Role of Macrophage PIST Protein in Regulating Leishmania major Infection.

PDZ protein interacting specifically with Tc10 or PIST is a mammalian trans-Golgi resident protein that regulates subcellular sorting of plasma membrane receptors. PIST has recently emerged as a key player in regulating viral pathogenesis. Nevertheless, the involvement of PIST in parasitic infections remains unexplored. Leishmania parasites infiltrate their host macrophage cells through phagocytosis, where they subsequently multiply within the parasitophorous vacuole (PV). Host cell autophagy has been found to be important in regulating this parasite infection. Since PIST plays a pivotal role in triggering autophagy through the Beclin 1-PI3KC3 pathway, it becomes interesting to identify the status of PIST during Leishmania infection. We found that while macrophage cells are infected with Leishmania major (L. major), the expression of PIST protein remains unaltered; however, it traffics from the Golgi compartment to PV. Further, we identified that in L. major-infected macrophage cells, PIST associates with the autophagy regulatory protein Beclin 1 within the PVs; however, PIST does not interact with LC3. Reduction in PIST protein through siRNA silencing significantly increased parasite burden, whereas overexpression of PIST in macrophages restricted L. major infectivity. Together, our study reports that the macrophage PIST protein is essential in regulating L. major infectivity.

Down-regulation of FA-BRCA Pathway in Cervical Carcinoma Gradually Reversed During the Development of Chemo-tolerance: Clinical Implications.

Cervical cancer is one of the leading causes of cancer death among females, worldwide. The contributory role of different cellular pathways in the process of carcinogenesis is still poorly understood. Our study was focused here to understand the functional evaluation of key regulatory genes of FA-BRCA pathway in the development of CACX and their role in chemo-tolerance of the disease by analyzing the molecular profile of the genes both in normal and tumour tissue of our sample pool, also validated in in silico datasets. Later on, prognostic importance of the genes was further evaluated in plasma DNA and cisplatin-treated in vitro system. We found that expression profile of FA-BRCA pathway genes was gradually reduced from undifferentiated basal-parabasal layers of normal tissue towards the progression of the disease. Further analysis revealed that frequent promoter methylation [32-55%] and deletion [34-52%] events were the plausible reasons for their reduced expression in CACX. Noticeably, invasion of promoter methylation of the genes [11-17%] in plasma CTCs of CACX patients was positively correlated [p < 0.001] with poor prognosis among patients. On the other hand, functional upregulation of these genes at higher concentrations [IC50-70] of cisplatin was a predictor for the development of drug tolerance, as evaluated in our in vitro study. This finding was supported further by low prevalence of γ-H2X foci formation and reduced expression of DNMT1 at higher concentrations of cisplatin. In totality, we discovered that the FA-BRCA pathway must be inactivated for cancer formation. In contrast, elevated gene expression played a substantial role in building of chemo-tolerance and might be associated with developing increased risk of disease recurrence among patients.

Across race, ethnicity, and language: An intervention to improve advance care planning documentation unmasks health disparities.

BACKGROUND: Racial and ethnic minority groups are less likely to have advance directives and living wills, despite the importance of advanced care planning (ACP) in end-of-life care. We aimed to understand the impact of an intervention to improve ACP documentation across race, ethnicity, and language on hospitalized patients at our institution. METHODS: We launched an intervention to improve the rates of ACP documentation for hospitalized patients aged >75 or with advanced illness defined by the International Classification of Diseases 10th Revision codes. We analyzed ACP completion rates, preintervention, and intervention, and used interrupted time-series analyses to measure the differential impact of the intervention across race, ethnicity, and language. KEY RESULTS: A total of 10,220 patients met the inclusion criteria. Overall rates of ACP documentation improved from 13.9% to 43.7% in the intervention period, with a 2.47% monthly increase in ACP documentation compared to baseline (p < .001). During the intervention period, the rate of ACP documentation increased by 2.72% per month for non-Hispanic White patients (p < .001), by 1.84% per month for Latinx patients (p < .001), and by 1.9% per month for Black patients (p < .001). Differences in the intervention trends between non-Hispanic White and Latinx patients (p = .04) and Black patients (p = .04) were significant. CONCLUSIONS: An intervention designed to improve ACP documentation in hospitalized patients widened a disparity across race and ethnicity with Latinx and Black patients having lower rates of improvement. Our findings reinforce the need to measure the impact of quality improvement interventions on existing health disparities and to implement specific strategies to prevent worsening disparities.

