Browse Articles

Generating the polymorph landscapes of amyloid fibrils using AI: RibbonFold

The concept that proteins are selected to fold into a well-defined native state has been effectively addressed within the framework of energy landscapes, underpinning the recent successes of structure prediction tools like AlphaFold. The amyloid fold, however, does not represent a unique minimum for a given single sequence. While the cross- β hydrogen-bonding pattern is common to all amyloids, other aspects of amyloid fiber structures are sensitive not only to the sequence of the aggregating peptides but also to the experimental conditions. This polymorphic nature of amyloid structures challenges structure predictions. In this paper, we use AI to explore the landscape of possible amyloid protofilament structures composed of a single stack of peptides aligned in a parallel, in-register manner. This perspective enables a practical method for predicting protofilament structures of arbitrary sequences: RibbonFold. RibbonFold is adapted from AlphaFold2, incorporating parallel in-register constraints within AlphaFold2’s template module, along with an appropriate polymorphism loss function to address the structural diversity of folds. RibbonFold outperforms AlphaFold2/3 on independent test sets, achieving a mean TM-score of 0.5. RibbonFold proves well-suited to study the polymorphic landscapes of widely studied sequences with documented polymorphisms. The resulting landscapes capture these observed polymorphisms effectively. We show that while well-known amyloid-forming sequences exhibit a limited number of plausible polymorphs on their “solubility” landscape, randomly shuffled sequences with the same composition appear to be negatively selected in terms of their relative solubility. RibbonFold is a valuable framework for structurally characterizing amyloid polymorphism landscapes.

Evaluation of pre- and in-hospital workflows and time intervals with acute ischemic stroke patients

Objective Stroke is one of the leading causes of death and disability globally. Rapid recanalization therapy for acute ischemic stroke (AIS) patients is critical for improving outcome. While in-hospital time intervals have decreased and treatment methods have improved over the past decade, pre-hospital time intervals have remained unchanged. This study aims to develop a comprehensive understanding of the prognosis of AIS patients based on pre-hospital and in-hospital data. Methods A retrospective study was conducted in Southwest Finland covering the period of 01/01/2022-31/12/2022. The study included a total of 174 AIS patients who were conveyed by the emergency medical services (EMS) to Turku University Hospital (TUH) and given intravenous thrombolysis (IVT) and/or endovascular treatment (EVT). Pre- and in-hospital care records of AIS patients were analyzed to evaluate workflows, time intervals, and the impacts of these time intervals on patient outcome. Binary logistic regression analysis was utilized to identify predictors of on-scene time (OST) and favorable outcome. Results The median OST for EMS was 19 minutes. Analysis indicated that the scene of the stroke event being an apartment building, barriers to care such as a locked door, vertigo as a symptom, and EMS taking measurements on-scene were predictive of longer OST. Longer OST was observed to negatively impact patient outcome, along with symptom severity and gender. Using the stroke code as the dispatch code and positive FAST signs were associated with shorter OST. In-hospital median door to needle time (DNT) was 14 minutes in the IVT group and 11 minutes in the IVT+EVT group. EMS prenotification was associated with shorter in-hospital time intervals. Conclusions The presence of vertigo as a symptom poses challenges to identification by EMS. Pre-hospital OST meets national targets, but EMS workflows could be optimized to reduce OST and thereby positively influence patient outcome. These findings underscore the need for targeted interventions in EMS protocols to improve stroke care outcomes.

A dynamic modeling approach for six-degree-of-freedom control of maglev planar motors with reference trajectory tracking

