also performed better than PRYM-Wheat-HI for simulating yield in verification years (2013–2015). In conclusion, the PRYM-Wheat-Fr model exhibited a better accuracy than the original PRYM-Wheat model, making it a useful tool for the simulation of regional winter wheat yield.

ABSTRACT: This experiment was conducted to investigate the effects of mulberry leaf extract (MLE) on alleviating fatty liver hemorrhagic syndrome (FLHS) in laying hens. The 576 Jing Fen laying hens of 56 weeks of age with good health and similar weights (1.76 ± 0.17 kg) were randomly divided into 6 groups, with 8 replicates in each group and 12 chickens in each replicate. The experiment lasted 56 d. The control group was fed a corn-soybean meal diet. The FLHS group was fed a high energy-low protein (HELP) diet, and the other four experimental groups were fed HELP diets supplemented with 0.04, 0.40, 0.80, and 1.20% MLE, respectively. The results showed that HELP treatment significantly induced liver injury, which indicated that the FLHS model was successfully established. MLE supplementation could alleviate the FLHS by reducing the liver index, abdominal fat percentage, total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) in the serum (P < 0.05), and subsequently increase the egg production rate (P < 0.05). The laying hens fed 0.8% MLE exhibited the greatest production performance (P < 0.05) and could improve serum lipid levels. In addition, the genes associated with fatty acid synthesis (ACC, HMGR and SREBP-1C) were downregulated (P < 0.05), and genes related to fatty acid oxidation (CPT1A, AMPK, and ATGL) were found to be upregulated (P < 0.05). Supplementation with 1.2% MLE significantly reduced the relative abundance of Firmicutes and Desulfurized Bacillus (P < 0.05) and significantly increased the relative abundance of Fecal Bacillus (P < 0.05). In conclusion, MLE may regulate the mRNA expression of lipid metabolism-related genes through the AMPK signaling pathway and improve cecal microbiota balance and serum lipid levels to alleviate FLHS in laying hens and subsequently improve egg production performance.

Heterosigma akashiwo is a harmful algal bloom species that causes significant detrimental effects on marine ecosystems worldwide. The algicidal bacterium Pseudalteromonas sp. LD-B1 has demonstrated potential effectiveness in mitigating these blooms. However, the molecular mechanisms underlying LD-B1’s inhibitory effects on H. akashiwo remain poorly understood. In this study, we employed the comprehensive methodology, including morphological observation, assessment of photosynthetic efficiency (Fv/Fm), and transcriptomic analysis, to investigate the response of H. akashiwo to LD-B1. Exposure to LD-B1 resulted in a rapid decline of H. akashiwo's Fv/Fm ratio, with cells transitioning to a rounded shape within 2 hours, subsequently undergoing structural collapse and cytoplasmic leakage. Transcriptomic data revealed sustained downregulation of photosynthetic genes, indicating impaired functionality of the photosynthetic system. Additionally, genes related to the respiratory electron transfer chain and antioxidant defenses were consistently downregulated, suggesting prolonged oxidative stress beyond the cellular antioxidative capacity. Notably, upregulation of autophagy-related genes was observed, indicating autophagic responses in the algal cells. This study elucidates the molecular basis of LD-B1's algicidal effects on H. akashiwo, advancing our understanding of algicidal mechanisms and contributing to the development of effective strategies for controlling harmful algal blooms.

Diabetic cardiomyopathy (DCM) is a major complication of diabetes and is characterized by left ventricular dysfunction. Currently, there is a lack of effective treatments for DCM. Ubiquitin-specific protease 7 (USP7) plays a key role in various diseases. However, whether USP7 is involved in DCM has not been established. In this study, we demonstrated that USP7 was upregulated in diabetic mouse hearts and NMCMs co-treated with HG+PA or H9c2 cells treated with PA. Abnormalities in diabetic heart morphology and function were reversed by USP7 silencing through conditional gene knockout or chemical inhibition. Proteomic analysis coupled with biochemical validation confirmed that PCG1β was one of the direct protein substrates of USP7 and aggravated myocardial damage through coactivation of the PPARα signaling pathway. USP7 silencing restored the expression of fatty acid metabolism-related proteins and restored mitochondrial homeostasis by inhibiting mitochondrial fission and promoting fusion events. Similar effects were also observed in vitro. Our data demonstrated that USP7 promoted cardiometabolic metabolism disorders and mitochondrial homeostasis dysfunction via stabilizing PCG1β and suggested that silencing USP7 may be a therapeutic strategy for DCM.