Reaction Mechanism and Kinetics for the Selective Hydrogenation of Carbon Dioxide to Formic Acid and Methanol over the [Cu2]0,±1 Dimer.

With the rapid growth of industrialization, deforestation, and burning of fossil fuels, undeniably there has been an incredible escalation of the CO2 concentration in the atmosphere. In order to mitigate the problem, the capture and utilization of CO2 in different value-added chemicals have thus remained topics of concerned research for more than a decade. Accordingly, we have performed molecular -level catalytic hydrogenation of CO2 to formic acid using bare [Cu2]0,±1 dimers as catalysts. The entire investigation has been performed using a density functional theory (DFT) method employing the Perdew-Burke-Ernzerhof (PBE) functional with the def2TZVPP basis set to explore the different possible routes and efficiency of the catalysts. Results reveal the feasibility of H2 dissociation on all three Cu2, Cu2+, and Cu2- dimers. The negatively charged hydride formed during H2 dissociation on Cu2 and Cu2+ dimers facilitates the formation of the HCOO* intermediate over COOH*, thereby providing product selectivity for HCOOH above CO. However, the reaction on the Cu2- dimer forms both HCOO* and COOH* intermediates, but HCOO*, being kinetically more favorable, results in HCOOH production. The free-energy change suggests that the complete reaction on Cu2 and Cu2+ dimers forms a stable product compared to the Cu2- dimer. Furthermore, H3COH production is studied using the title catalysts via the obtained HCOOH* intermediate from the reaction channel. Transition state theory (TST) has been considered to evaluate the rate constants for each step of the reaction. Overall results suggest Cu2 to be better compared to Cu2+ and Cu2- dimers for HCOOH formation and Cu2+ over Cu2 and Cu2- dimers to be more efficient for H3COH formation. This work opens the way for further investigation of the reaction mechanism and development of an efficient catalyst for CO2 hydrogenation.

Molecularly Imprinted Polymer Interface on Screen-Printed ZnO Nanorod Field Effect Transistors for Serotonin Detection in Clinical Samples.

Ultrasensitive detection of serotonin is crucial for the early diagnosis of several diseases like Parkinson's and Alzheimer's. Most of the existing detection strategies are still not suitable for sensitive point-of-care applications. This study presents direct molecular imprinting of serotonin on the surface of three-dimensional zinc oxide (ZnO) nanorod devices connected in a field effect transistor (FET) configuration to achieve ultrasensitive, real-time, and rapid detection with a convenient and affordable approach, which has significant potential for translation to clinical settings. This strategy has enabled pushing the detection limit to 0.1 fM in a physiological analyte in real time with screen-printed electrodes, thereby resulting in the convenient batch fabrication of sensors for clinical validation. The response of the sensor with the clinical sample has been correlated with that of the gold standard and has been observed to be statistically similar.

Role of MLH1 and MSH2 deficiency in the development of tumorigenesis and chemo-tolerance of cervical Carcinoma: Clinical implications.

Cervical cancer (CACX) is one of the top causes of cancer death in women globally. The involvement of several cellular pathways in carcinogenesis is still poorly understood. Here, we focused to evaluate the contributory role of Mismatch Repair (MMR) pathway genes-MLH1 and MSH2 in CACX and their association with chemo-tolerance of the disease. For this purpose, molecular profiles (expression/promoter methylation/deletion) of the genes were analysed in both normal cervical epithelium and tumour tissue, also validated in in-silico dataset as well. Later on, prognostic importance of the genes was identified through analysis of their methylation/expression status in plasma DNA of circulating tumour cells (CTCs) and cisplatin-tolerant CACX cell lines respectively. It was found that the expression profile of MLH1 and MSH2 genes was considerably reduced from undifferentiated basal-parabasal layers of normal cervical epithelium towards progression of the disease. Further analysis showed that frequent deletion [34-48%] and promoter methylation events [28-46%] of the genes were the plausible reasons for their reduced expression during tumorigenesis. Incidentally, the prevalence of MLH1 [32%] and MSH2 [27%] promoter methylation found in CTCs of plasma of the clinically advanced CACX patients implicated their prognostic importance of the disease. In addition, the patients having high alterations of those genes resulted in poor patient outcomes even after the therapy. In in-depth analysis of this result in cisplatin-tolerant CACX cell lines, we discovered that increased promoter methylation frequency of those genes at higher concentrations of cisplatin and gradual accumulation of the cells in the G2/M phase of the cell cycle were the rational causes for their reduced expression and MMR deficiency in the system. Hence, it is possible to conclude that the gradual down-regulation of MLH1 and MSH2 proteins may be a key event for MMR pathway inactivation in CACX. This might also be associated with chemo-tolerance and overall poor survival among the patients.

