Critical Response Research Articles

The configuration of the vacuole is driven by clathrin-mediated trafficking in root cells of Arabidopsis thaliana.

The central vacuole is a multifunctional organelle with the most significant occupancy in a differentiated plant cell. Plants depend on the function of the vacuole for critical development, growth, and environmental responses. As the cell expands, the vacuole changes shape and size, increasing its membrane and luminal content. The set of these events is called the vacuolar configuration process, which is scarcely described. Our research highlights the impact of plasma membrane internalization on vacuole morphology during the vacuolar configuration process. We observed a direct correlation between differential endocytosis rates and the enrichment of vacuolar membranous structures. Chemical and genetic interference of Clathrin-Mediated Endocytosis (CME) revealed that it is required for the vacuolar configuration of growing root cells. The contribution of CME to the vacuole configuration process co-occurs with the induction of post-TGN/EE trafficking with the participation of the Rab GTPases ARA6 and ARA7. Our results show that the CME plays an active role during the vacuole configuration, most likely carrying the material that allows the establishment of the vacuole on elongating cells. Since membrane trafficking through the EE/TGN is required to reach the vacuole, additional actors must be defined.

Critical response of a single-degree-of-freedom system with bilinear hysteresis and viscous damping under triple impulse

A triple impulse is used as a mathematical model of forward-directivity inputs, which are fault-normal components of near-fault earthquake ground motions. In this paper, two types of the triple impulse input are employed. One is the triple impulse with the same time interval. The critical triple impulse of this sequence is defined as the triple impulse with the critical time intervals maximizing the displacement response, and the critical time intervals are necessary to be captured by changing the time intervals. The other is the triple impulse, with second and third impulses acting at zero-restoring force points. The elastic–plastic responses of single-degree-of-freedom (SDOF) systems with bilinear hysteresis and viscous damping under the two types of triple impulses are obtained by time-history response analysis and compared. Furthermore, approximate expressions are derived for the responses of the damped bilinear hysteretic SDOF system under the triple impulse (the latter triple impulse stated above), with impulses acting at the zero-restoring force timing. In response derivation, a quadratic function approximation of the damping force–displacement relationship and an energy balance approach are employed. The validity of the triple impulse as the model of the forward-directivity input and the accuracy of approximate expressions to the triple impulse (the latter triple impulse stated above) are checked by comparing them with responses under the equivalent three wavelets of sinusoidal waves and the Ricker wavelet.

Novel Approach to Screen Endocrine-Disrupting Chemicals via Endocrine-Enhanced Reduced Human Transcriptome.

Endocrine-disrupting chemicals (EDCs) can interfere with multiple pathways and trigger different modes of action. Thus, the traditional EDC in vitro screening processes often require a battery of bioassays to cover multiple target pathways. Here we developed an endocrine-enhanced reduced human transcriptome (ERHT) focused on hormone receptor signaling induced by the EDCs regulating specific genes. ERHT was developed based on 1200 prioritized genes covering 110 endocrine-related biological pathways across eight potential adverse outcomes. The ability of this approach to identify EDCs was derived from machine learning of 1068 dose-dependent transcriptome profiles and enhanced by quantifying chemical-induced critical pathway responses, and thus, it demonstrated excellent classification performance (AUC = 0.84 ± 0.03) in internal cross-validation. We ultimately applied this approach to known EDCs and inactive substances to validate the reliability of this approach. Through external validation on 210 chemicals, the extrapolation accuracy exceeded 80%, demonstrating the outstanding practical performance of this approach. Meanwhile, the pathway responses induced by the same chemical were consistent with the experimental results reported by multiple sequencing platforms, highlighting the robustness of this approach. The above results demonstrate that this approach can provide novel insights for EDCs' high-throughput screening and comprehensive toxic mechanisms through biological pathways.

Unveiling the Catalytic Mechanism of Abl1 Kinase: A Single-Magnesium Ion Pathway for Phosphoryl Transfer.