The value of Baijiu is affected by its flavor, age, and adulteration. Therefore, a simple and rapid identification method is crucial for the market. In this study, we present a rapid, non-intrusive identification technique for Baijiu utilizing the Tyndall effect combined with chemometrics analysis. Our experiment begins illuminating Baijiu with a 405 nm wavelength laser and recording the resulting bright light path due to the Tyndall effect. To further analyze the color and brightness information, Principal Component Analysis (PCA), Linear Discriminant Analysis (LDA), Hierarchical Cluster Analysis (HCA), and Multilayer Perceptron (MLP) were employed. This study establishes correlations between the brightness of the Tyndall light path and seven trace flavor compounds in Baijiu. The findings demonstrate that this method effectively identifies the flavor, age cellar, and adulteration of Baijiu and also quantitatively detects the concentrations of flavor compounds. Additionally, an analysis platform was developed to enable the rapid identification of Baijiu.

ABSTRACT: This study aimed to systematically determined the effect of 28 h ahemeral light cycle on production performance, egg quality, blood parameters, uterine morphological characteristics, and gene expression of hens during the late laying period. At 74 wk, 260 Hy-Line Brown layers were randomly divided into 2 groups of 130 birds each and in duplicates. Both a regular (16L:8D) and an ahemeral light cycle (16L:12D) were provided to the hens. The oviposition pattern in an ahemeral cycle shifted into darkness, with oviposition mostly occurring 3 to 5 h after light out. Production performance was unaffected by light cycle (P > 0.05). Nonetheless, compared to the normal group, the ahemeral group exhibited increased egg weight, eggshell weight, eggshell percentage, yolk percentage, eggshell thickness, and eggshell strength (P < 0.05). There were rhythmic changes in the uterine morphological structure in both cycles, however, the ahemeral group maintained a longer duration and had more uterine folds than the normal group. In the ahemeral cycle, the phases of the CLOCK and PER2 genes were phase-advanced for 3.96 h and 4.54 h compared to the normal cycle. The PHLPP1 gene, which controls clock resetting, exhibited a substantial oscillated rhythm in the ahemeral group (P < 0.05), while the expression of genes presenting biological rhythm, such as CRY2 and FBXL3, was rhythmically oscillated in normal cycle (P < 0.05). The ITPR2 gene, which regulates intracellular Ca2+ transport, displayed a significant oscillated rhythm in ahemeral alone (P < 0.05), while the CA2 gene, which presents biomineralization, rhythmically oscillated in both cycles (P < 0.05). The ahemeral cycle caused 2.5 h phase delays in the CA2 gene compared to the normal cycle. In conclusion, the 28 h ahemeral light cycle preserved the high condition of the uterine folds and changed the uterine rhythms of CLOCK, PER2, ITPR2, and CA2 gene expression to improve ion transport and uterine biomineralization.