Differential association of hedgehog pathway in development of cervical carcinoma and its chemo-tolerance.

Cervical carcinoma (CACX) is still a dreadful threat to women in developing countries. Available conventional chemo-radiation therapies are not sufficient to restrict the disease recurrence. To unravel the mechanism of the disease recurrence, alteration of hedgehog self-renewal pathway was evaluated during development of CACX and in chemo-tolerance of the tumor. We have analyzed the alterations (expression/methylation/deletion) of some key regulatory genes (HHIP/SUFU/SHH/ SMO/GLI1) of hedgehog self-renewal pathway in cervical lesions at different clinical stages and compared with different datasets, followed by their clinico-pathological correlations. The changes in expression/methylation of the genes were then evaluated in two CACX cell lines (SiHa/HeLa) after treatment with chemotherapeutic drug cisplatin at different concentrations. Down regulation (mRNA/protein) of the antagonists HHIP and SUFU due to promoter methylation and/or deletion along with upregulation (protein) of agonists SHH, SMO and GLI1 was seen in early invasive lesions and subsequent clinical stages. Reduced protein expression of HHIP and SUFU showed significant association with high/intermediate expression of agonists SHH, SMO, GLI1 in the tumors and also poor prognosis of the patients. It was evident that cisplatin could restrict the growth of HeLa and SiHa cells through significant upregulation of antagonists HHIP and SUFU due to their promoter hypomethylation and down regulation of SHH in a concentration dependent manner without any significant changes in expression of SMO and GLI1, leading to the tumor cells in a dormant state. Thus, interplay of the agonists and antagonists has important role in activation of hedgehog pathway during development of CACX, whereas inactivation of the pathway due to upregulation of the antagonists is an important phenomenon in chemo-tolerance of the tumor. This suggests importance of epigenetic modification in chemo-resistance of CACX.

High nuclear expression of DNMT1 in correlation with inactivation of TET1 portray worst prognosis among the cervical carcinoma patients: clinical implications.

In this study, we aimed to understand the interplay of the epigenetic modifier genes DNMT1 and TET1 along with HPV infection in the cervical epithelium and how it changes during tumorigenesis. For this purpose, initially the bioinformatical analysis (methylation and expression profile) of DNMT1 and TET1 was analyzed in the TCGA dataset. Next genetic (deletion) and epigenetic profiling (promoter methylation) of DNMT1 and TET1 were done in our sample pool and also validated in CACX cell lines as well. The results were further correlated with different clinicopathological parameters. Our data revealed that HPV infection in basal/parabasal layers of cervical epithelium actually disrupts the epigenetic homeostasis of DNMT1 and TET1 proteins which ultimately leads to the high expression of DNMT1 along with further reduction in TET1 protein during the development of carcinoma. Further, in-depth look into the results revealed that comparatively low methylation frequency of DNMT1 coupled with high promoter methylation and deletion frequency [22-46%] of TET1 were the plausible reasons of their antagonistic expression profile during the progression of the disease. Interestingly, the prevalence of DNMT1 [9.1%] and TET1 promoter methylation [22.7%] found in both the plasma DNA of the respective CACX patients implicated its diagnostic importance in this study. Lastly, molecular alteration of TET1 alone or in combination with DNMT1 showed the worst overall survival among the patients. Hence, it may be concluded that an inverse molecular profile of DNMT1 and TET1 genes seen in the proliferative basal-parabasal layers of the cervical epithelium was aggravated during the development of CACX along with genetic and epigenetic changes due to HPV infection.

Assessment and clinicopathological correlation of p16 expression in cervical squamous cell carcinoma of Indian population: Diagnostic implications.

BACKGROUND: Our aim was to assess the p16 expression in normal cervical epithelium and cervical lesions and how it correlated with HPV oncoprotein E7 and other etiological parameters of cervical cancer. METHODS: For this purpose, we analyzed protein expression of p16 and E7 oncoprotein in total 20 normal cervical epithelium tissue (as control) and 62 cervical lesions. Next, the result was correlated with different clinico-pathological parameters. RESULTS: Out of 62 cases of cervical lesions, we found around 75%-100% of the cervical lesion samples exhibited E7 nuclear protein expression, whereas around 33.33%-75% samples were p16 positive. On the other hand, p16 expression showed strong association with E7 oncoprotein and other clinico-pathological parameters (like high parity, early age of sextual debut) in the same set of samples of our study. CONCLUSION: We concluded that overexpression of p16 is very practical and can be readily implemented in most diagnostic pathology laboratories.