Abl1, a nonreceptor tyrosine kinase closely related to Src kinase, regulates critical cellular processes like proliferation, differentiation, cytoskeletal dynamics, and response to environmental cues through phosphorylation-driven activation. Dysregulation places it centrally in the oncogenic pathway leading to blood cancers. making it an ideal drug target for small molecule inhibitors. We sought to understand the underlying mechanism of the phosphoryl-transfer step from the ATP molecule to the substrate tyrosine, as carried out by the Abl1 enzyme. By calculating free energy profiles for the reaction using the empirical valence bond representation of the reacting fragments paired with molecular dynamics and free energy perturbation calculations, a combination of several plausible reaction pathways, ATP conformations, and the number of magnesium ion cofactors have been investigated. For the best-catalyzed pathway, which proceeds through a dissociative mechanism with a single magnesium ion situated in Site I, a close agreement was reached with the experimentally determined catalytic rates. We conclude that the catalytic mechanism in Abl1 requires one magnesium ion for efficient catalysis, unlike other kinases, where two ions are utilized. A better overall understanding of the phosphoryl-transfer reactions in Abl1 can be used for type-I inhibitor development and generally contributes to a comprehensive overview of the mechanism for ATP-driven reactions.

Impact of the COVID-19 pandemic on mHealth adoption: Identification of the main barriers through an international comparative analysis.

Impact of the COVID-19 pandemic on mHealth adoption: Identification of the main barriers through an international comparative analysis.

TGF-beta plays dual roles in immunity and pathogenesis in leishmaniasis.

TGF-beta plays dual roles in immunity and pathogenesis in leishmaniasis.

Surviving in a Warmer Marine World: A Study on the Impact of Thermal Effluent on Posidonia oceanica Meadows and Associated Fish Assemblages in the Maltese Islands

Ocean warming poses significant threats to coastal ecosystems. This study investigates the impact of thermal effluents from power plants, as proxies for climate-driven temperatures increase, on Posidonia oceanica meadows and associated fish communities. Using a gradient-based approach, we analyzed environmental variables, seagrass indicators, fish assemblages, and functional group (FG) dynamics across a thermal gradient extending from the effluent outfall itself. Results indicate that temperature is the dominant factor influencing P. oceanica, with reduced leaf length, shoot density, and rhizome weight characterizing samples closest to the effluent. Despite compensatory mechanisms, the overall photosynthetic biomass and resilience declined under thermal stress. Fish assemblages exhibited reduced species richness and biodiversity close to the thermal effluent, with opportunistic and thermophilic species dominating. An FG analysis revealed disrupted seasonal patterns, shifts in trophic dynamics, and functional compensation among species, highlighting potential ecological imbalances. Notably, transient predators thrived near the effluent, while more sedentary and temperate species were displaced. These findings underscore the cascading effects of rising temperatures on coastal habitats such as P. oceanica meadows and their associated communities, emphasizing the urgency for conservation measures. By identifying critical thresholds and adaptive responses, this study contributes valuable insights into the consequences of localized impacts of thermal stress on coastal biodiversity and ecosystem services.

A comprehensive numerical and experimental studies on static, buckling and dynamic behaviour of graphene-reinforced GFRP tapered laminated composite plates

This study developed a numerical model to analyze Glass/Epoxy composites enhanced with nanographene fillers across three tapered configurations (TM1, TM2, TM3). The incorporation of graphene demonstrated significant resistance to material property degradation under thermal loading, resulting in improved critical buckling loads and natural frequencies. The developed numerical model is validated with experimental work with numerical results such as critical buckling load and natural frequencies of tapered plates for a few cases and additionally with numerical study available with literature. A detailed parametric study has been conducted to understand the effects of the weight fraction of fiber, weight fraction of graphene, temperature on critical, buckling load, natural frequencies and dynamic response of various composite tapered plates. The numerical analysis showed that adding graphene to the composite plates increased their critical buckling load, with the TM-3 configuration showing the highest values (6.992 kN), followed by TM-2 (6.456 kN) and TM-1 (6.079 kN). Static deflection analysis identified an optimal graphene content of 0.5% at 45 °C, with deflection resistance showing marked improvement across temperature ranges - specimens with 0.0075% graphene exhibited only a 7.2% deflection increase from 30 °C to 90 °C compared to 12.4% in pure GFRP specimens. The natural frequency measurements established TM-2 as the most dynamically responsive configuration with the highest frequency of 65.4 Hz with 1% graphene, representing a 12% improvement over the uniform plate configuration (58.3 Hz), while mode (1,2) demonstrated even greater sensitivity with TM-2 frequency increasing from 55.445 Hz to 63.572 Hz.