Qingqiao Kangdu granule (QQKDG), a traditional Chinese medicine (TCM), has been used clinically to treat various viral diseases, including flu, mumps, and viral hepatitis, owing to its abundant bioactivities. Nevertheless, the chemical components of QQKDG have not been sufficiently elucidated; consequently, the development of standards for quality evaluation and complete understanding of the pharmacological mechanisms of action are hindered. Therefore, a systematic approach must be developed to efficiently discover novel compounds and advance pharmacological research. In this regard, this study proposed an integrated strategy for the comprehensive characterization of the chemical components in QQKDG by UHPLC-Q-Exactive-MS coupled with feature-based molecular networking (FBMN) to improve annotation accuracy and achieve visualization. First, the chromatographic and mass spectrum conditions were optimized to obtain good separation and abundant signal response. Subsequently, an in-house library was established by searching for relevant literature to improve annotation confidence. Finally, the raw data acquired under optimized conditions were uploaded to the FBMN to achieve component visualization by connecting precursor ions of the same color, in which compounds have similar structural features. Thus, a total of 231 compounds, including 89 flavonoids, 36 phenolic acids, 26 phenylethanoid glycosides, 23 coumarins, 17 chlorogenic acid derivatives, 14 terpenoids, 10 alkaloids, 10 lignans and 6 other compounds, were characterized, and numerous novel compounds with new structures were explored. Thus, this study provides a strategy for comprehensive characterization, which can also be applied to other TCMs.

Objective: To assess the relationship between optic disc microvasculature and renal function in subjects with diabetes mellitus without diabetic retinopathy (DR). Design: Prospective, cross-sectional study. Participants: A total 1629 patients with type 2 diabetes mellitus without DR were recruited from the community of Guangzhou, China. Methods: All subjects underwent 6 mm × 6 mm OCT angiography (OCTA) centered on the optic nerve head. Four state-of-the-art microcirculation parameters, including peripapillary vessel density (PVD) in the radial peripapillary capillaries (RPC), superficial capillary plexus, deep capillary plexus (DCP), and a choriocapillaris flow void density percentage (CC FVD%) were assessed via swept-source OCTA. Primary Outcomes: Renal function was assessed by levels of microalbuminuria (MAU) and estimated glomerular filtration rate (eGFR). Results: Compared with non-chronic kidney disease (CKD) participants, PVD was significantly lower in subjects in the CKD group and worsened as eGFR declined. After adjustment for covariates, higher eGFR was significantly associated with higher PVD in the RPC (β = 0.01; 95% confidence interval [CI], 0.01–0.02; P < 0.001), in the superficial capillary plexus (β = 0.010; 95% CI, 0.002–0.019; P = 0.020), in the DCP (β = 0.02; 95% CI, 0.01–0.03; P < 0.001), and lower CC FVD% (β = −0.01; 95% CI, −0.03 to −0.001; P = 0.040) in the entire images. After they were fully adjusted, the parameters in the inner ring of the RPC, DCP, and CC FVD% were significantly associated with MAU (P < 0.05). Conclusion: Decrease in retinal and choroidal microcirculation in the optic nerve head was independently associated with renal dysfunction. Further longitudinal studies are needed to clarify the peripapillary vessel changes during CKD progression. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Pulmonary fibrosis is highly lethal with limited treatments. Butaselen (BS) is an inhibitor of thioredoxin reductase (TrxR)/thioredoxin (Trx) with anti-tumor activity. However, its impact on pulmonary fibrosis and the involved mechanisms remain unclear. Here, we demonstrate that BS is a potential drug for the treatment of pulmonary fibrosis. Specifically, BS can inhibit pulmonary fibrosis both in vitro and in vivo, with comparable efficacy and enhanced safety when compared with pirfenidone. BS and dexamethasone display a synergistic effect in inhibiting pulmonary fibrosis both in vitro and in vivo. Mechanistic studies reveal that BS can inhibit the TrxR activity during pulmonary fibrosis. RNA-sequencing analysis identifies that genes of ECM-related signaling pathways are notably affected by BS. BS can not only inhibit the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and reduce pulmonary fibrosis-related inflammation, but also reduce NF-κB-activated transcriptional expression of transforming growth factor-β1 (TGF-β1), which leads to the inactivation of Smad2/Smad3 and decrease of collagen formation and fibrosis. Moreover, the knockdown of Trx1 with siRNA can also inhibit NF-κB/TGF-β1/Smads signaling. In conclusion, the TrxR/Trx inhibitor butaselen can suppress pulmonary fibrosis by inhibiting NF-κB/TGF-β1/Smads signaling.