Environmental gas sensors based on electroactive hybrid organic-inorganic nanocomposites using nanostructured materials.

Advanced gas sensing devices are urgently demanded in the modern scientific world to control air pollution and protect human life. For this purpose, semiconducting electroactive materials can revolutionize the idea of conventional gas sensors. Chemi-resistive gas sensors based on electroactive hybrid organic-inorganic nanocomposites are incredibly promising gas sensing materials because they possess the advantages of excellent selectivity, high sensitivity, low response time, repeatability, high stability, cost-effectiveness, and simple fabrication techniques, and they can be operated at room temperature. This review emphasizes the recent developments of organic-inorganic hybrid nanocomposite-based electroactive gas sensors, including metal oxide nanocomposites, which are potential gas sensing materials due to the presence of numerous charge carriers. The review also focuses on nanostructured materials of different dimensions, such as semiconducting quantum dots, carbon dots, nanotubes, nanowires, and nanosheets, used for developing these gas sensing compounds and their significance and challenges. Some possible fabrication techniques for developing efficient gas sensors with different morphologies are discussed, with their probable sensing mechanism behind the detection of toxic vapours. Subsequently, a summary and possible outcome of this study, along with the various achievements and prospects in this field, are also discussed.

PTPRJ is downregulated in cervical squamous cell carcinoma.

Squamous cell carcinoma of the uterine cervix (CSCC) is one of the leading causes of death in Indian women. Protein tyrosine phosphatase receptor (PTPR) type J (also known as DEP1) is a recently reported tumour suppressor receptor phosphatase. Critical molecular analysis of PTPRJ/DEP1 (11p11.2) has not performed in CSCC to date. Here, we observed frequent downregulation of cancer samples (n=31) at the transcriptional level. Immunohistochemistry revealed concordant low expression of PTPRJ protein with a few samples showing intermediate expression. To probe for the cause of such downregulation of the gene in CSCC (n=155), we analysed the copy number and promoter methylation of PTPRJ. The genetic locus showed deletion (14.8%) and the promoter showed methylation (33.5%) of PTPRJ. To the best of our knowledge, for the first time we explored the molecular status of PTPRJ although we observed no statistically significant association with the prognosis of Indian CSCC patients (n=76). However, we observed enhanced expression of PTPRJ protein levels that contributes to effective cisplatin chemotherapy in the SiHa cell line. Thus, the present study paves the way for further research into the plausible mechanisms of downregulation of PTPRJ in cervical cancer.

SAM 40: Dataset of 40 subject EEG recordings to monitor the induced-stress while performing Stroop color-word test, arithmetic task, and mirror image recognition task.

This paper presents a collection of electroencephalogram (EEG) data recorded from 40 subjects (female: 14, male: 26, mean age: 21.5 years). The dataset was recorded from the subjects while performing various tasks such as Stroop color-word test, solving arithmetic questions, identification of symmetric mirror images, and a state of relaxation. The experiment was primarily conducted to monitor the short-term stress elicited in an individual while performing the aforementioned cognitive tasks. The individual tasks were carried out for 25 s and were repeated to record three trials. The EEG was recorded using a 32-channel Emotiv Epoc Flex gel kit. The EEG data were then segmented into non-overlapping epochs of 25 s depending on the various tasks performed by the subjects. The EEG data were further processed to remove the baseline drifts by subtracting the average trend obtained using the Savitzky-Golay filter. Furthermore, the artifacts were also removed from the EEG data by applying wavelet thresholding. The dataset proposed in this paper can aid and support the research activities in the field of brain-computer interface and can also be used in the identification of patterns in the EEG data elicited due to stress.

Emerging insights into the structure and function of ionotropic glutamate delta receptors.

Glutamate delta-1 (GluD1) and delta-2 (GluD2) receptors belong to the orphan GluD subfamily of ionotropic glutamate receptors (iGluRs). GluDs were classified as ionotropic glutamate receptors based on their sequence similarity. Two decades after these GluDs were first cloned they are still considered "orphan" due to a lack of knowledge of the endogenous ligands that can activate them. Nevertheless, they are crucial for synapse formation, maturation and maintenance of CNS functions, and are implicated in multiple neuronal disorders, including schizophrenia, autism spectrum disorder and depressive disorders. Over the last decade significant discoveries have been made, include role of GluD receptors in mediating trans-synaptic interactions and their unique non-swapped architecture, which is distinct from other ionotropic glutamate receptors. Also, the prospect of GluD ionotropic activity being regulated by direct interaction with metabotropic glutamate receptors is exciting. These discoveries will likely drive the field in the future, providing direction to GluD research. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.