CD70 recruitment to the immunological synapse is dependent on CD20 in B cells

CD20 is a four-transmembrane protein expressed at the surface of B cells from late pro-B cells to memory B cells, with the exception of plasma cells. Its expression pattern makes it an attractive therapeutic target for different B cell malignancies and autoimmune diseases. Despite the clinical success of CD20-targeting antibodies, the biology of the CD20 protein is still not well understood. We investigated CD20 binding partners in the membrane of human B cells using immunoprecipitation followed by mass spectrometry analysis. We identified a molecular interaction between CD70 and CD20, and confirmed this using proximity ligation assays. CD20–CD70 spatiotemporal colocalization was validated at the plasma membrane of B cells using high-resolution microscopy. Cell surface expression of CD70 was found to be enhanced upon CD20 overexpression, suggesting a role for CD20 in stabilizing CD70 at the B cell membrane. Moreover, we observed impaired B-T cell synapse formation and defective recruitment of CD70 to the immunological synapse in the absence of CD20. Impaired synapse formation was confirmed by deleting CD20 in primary B cells, and analysis of B cells from a CD20-deficient patient. Finally, CD20-deletion resulted in diminished T cell activation and cytokine secretion. Together, this study demonstrates that CD20 interacts with CD70 at the B cell membrane, and that CD20 is required for immune synapse formation between B and T cells and consequent T cell activation.

Real-world evidence in gynecologic cancers presented at key oncology conferences in the United States: Distribution and factors related to high-tier acceptance

Purpose To describe the distribution, trends, and characteristics of types of real-world evidence (RWE) abstracts presented at key oncology congresses. Methods Data on gynecologic cancers (cervical, ovarian, endometrial, and multiple gynecologic/other) were extracted from the American Society of Clinical Oncology (ASCO) and the Society of Gynecologic Oncology (SGO) conference databases (2018–2020) to: a) identify the proportion of clinical trial (CT) versus RWE abstracts accepted; b) describe the distribution and tier of acceptance of RWE versus CTs; c) analyze the characteristics (authorship, data source, data type, study design, outcome[s], and presence of statistically significant results) associated with RWE acceptance. Results Of 3163 abstracts screened, 2271 (77% RWE, 23% CTs) were included. RWE represented a higher proportion of work at SGO versus ASCO (70% vs 30%). Overall, more RWE studies versus CTs were accepted as posters (75% vs 60%), while fewer were accepted as oral presentations (4% vs 20%; p < 0.001 for both). Among RWE abstracts, 90% had academic author(s), 68% of studies were from North America, 45% used other clinical data sources, and nearly 32% reported statistically significant results. Approximately 60% of RWE were retrospective and 9% were prospective. The most common outcomes in RWE abstracts were molecular analyses (18%) and survival based on treatment efficacy (13%; p < 0.001). Conclusion RWE abstracts were accepted for presentation more frequently at SGO versus ASCO, and majority of them were presented as posters. While RWE abstracts are prevalent and provide valuable data for healthcare decision-making, they do not always achieve the visibility of CTs.

Women who hate men: a comparative analysis across extremist Reddit communities

Protein Phosphatase 1 Regulatory Subunit 3C integrates cholesterol metabolism and isocitrate dehydrogenase in chondrocytes and neoplasia

Enchondromas are common bone tumors composed of chondrocytes originating from growth plate cells which can progress to malignant chondrosarcoma. Mutations in the genes encoding isocitrate dehydrogenase (IDH1 and IDH2) are identified in a large proportion of these tumors. IDH enzymes convert isocitrate to alpha-ketoglutarate (α-KG), an essential component of the citric acid cycle. While mutant IDH enzymes produce 2-hydroxyglutarate, which has epigenetic effects important in tumor initiation, cell maintenance and growth rely on additional factors. Prior work shows that intracellular cholesterol and glycogen are upregulated in mutant IDH chondrocytes. Here, we show that Protein Phosphatase 1 Regulatory Subunit 3C (PPP1R3C, previously termed Protein Targeting to Glycogen or PTG) is highly expressed in chondrocytes harboring a mutant IDH. Furthermore, Sterol Regulatory Element-Binding Proteins (SREBPs), transcriptional regulators of sterol biosynthesis, regulate PPP1R3C expression. We found that PPP1R3C regulates glycolysis and glycolytic capacity in chondrocytes. Depletion of PPP1R3C in mouse chondrocytes in vivo suppresses the neoplastic phenotype. The growth plate phenotype associated with the genetic inhibition of cholesterol biosynthesis is partially rescued by PPP1R3C overexpression. Taken together, our data show that PPP1R3C integrates cholesterol metabolism and isocitrate dehydrogenase in growth plate and neoplastic chondrocyte metabolism by regulating intracellular glycogen levels.