Market dynamics and critical responses of leading European banks to ECB’s expansionary policies

Market dynamics and critical responses of leading European banks to ECB’s expansionary policies

Dam Deformation Data Preprocessing with Optimized Variational Mode Decomposition and Kernel Density Estimation

Deformation is one of the critical response quantities reflecting the structural safety of dams. To enhance outlier identification and denoising in dam deformation monitoring data, this study proposes a novel preprocessing method based on optimized Variational Mode Decomposition (VMD) and Kernel Density Estimation (KDE). The approach systematically processes data in three steps: First, VMD decomposes raw data into intrinsic mode functions without recursion. The parallel Jaya algorithm is used to adaptively optimize VMD parameters for improved decomposition. Second, the intrinsic mode functions containing outlier and noise characteristics are identified and separated using sample entropy and correlation coefficients. Finally, KDE thresholds are applied for outlier localization, while a data superposition method ensures effective denoising. Validation using simulated deformation data and Global Navigation Satellite Systems (GNSS)-based observed horizontal deformation from dam engineering demonstrates the method’s robustness in accurately identifying outliers and denoising data, achieving superior preprocessing performance.

Universals, difference, and ghosts: A response to Joseph Blankholm's the secular paradox

This essay provides a critical response to Joseph Blankholm’s new work The Secular Paradox. I praise the book for its ingenuity and then raise questions about how the experience of what he calls the “secular paradox” might vary by racial identity. I also explore the intolerance of western liberalism toward ghosts to explore how Blankholm’s account of the secular paradox might also offer insight into America’s unwillingness to grapple with its primitive past.

Lipid remodeling and response mechanisms during the germination of aged oat seeds

BackgroundThe high fat content in oat seeds makes them susceptible to aging during storage, leading to reduced seed vigor, delayed germination, and even seed death. Much evidence suggests that lipid remodeling is closely associated with successful seed germination. However, the dynamic behavior and response mechanisms of lipids during the germination of aged oat seeds remain unclear. In this study, ‘Monida’ (aging-tolerant) and ‘Haywire’ (aging-sensitive), were used to investigate the lipid profiles in the embryo and endosperm and the dynamic transcriptomic differences in the embryo during the germination.ResultsThe results demonstrate that phospholipid alterations during the germination of aged seeds are more significant compared to unaged seeds, indicating that aging affects lipid remodeling during germination, particularly in the ‘Haywire’. Further analysis revealed that the most critical lipid response events occurred at the end of germination stage II (32 h) in embryo, primarily regulated through the PLC-DGK pathway to modulate phospholipid and glycerolipid molecules. Specifically, transcripts of PLC, DGK, and DGAT were upregulated, promoting the generation of diacylglycerol (DG) from various phospholipids, which further increased the monogalactosyldiacylglycerol/digalactosyldiacylglycerol (MGDG/DGDG) ratio, thereby influencing membrane repair. Additionally, at 6 h of germination in aged seeds, PC(3:0/0:0) levels significantly decreased. Compared to ‘Monida,’ the aging-sensitive ‘Haywire’ seeds exhibited substantial production of PE(19:0/0:0) and PC(15:0/0:0) at 32 h of germination, which may be key factors contributing to the seed's sensitivity to aging and the significant reduction in germination percentage after aging. Therefore, PC(3:0/0:0), PE(19:0/0:0), and PC(15:0/0:0) could serve as important lipid metabolic markers in future studies on the mechanisms of oat seed vigor.ConclusionsThe findings of this study provide insights into the specificity of lipid remodeling and its response mechanisms during the germination of aged oat seeds, providing a theoretical foundation for the safe preservation of oat germplasm and the development of aging-tolerant varieties.