Role of actin cytoskeleton in the organization and function of ionotropic glutamate receptors.

Neural networks with precise connection are compulsory for learning and memory. Various cellular events occur during the genesis of dendritic spines to their maturation, synapse formation, stabilization of the synapse, and proper signal transmission. The cortical actin cytoskeleton and its multiple regulatory proteins are crucial for the above cellular events. The different types of ionotropic glutamate receptors (iGluRs) present on the postsynaptic density (PSD) are also essential for learning and memory. Interaction of the iGluRs in association of their auxiliary proteins with actin cytoskeleton regulated by actin-binding proteins (ABPs) are required for precise long-term potentiation (LTP) and long-term depression (LTD). There has been a quest to understand the mechanistic detail of synapse function involving these receptors with dynamic actin cytoskeleton. A major, emerging area of investigation is the relationship between ABPs and iGluRs in synapse development. In this review we have summarized the current understanding of iGluRs functioning with respect to the actin cytoskeleton, scaffolding proteins, and their regulators. The AMPA, NMDA, Delta and Kainate receptors need the stable underlying actin cytoskeleton to anchor through synaptic proteins for precise synapse formation. The different types of ABPs present in neurons play a critical role in dynamizing/stabilizing the actin cytoskeleton needed for iGluRs function.

Coupling of dynamic microtubules to F-actin by Fmn2 regulates chemotaxis of neuronal growth cones.

Dynamic co-regulation of the actin and microtubule subsystems enables the highly precise and adaptive remodelling of the cytoskeleton necessary for critical cellular processes, such as axonal pathfinding. The modes and mediators of this interpolymer crosstalk, however, are inadequately understood. We identify Fmn2, a non-diaphanous-related formin associated with cognitive disabilities, as a novel regulator of cooperative actin-microtubule remodelling in growth cones of both chick and zebrafish neurons. We show that Fmn2 stabilizes microtubules in the growth cones of cultured spinal neurons and in vivo. Super-resolution imaging revealed that Fmn2 facilitates guidance of exploratory microtubules along actin bundles into the chemosensory filopodia. Using live imaging, biochemistry and single-molecule assays, we show that a C-terminal domain in Fmn2 is necessary for the dynamic association between microtubules and actin filaments. In the absence of the cross-bridging function of Fmn2, filopodial capture of microtubules is compromised, resulting in destabilized filopodial protrusions and deficits in growth cone chemotaxis. Our results uncover a critical function for Fmn2 in actin-microtubule crosstalk in neurons and demonstrate that the modulation of microtubule dynamics via associations with F-actin is central to directional motility.

Riboflavin based conjugated biomolecule for ultrasensitive detection of nitrophenols.

Real time detection of explosive compounds in today's time is of utmost necessity due to security and severe environmental safety issues. Herein, we have synthesized a biobased conjugated molecular system from riboflavin and l-cystine utilized it for detecting picric acid in trace amount using optical sensing technique. The bioconjugate probe showed high quenching efficiency towards picric acid, which is 92.2%. In depth mechanistic study showed that ground state electrostatic interaction and inner filter effect are the factors leading to the diminishing of the probe's fluorescence intensity on addition of trace amount of the nitrophenol, picric acid. The detection limit of the conjugate is 0.37 nM which is extremely low and highly desirable for clinical applications of this system.

Integrated graphene quantum dot decorated functionalized nanosheet biosensor for mycotoxin detection.

Decoration of graphene quantum dots (GQDs) on molybdenum disulfide (MoS2) nanosheets serves as an active electrode material which enhances the electrochemical performance of the analyte detection system. Herein, ionic surfactant cetyltrimethylammonium bromide (CTAB)-exfoliated MoS2 nanosheets decorated with GQD material are used to construct an electrochemical biosensor for aflatoxin B1 (AFB1) detection. An antibody of AFB1 (aAFB1) was immobilized on the electrophoretically deposited MoS2@GQDs film on the indium tin oxide (ITO)-coated glass surface using a crosslinker for the fabrication of the biosensor. The immunosensing study investigated by the electrochemical method revealed a signal response in the range of 0.1 to 3.0 ng/mL AFB1 concentration with a detection limit of 0.09 ng/mL. Also, electrochemical parameters such as diffusion coefficient and heterogeneous electron transfer (HET) were calculated and found to be 1.67 × 10-5 cm2/s and 2 × 10-5 cm/s, respectively. The effective conjugation of MoS2@GQDs that provides abundant exposed edge sites, large surface area, improved electrical conductivity, and electrocatalytic activity has led to an excellent biosensing performance with enhanced electrochemical parameters. Validation of the fabricated immunosensor was performed in a spiked maize sample, and a good percentage of recoveries within an acceptable range were obtained (80.2 to 98.3%).Graphical abstract.