Endochondral ossification (ECO) plays an integral part in bone augmentation, which undergoes sequential processes including mesenchymal stem cells (MSC) condensation, chondrocyte differentiation, chondrocyte hypertrophy, and mineralized bone formation. Thus, accelerating these steps will speed up the osteogenesis process through ECO. Herein, inspired by the marine mussels' adhesive mechanism, a bioactive glass-dopamine (BG-Dopa) hydrogel was prepared by distributing the micro-nano BG to aldehyde modified hyaluronic acid with dopamine-modified gelatin. By in vitro and in vivo experiments, we confirm that after implanting in the bone augmentation position, the hydrogel can adhere to the cortical bone surface firmly without sliding. Moreover, the condensation and hypertrophy of stem cells were accelerated at the early stage of ECO. Whereafter, the osteogenic differentiation of the hypertrophic chondrocytes was promoted, which lead to accelerating the late stage of ECO process to achieve more bone augmentation. This experiment provides a new idea for the design of bone augmentation materials.

Fractures and rock blocks are the essential components of rock mass, random fractured rock is the general manifestation of fractured rock mass, which is particularly significant in scale effect. To facilitate the tests, most of the previous studies on fractured rock mass were conducted on regular fractured rocks, which is not conducive to fully revealing the mechanical properties and failure characteristics of fractured rock mass. In this paper, the random fractured rock samples were produced with rock-like materials to investigate the fracture propagation and scale effect under compression-shear condition. Specifically, the samples were loaded by controlling the compression-shear angle to study the mechanical responses. In the test, speckle changes on the samples surface were recorded in real time, and the evolution of strain field was analyzed by digital image processing technology. Then, the internal relations among compression-shear angle, fracture distribution and crack propagation were discussed. Meanwhile, the failure modes of the random fractured samples with different compression-shear angles were summarized to reveal the influence of compression-shear angle on failure mode. Combined with PFC2D, the random fractured rock models of different scales were established to explore the mechanical characteristic variation, and the representative elementary volume of shear modulus was finally determined.

ABSTRACT: Feather pecking (FP) is a multifactorial abnormal behavior in laying hens where they display harmful pecks in conspecifics. FP has been associated with the altered functioning of the microbiome-gut-brain axis affecting host emotions and social behavior. The altered levels of serotonin (5-HT), a key monoaminergic neurotransmitter at both terminals of the gut-brain axis, affect the development of abnormal behavior, such as FP in laying hens. However, the underlying mechanism involving reciprocal interactions along the microbiota-gut-brain axis, particularly about the metabolism of 5-HT, remains unclear in FP phenotypes. This study examined the microbiota diversity, intestinal microbial metabolites, inflammatory responses, and 5-HT metabolism in divergently selected high (HFP; n = 8) and low (LFP; n = 8) FP hens to investigate the possible interconnections between FP behavior and the examined parameters. The 16S rRNA analysis revealed that compared to LFP birds, the gut microbiota of HFP birds exhibited a decrease in the abundance of phylum Firmicutes and genera Lactobacillus, while an increase in the abundance of phylum Proteobacteria and genera Escherichia Shigella and Desulfovibrio. Furthermore, the intestinal differential metabolites associated with FP phenotypes were mainly enriched in the tryptophan metabolic pathway. HFP birds had higher tryptophan metabolites and possibly a more responsive immune system compared to the LFP birds. This was indirectly supported by altered TNF-α levels in the serum and expression of inflammatory factor in the gut and brain. Moreover, HFP birds had lower serum levels of tryptophan and 5-HT compared to LFP birds, which was consistent with the downregulation of 5-HT metabolism-related genes in the brain of HFP birds. The correlation analysis revealed that genera Lactobacillus and Desulfovibrio were associated with differences in intestinal metabolites, 5-HT metabolism, and inflammatory response between the LFP and HFP birds. In conclusion, differences in the cecal microbiota profile, immune response and 5-HT metabolism drive FP phenotypes, which could be associated with the gut abundance of genera Lactobacillus and Desulfovibrio.