A study of text classification algorithms for live-streaming e-commerce comments based on improved BERT model

As e-commerce live streaming becomes increasingly popular, the textual analysis of bullet comments is becoming more and more important. Bullet comments is characterized by its brevity, diverse content, and vast quantity. Faced with these challenges, this study proposes an improved BERT model based on a hierarchical structure for classifying e-commerce bullet comments. First, a parent class BERT model is trained to categorize bullet comments into six designated categories (parent categories). Subsequently, subclass BERT models are trained to classify bullet comments into subcategories. The model combines BERT’s profound semantic comprehension with the closely categorized capabilities of the hierarchical structure. Empirical evidence shows that the proposed model significantly improves classification accuracy and efficiency, aiding in further analysis of bullet comments, extracting valuable information, and achieving effective marketing.

Metagenomic NGS reveals determinants of polymicrobial spinal infection pathogenesis

Sexual harassment thrives in silence, even in gender-equality hotspots

The evolution of robustness and fragility during long-term bacterial adaptation

Theory predicts that well-adapted populations may evolve mechanisms to counteract the inevitable influx of deleterious mutations. While mutational robustness can be directly selected in the laboratory, evidence for its spontaneous evolution during general adaptation is mixed. Moreover, whether robustness evolves to include pleiotropic effects remains largely unexplored. Here, we studied the effects of point mutations in the RNA polymerase of Escherichia coli over a 15,000-generation adaptive trajectory. Fitness effects of both beneficial and deleterious mutations were attenuated in fitter backgrounds. In contrast, pleiotropic effects became more severe and widespread with greater adaptation. These results show that trade-offs between robustness and fragility can evolve in regulatory networks, regardless of whether driven by adaptive or nonadaptive processes. More broadly, they illustrate how adaptation can generate hidden variability, with unpredictable evolutionary consequences in new environments.

Correction: Different dry-wet pulses favor different functional strategies: A test using tropical dry forest tree species

The shallowest transparent and interpretable deep neural network for image recognition

Genomic signatures associated with the evolutionary loss of egg yolk in parasitoid wasps

Trait regression and loss have occurred repeatedly in numerous lineages in response to environmental changes. In parasitoid wasps, a megadiverse group of hymenopteran insects, yolk protein reduction or loss has been observed in many species, likely linked to the transition from ectoparasitism to endoparasitism. However, the genetic basis of this trait and the impact of its loss on genome evolution remain poorly understood. Here, we performed a comparative genomic analysis of 64 hymenopteran insects. The conserved insect yolk protein gene vitellogenin ( Vg ) underwent five independent loss events in four families, involving 23 of the analyzed endoparasitoid species. Whole-genome alignment suggested that Vg loss occurred during genome rearrangement events. Analysis of Vg receptor gene ( VgR ) loss, selection, and structural variation in lineages lacking Vg demonstrated functional biases in the patterns of gene loss. The ectoparasitism to endoparasitism transition did not appear to be the primary driver of Vg loss or the subsequent VgR evolution. Together, these findings reveal the genomic changes underlying a unique trait loss in parasitoid wasps. More broadly, this study enhances our understanding of yolk protein loss evolution outside the class Mammalia, highlighting a potential evolutionary trend arising from the availability of an alternative nutrient source for embryonic development.

Population interest in and adequacy of the information on the safety of antineoplastic agents in the Spanish edition of Wikipedia