Reactivity mapping of luminescence in space: Insights into heterogeneous electrochemiluminescence bioassays.

Electrochemiluminescence (ECL) is a powerful (bio)analytical method based on an optical readout. It is successfully applied in the heterogeneous format for immunoassays and imaging using the model and most widely used ECL system, which consists of the immobilized [Ru(bpy)3]2+ label with tripropylamine (TPA) as a coreactant. However, a major drawback is the significant decrease of the ECL intensity over time. Herein, to decipher the process responsible for this progressive loss of ECL signal, we investigated its electrochemical and photophysical properties by mapping the luminescence reactivity at the level of single micrometric beads. Polystyrene beads were functionalized by the [Ru(bpy)3]2+ dye via a sandwich immunoassay or a peptide bond. ECL emission was generated in presence of the very efficient TPA coreactant. Imaging both photoluminescence and ECL reactivities of different regions (located near or far from the electrode surface) of a [Ru(bpy)3]2+-decorated bead allows us to demonstrate the remarkable photophysical stability of the ECL label, even in presence of the very reactive electrogenerated TPA radicals. We show that the ECL vanishing correlates directly with the lower TPA oxidation current. Finally, we propose a simple electrochemical treatment, which allows to regenerate the electrode surface and thus to recover several times the strong initial ECL signal. The reactivity imaging approach provides insights into the ECL mechanism and the main factors governing the stability of the emission, which should find promising ECL applications in bioassays and microscopy.

Planar Asymmetries in the C. elegans Embryo Emerge by Differential Retention of aPARs at Cell-Cell Contacts.

Formation of the anteroposterior and dorsoventral body axis in Caenorhabditis elegans depends on cortical flows and advection of polarity determinants. The role of this patterning mechanism in tissue polarization after formation of cell-cell contacts is not fully understood. Here, we demonstrate that planar asymmetries are established during left-right symmetry breaking: Centripetal cortical flows asymmetrically and differentially advect anterior polarity determinants (aPARs) from contacts to the medial cortex, resulting in their unmixing from apical myosin. Contact localization and advection of PAR-6 requires balanced CDC-42 activation, while asymmetric retention and advection of PAR-3 can occur independently of PAR-6. Concurrent asymmetric retention of PAR-3, E-cadherin/HMR-1 and opposing retention of antagonistic CDC-42 and Wnt pathway components leads to planar asymmetries. The most obvious mark of planar asymmetry, retention of PAR-3 at a single cell-cell contact, is required for proper cytokinetic cell intercalation. Hence, our data uncover how planar polarity is established in a system without the canonical planar cell polarity pathway through planar asymmetric retention of aPARs.

Mechanical stress induces a scalable switch in cortical flow polarization during cytokinesis.

During animal development, cells need to sense and adapt to mechanical forces from their environment. Ultimately, these forces are transduced through the actomyosin cortex. How the cortex simultaneously responds to and creates forces during cytokinesis is not well understood. Here we show that, under mechanical stress, cortical actomyosin flow can switch polarization during cytokinesis in the C. elegans embryo. In unstressed embryos, longitudinal cortical flow contributes to contractile ring formation, while rotational cortical flow is additionally induced in uniaxially loaded embryos, i.e. embryos compressed between two plates. Rotational flow depends on astral microtubule signals and is required for the redistribution of the actomyosin cortex in loaded embryos. Rupture of longitudinally aligned cortical fibers during cortex rotation releases tension, initiates orthogonal longitudinal flow and, thereby, contributes to furrowing in loaded embryos. Moreover, actomyosin regulators involved in RhoA regulation, cortical polarity and chirality are all required for rotational flow, and become essential for cytokinesis under mechanical stress. In sum, our findings extend the current framework of mechanical stress response during cell division and show scaling of orthogonal cortical flows to the amount of mechanical stress.