The PAZ domain of Aedes aegypti Dicer 2 is critical for accurate and high-fidelity size determination of virus-derived small interfering RNAs.

The exogenous siRNA (exo-siRNA) pathway is a critical RNA interference response involved in controlling arbovirus replication in mosquito cells. It is initiated by the detection of viral long double-stranded RNA (dsRNA) by the RNase III enzyme Dicer 2 (Dcr2), which is processed into predominantly 21 nucleotide (nt) virus-derived small interfering RNAs, or vsiRNAs that are taken up by the Argonaute 2 (Ago2) protein to target viral single-stranded RNAs. The detailed understanding of Dicer structure, function and domains owes much to studies outside the context of viral infection and studies in model organisms, and as such how Dcr2 domains contribute to detecting viral dsRNA to mount antiviral responses in infected mosquito cells remains less well understood. Here, we used a Dcr2 reconstitution system in Aedes aegypti derived Dcr2 KO cells to assess the contribution of the PAZ domain to induction of the exo-siRNA pathway following infection with Semliki Forest virus (SFV; Togaviridae, Alphavirus). Amino acids critical for PAZ activity were identified, and loss of PAZ function affected the production of 21 nt vsiRNAs -with enrichment of 22 nt SFV-derived small RNAs observed- and silencing activity. This study establishes PAZ domain's functional contribution to Dcr2 processing of viral dsRNA to 21 nt vsiRNAs.

Life in the Posthuman Condition. Critical Responses to the Anthropocene

Life in the Posthuman Condition. Critical Responses to the Anthropocene

Why (not) therapy? A Lacanian psychosocial critique of the Therapeutic Turn

ABSTRACT In recent decades, the language of therapy has permeated various social contexts: from classrooms to policymaking, media, and the workplace, references to ‘boundaries,’ ‘attachment styles,’ and ‘self-care’ are proliferating. At the same time, psychotherapeutic practices have become integrated into the lifestyle of neoliberal subjects. This article critically examines debates on the therapeutic turn, proposing strategies to resist the ideological cooptation of therapeutic discourses and practices. We begin with a review of the literature, highlighting two key issues: (1) how therapeutic vocabulary obscures the social roots of psychic suffering; and (2) how therapeutic expert-knowledge serves as a privileged resource for contemporary subjects to navigate conflicting social demands. In the second part, we apply psychosocial and Lacanian theories to offer a critical response. We argue that the notion of the psychosocial subject is better equipped to theorise subjective suffering than traditional ideas of selfhood. Additionally, we draw on Lacanian epistemology to argue that clinical knowledge retains its radical edge when it challenges and unsettles accepted explanations. In a final reflection, we suggest that psychotherapists should resist taking up positions of expert-knowledge, having the courage to “remain stupid,” both inside and outside the clinic.

Book review: Cyborg Conception: Cultural and Critical Responses to Solo Motherhood by Choice

Book review: Cyborg Conception: Cultural and Critical Responses to Solo Motherhood by Choice

Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis.

Induction of podoplanin (PDPN) expression is a critical response of macrophages to LPS stimulation or bacterial infection in sepsis, but how this key process of TLR4-stimulated PDPN upregulation is regulated and the impact of PDPN expression on macrophage function remain elusive. Here, we determined how this process is regulated in vitro and in vivo. PDPN failed to be upregulated in TLR4 stimulated macrophages deficient in adhesion and degranulation-promoting adapter protein (ADAP), which could be rescued by the reconstitution of ADAP. A distinct PDPNhi peritoneal macrophage (PM) subset, which exhibited an M2-like phenotype and enhanced phagocytic activity, was generated in WT but not in ADAP-deficient septic mice. The blockade of PDPNhi PMs mimicked the effect of ADAP deficiency, which exacerbated sepsis. Mechanistically, BTK-mediated ADAP Y571 phosphorylation worked together with mTOR to converge on STAT3 activation for the transactivation of the PDPN promoter. Moreover, agonist activation of STAT3 profoundly potentiated the PDPNhi PM subset generation and alleviated sepsis severity in mice. Together, our findings reveal a mechanism whereby ADAP resets macrophage function by controlling the TLR4-induced upregulation of PDPN as a host innate immune defense during sepsis.