Objective To analyse the trend in use of the main antineoplastic agents (ANP) in Spain, to determine the association of this trend with the number of visits to the related pages in the Spanish edition of Wikipedia and to verify the existence of information aimed at reducing the associated risks of exposure to these drugs. Methods This study had an ecological, descriptive cross-sectional design. The ANP for which more than 100,000 units were used per year in the Spanish Health System were included in the analyses. The trend in the use of these ANP and the number of visits to the pages for these ANP in Wikipedia were analysed using a regression model, and the correlation of these variables was evaluated. Fulfilment of the criteria related to medical-pharmaceutical information (MPI) and safety measure information (SMI) was determined. Results An increasing trend in the use of ANP was observed for the 9 ANP included in this study: paclitaxel, fluorouracil, azacitidine, oxaliplatin, rituximab, carboplatin, doxorubicin, etoposide, cyclophosphamide, and fluorouracil, which were the most commonly used ANP in the study period. Visits to the Wikipedia pages for the 9 ANP showed a decreasing trend, with an inverse relationship between use and visits to the related Wikipedia pages. Regarding MPI criteria, only the indication/use was included in all ANP pages, and no more than 30% of the remaining criteria were met, with the exception of rituximab, for which 50% of the remaining criteria were met. The SMI criteria were not fulfilled by the ANP pages; effects on fertility were included in 2 (22%) ANP pages and effects on pregnancy were included in 4 (44%) ANP pages. A molecular identifier appeared in 7 of the ANP pages. Conclusions The consumption of ANP increased, whereas the population interest in visiting related Wikipedia pages decreased. Neither MFI nor SMI were readily available in the ANP articles (pages), including information on the risk of exposure to these dangerous drugs or how to reduce this risk.

A predictive model based on program cell death genes for prognosis and therapeutic response in early stage hepatocellular carcinoma

The Q226L mutation can convert a highly pathogenic H5 2.3.4.4e virus to bind human-type receptors

H5Nx viruses continue to wreak havoc in avian and mammalian species worldwide. The virus distinguishes itself by the ability to replicate to high titers and transmit efficiently in a wide variety of hosts in diverse climatic environments. Fortunately, transmission to and between humans is scarce. Yet, if such an event were to occur, it could spark a pandemic as humans are immunologically naïve to H5 viruses. A significant determinant of transmission to and between humans is the ability of the influenza A virus hemagglutinin (HA) protein to shift from an avian-type to a human-type receptor specificity. Here, we demonstrate that a 2016 2.3.4.4e virus HA can convert to human-type receptor binding via a single Q226L mutation, in contrast to a cleavage-modified 2016 2.3.4.4b virus HA. Using glycan arrays, X-ray structural analyses, tissue- and direct glycan binding, we show that L133a Δ and 227Q are vital for this phenotype. Thus, whereas the 2.3.4.4e virus HA only needs a single amino acid mutation, the modified 2016 2.3.4.4b HA was not easily converted to human-type receptor specificity.

Correction: Fall prediction in a quiet standing balance test via machine learning: Is it possible?

Optimal distributed generation placement and sizing using modified grey wolf optimization and ETAP for power system performance enhancement and protection adaptation

Mechanism of allosteric activation in human mitochondrial ClpP protease

Human ClpP protease contributes to mitochondrial protein quality control by degrading misfolded proteins. ClpP is overexpressed in cancers such as acute myeloid leukemia (AML), where its inhibition leads to the accumulation of damaged respiratory chain subunits and cell death. Conversely, hyperactivating ClpP with small-molecule activators, such as the recently discovered ONC201, disrupts mitochondrial protein degradation and impairs respiration in cancer cells. Despite its critical role in human health, the mechanism underlying the structural and functional properties of human ClpP remains elusive. Notably, human ClpP is paradoxically activated by active-site inhibitors. All available structures of human ClpP published to date are in the inactive compact or compressed states, surprisingly even when ClpP is bound to an activator molecule such as ONC201. Here, we present structures of human mitochondrial ClpP in the active extended state, including a pair of structures where ClpP is bound to an active-site inhibitor. We demonstrate that amino acid substitutions in the handle region (A192E and E196R) recreate a conserved salt bridge found in bacterial ClpP, stabilizing the extended active state and significantly enhancing ClpP activity. We elucidate the ClpP activation mechanism, highlighting a hormetic effect where substoichiometric inhibitor binding triggers an allosteric transition that drives ClpP into its active extended state. Our findings link the conformational dynamics of ClpP to its catalytic function and provide high-resolution structures for the rational design of potent and specific ClpP inhibitors, with implications for targeting AML and other disorders with ClpP involvement.