In present work, a novel heavy density matrix alloy (Ni–W–Co) was produced through vacuum induction melting (VIM) and vacuum arc remelting (VAR). The as-cast microstructure, element segregation, and mechanical properties were characterized by optical microscopy, scanning electron microscopy, electron probe microanalysis, and universal tensile testing machine. Results indicated that the present matrix alloy displays a considerable purity and chemical homogeneity. The microstructure exhibits typical dendritic features, which is composed of austenite single-phase structure entirely. The elements Ni and Co are evenly distributed in the matrix, while W shows a distinct segregation trend in the as-cast ingot. The tensile properties of the as-cast alloy at room temperature show that the maximum ultimate tensile strength and fracture elongation are up to 560Mpa and 55.79%, respectively. Tensile fracture morphologies reveal the presence of complex quasi cleavage and ductile fractures. The true stress-plastic strain curves display distinct linear deviation in the region of uniform plastic deformation and exhibit two groups of positive and negative slopes at the lower and higher strains, respectively. The instantaneous work hardening rate-true strain curves depict typical “three stages” hardening characteristics.

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.

PtRh alloys are highly active in the anodic methanol oxidation reaction (MOR) but few studies have looked at their evolution in the composition and structure during the catalytic process. Herein, a uniformly dispersed carbon-supported PtRh (PtRh/C) catalyst with Rh-enriched surface was synthesized via a facial hydrothermal method. By recording the performance of different cyclic voltammetry (CV) cycles during electrocatalytic MOR process in acid, the evolution of PtRh/C in composition and structure was elucidated. During the first 80 CV cycles, the rapid dissolution of the surface Rh atoms and the exposure of active Pt sites lead to the dramatic enhancement of the current density. When further continue the CV cycling, Pt atoms on the surface have aggregated and recombined to form a tightly aligned Pt-enriched surface. But Rh tends to be stable and catalytic performance reaches a relatively stable status with slightly decreased activity. Compared with the performance of PtRu/C catalyst, it can be concluded that PtRh/C has better stability and higher activity based on the less soluble property of Rh than Ru. Keywords: PtRh alloys, Anode catalysts, Methanol electrooxidation, Structural evolution, Compositional evolution

Summary: This study investigates stress’s impact on Alzheimer’s disease (AD) using male APP/PS1 transgenic mice. Negative stressors (chronic social defeat, restraint) and positive hedonia (environmental enrichment, EE) were applied. Stress worsens AD pathology, while EE slows progression. Brain RNA sequencing reveals interleukin-6 (IL-6) and IL-10 as key stress-related AD regulators. Flow cytometry shows that the CD8+/CD4+ T cell ratio shifts in response to stress exposure and EE. Stress exposure increases CD8+/CD4+ ratio, opposite to EE. Depletion and enrichment of CD8+ T cells both accelerate AD, indicating immune intervention’s negative impact. Stress management and balanced immunity may aid AD therapy, highlighting novel potential treatment.

Summary: Capturing conformational snapshots by single-particle cryo-EM facilitates the analysis of ligand binding and activation mechanisms for ion channels and other receptor complexes. Here, we present a protocol to capture intermediate states of nanodisc-reconstituted TRPV1. This protocol covers sample preparation, data acquisition, and image processing with focuses on the symmetry expansion and focused 3D classification. This protocol can be adapted to different proteins and samples.For complete details on the use and execution of this protocol, please refer to Zhang et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Antibody-dependent enhancement (ADE) exists in several kinds of virus. It has a negative influence on antibody therapy for viral infection. This effect was first identified in dengue virus and has since also been described for coronavirus. To date, the rapid spread of the newly emerged coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has affected over 3.8 million people across the globe. The novel coronavirus poses a great challenge and has caused a wave of panic. In this review, antibody-dependent enhancements in dengue virus and two kinds of coronavirus are summarized. Possible solutions for the effects are reported. We also speculate that ADE may exist in SARS-CoV-2.