Blue applicability grade index assessment and response surface modelling to synchronous determination of metformin hydrochloride, vildagliptin and dapagliflozin propanediol monohydrate by HPTLC method

Diabetes mellitus is major chronic disease found in human due to stressful lifestyle and bad food habit. Recently, the Central Drugs Standard Control Organization of India has approved combination of metformin hydrochloride, vildagliptin and dapagliflozin propanediol monohydrate for the management of diabetes mellitus. Numerous chromatographic methods have been published in the literature for estimation of these anti-diabetic drugs on individual basis and their combinations. But these chromatographic analyses promoted usage of toxic organic solvents which are harmful to the environment and aquatic animal lives. In addition, no chromatographic method was found in the literature for simultaneous estimation of these anti-diabetic drugs using green solvents. In recent days, white analytical chemistry approach has been introduced in the literature for development and assessment of green, accurate, precise, cost-effective and user-friendly chromatographic methods. Hence, white analytical chemistry-driven risk-based HPTLC method was developed for synchronous estimation of these anti-diabetic drugs using green solvents and response surface modelling. The analytical quality risk assessment was applied for identification of critical method variables and response variables using risk priority number ranking and filtering method. The critical method variables were linked with critical response variables using response surface modelling by Box–Behnken design. The analytical design space was navigated control strategy was framed for robust densitometric estimation of anti-diabetic drugs. The chromatographic method was validated as per ICH Q2 (R2) guideline. The developed method was applied for synchronous assay of multiple combinations of metformin, vildagliptin and dapagliflozin using single chromatographic condition to save time, cost and resources for analysis. The assay results of these anti-diabetic drug combinations were found to be complied with the respective labelled claim of the drugs. The developed and published chromatographic methods were assessed for their redness, greenness, blueness and whiteness profiles using green analytical metrics and RGB model scoring system. The proposed method was found to be green, cost-effective, robust and user-friendly for synchronous estimation of metformin, vildagliptin and dapagliflozin.

Jeffrey Eugenides “the virgin suicides” and the convergence of literary, psychological, and social discourses on suicide

This article critically examines the representation of suicide in Jeffrey Eugenides’s The Virgin Suicides, analyzing the text as a literary work that interweaves psychological despair, social alienation, and aesthetic ambiguity. Through a close reading of narrative structure, thematic motifs, and symbolic imagery, the study explores how the novel reflects broader cultural preoccupations with suicide and the disintegration of social order. Employing a multidisciplinary methodology that integrates literary analysis, psychological criticism, and cultural studies, the article demonstrates that The Virgin Suicides not only portrays individual tragedy but also critiques the societal forces and existential dilemmas underlying contemporary experiences of despair. Additionally, the article incorporates various authors’ perceptions, highlighting the diverse critical responses that have contributed to the understanding of the text’s thematic complexity.

On the nature of signal 1 delivered to lymphocytes: A critical response to some considerations put forward in support of the quantum model of T cell activation.

The original Two Signal Model of lymphocyte activation stated that antigen-dependent lymphocyte cooperation is required for lymphocyte activation, whereas a single or a few antigen-specific lymphocytes can be inactivated by antigen. A virtue of this model is its ability to account for peripheral tolerance. Both the activation and inactivation of lymphocytes were envisaged to require the lymphocytes' antigen-specific receptors to interact with antigen, leading to signal 1. We consider here the proposition that the sensitivity to antigen concentration for the generation of signal 1, to support both differentiation processes, is the same. This situation optimizes the reliability of peripheral tolerance and minimizes the effects of lymphocyte inactivation in decreasing the diversity of the lymphocytes. We consider the broader implications of this Principle of Parsimonious Sensitivity in regulating the activity of lymphocytes.