AreTomo, an abbreviation for Alignment and Reconstruction for Electron Tomography, is a GPU accelerated software package that fully automates motion-corrected marker-free tomographic alignment and reconstruction in a single package. By correcting in-plane rotation, translation, and importantly, the local motion resulting from beam-induced motion from tilt to tilt, AreTomo can produce tomograms with sufficient accuracy to be directly used for subtomogram averaging. Another major application is the on-the-fly reconstruction of tomograms in parallel with tilt series collection to provide users with real-time feedback of sample quality allowing users to make any necessary adjustments of collection parameters. Here, the multiple alignment algorithms implemented in AreTomo are described and the local motions measured on a typical tilt series are analyzed. The residual local motion after correction for global motion was found in the range of ± 80 Å, indicating that the accurate correction of local motion is critical for high-resolution cryo-electron tomography (cryoET).

The coronavirus disease 2019 (COVID-19) is a new type of pneumonia caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. COVID-19 is affecting millions of patients, and the infected number keeps increasing. SARS-CoV-2 is highly infectious, has a long incubation period, and causes a relatively high death rate, resulting in severe health problems all over the world. Currently there is no effective proven drug for the treatment of COVID-19; therefore, development of effective therapeutic drugs to suppress SARS-CoV-2 infection is urgently needed. In this review, we first summarize the structure and genome features of SARS-CoV-2 and introduce its infection and replication process. Then, we review the clinical symptoms, diagnosis, and treatment options of COVID-19 patients. We further discuss the potential molecular targets and drug development strategies for treatment of the emerging COVID-19. Finally, we summarize clinical trials of some potential therapeutic drugs and the results of vaccine development. This review provides some insights for the treatment of COVID-19.

The hexameric AAA+ ATPases Rvb1 and Rvb2 (Rvbs) are essential for diverse processes ranging from metabolic signaling to chromatin remodeling, but their functions are unknown. While originally thought to act as helicases, recent proposals suggest that Rvbs act as protein assembly chaperones. However, experimental evidence for chaperone-like behavior is lacking. Here, we identify a potent protein activator of the Rvbs, a domain in the Ino80 ATPase subunit of the INO80 chromatin-remodeling complex, termed Ino80INS. Ino80INS stimulates Rvbs’ ATPase activity by 16-fold while concomitantly promoting their dodecamerization. Using mass spectrometry, cryo-EM, and integrative modeling, we find that Ino80INS binds asymmetrically along the dodecamerization interface, resulting in a conformationally flexible dodecamer that collapses into hexamers upon ATP addition. Our results demonstrate the chaperone-like potential of Rvb1/Rvb2 and suggest a model where binding of multiple clients such as Ino80 stimulates ATP-driven cycling between hexamers and dodecamers, providing iterative opportunities for correct subunit assembly.

Summary: As a Ca2+-activated lipid scramblase and ion channel that mediates Ca2+ influx, TMEM16F relies on both functions to facilitate extracellular vesicle generation, blood coagulation, and bone formation. How a bona fide ion channel scrambles lipids remains elusive. Our structural analyses revealed the coexistence of an intact channel pore and PIP2-dependent protein conformation changes leading to membrane distortion. Correlated to the extent of membrane distortion, many tightly bound lipids are slanted. Structure-based mutagenesis studies further reveal that neutralization of some lipid-binding residues or those near membrane distortion specifically alters the onset of lipid scrambling, but not Ca2+ influx, thus identifying features outside of channel pore that are important for lipid scrambling. Together, our studies demonstrate that membrane distortion does not require open hydrophilic grooves facing the membrane interior and provide further evidence to suggest separate pathways for lipid scrambling and ion permeation. : TMEM16F is a calcium-activated ion channel and lipid scramblase linked to the bleeding disorder Scott syndrome. Feng et al. examine cryo-EM structures of TMEM16F with or without Ca2+ ions and PIP2 nanodisc supplementation and identify structural features for lipid binding and membrane distortion critical for lipid scrambling activity. Keywords: TMEM16F, cryo-EM, membrane distortion, lipid scramblase, ion channel, calcium, PIP2 modulation