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Abstract Integrating diverse types of biological data is essential for a holistic understanding of cancer biology, yet it remains challenging due to data heterogeneity, complexity, and sparsity. Addressing this, our study introduces an unsupervised deep learning model, MOSA (Multi-Omic Synthetic Augmentation), specifically designed to integrate and augment the Cancer Dependency Map (DepMap). Harnessing orthogonal multi-omic information, this model successfully generates molecular and phenotypic profiles, resulting in an increase of 32.7% in the number of multi-omic profiles and thereby generating a complete DepMap for 1523 cancer cell lines. The synthetically enhanced data increases statistical power, uncovering less studied mechanisms associated with drug resistance, and refines the identification of genetic associations and clustering of cancer cell lines. By applying SHapley Additive exPlanations (SHAP) for model interpretation, MOSA reveals multi-omic features essential for cell clustering and biomarker identification related to drug and gene dependencies. This understanding is crucial for developing much-needed effective strategies to prioritize cancer targets.

Abstract Prostate cancer exhibits high prevalence and accounts for a high number of cancer-related deaths. The discovery and characterization of molecular determinants of aggressive prostate cancer represents an active area of research. The Immediate Early Response (IER) family of genes, which regulate Protein Phosphatase 2A (PP2A) activity, has emerged among the factors that influence cancer biology. Here, we show that the less studied member of this family, Immediate Early Response 5 like (IER5L), is upregulated in aggressive prostate cancer. Interestingly, the upregulation of IER5L expression exhibits a robust association with metastatic disease in prostate and is recapitulated in other cancer types. In line with this observation, IER5L silencing reduces foci formation, migration and invasion ability in a variety of human and murine prostate cancer cell lines. In vivo, using zebrafish and immunocompromised mouse models, we demonstrate that IER5L-silencing reduces prostate cancer tumor growth, dissemination, and metastasis. Mechanistically, we characterize the transcriptomic and proteomic landscapes of IER5L-silenced cells. This approach allowed us to identify DNA replication and monomeric G protein regulators as downstream programs of IER5L through a pathway that is consistent with the regulation of PP2A. In sum, we report the alteration of IER5L in prostate cancer and beyond and provide biological and molecular evidence of its contribution to tumor aggressiveness.

Urinary dysfunction encompasses a wide range of syndromes and symptoms and is highly prevalent among the adult population. Urinary issues have been associated with psychosocial sequelae. The interplay between psychosocial comorbidity and symptoms impacts perceived severity and treatment success. While the correlation has been described in the literature, much remains unknown. This article describes the psychosocial impact on conditions such as overactive bladder (OAB), neurogenic lower urinary tract dysfunction (LUTD), recurrent urinary tract infection (UTI), and interstitial cystitis/bladder pain syndrome (IC/BPS). This article also highlights potential interventions for patients afflicted with both urinary disorders and psychosocial comorbidity to improve overall treatment success.

Abstract A better understanding of the relative roles of internal climate variability and external contributions, from both natural (solar, volcanic) and anthropogenic greenhouse gas forcing, is important to better project future hydrologic changes. Changes in the evaporative demand play a central role in this context, particularly in tropical areas characterized by high precipitation seasonality, such as the tropical savannah and semi-desertic biomes. Here we present a set of geochemical proxies in speleothems from a well-ventilated cave located in central-eastern Brazil which shows that the evaporative demand is no longer being met by precipitation, leading to a hydrological deficit. A marked change in the hydrologic balance in central-eastern Brazil, caused by a severe warming trend, can be identified, starting in the 1970s. Our findings show that the current aridity has no analog over the last 720 years. A detection and attribution study indicates that this trend is mostly driven by anthropogenic forcing and cannot be explained by natural factors alone. These results reinforce the premise of a severe long-term drought in the subtropics of eastern South America that will likely be further exacerbated in the future given its apparent connection to increased greenhouse gas emissions.

Abstract Background Carcinoma of unknown primary (CUP) remains an important tumor entity and a disproportionate cause of cancer mortality. Little is known about the contemporary clinical characteristics, treatment patterns, and outcomes of CUP patients based on updated international classification guidelines. We evaluated a contemporary CUP cohort to provide insight into current clinical practice and the impact of tissue of origin assignment, site‐specific and empirical therapy in a real‐world setting. Methods We conducted a retrospective cohort study of CUP patients, as defined by the updated European Society of Medical Oncology (ESMO) 2023 guidelines, across three tertiary referral centers in Australia between 2015 and 2022. We analyzed clinical characteristics, treatment patterns, and survival outcomes using the Kaplan–Meier method and Cox regression proportional hazard model between favorable and unfavorable risk groups. Results We identified a total of 123 CUP patients (n = 86 unfavorable, n = 37 favorable risk as per the 2023 ESMO guidelines). Sixty‐four patients (52%) were assigned a tissue of origin by the treating clinician. Median progression free survival (PFS) was 6.8 (95% confidence interval (CI) 5.1–12.1) months and overall survival (OS) 10.2 (95% CI 6.0–18.5) months. Unfavorable risk (hazard ratio [HR] 2.9, p = 0.006), poor performance status (HR 2.8, p

Abstract Background Overactive bladder (OAB) is defined as urinary urgency accompanied by frequency and nocturia, with or without urge urinary incontinence (UUI). Vibegron, a selective β3-adrenergic receptor agonist approved in the US in December 2020, demonstrated efficacy in reducing symptoms of OAB and was safe and well tolerated in the 12-week EMPOWUR trial and its 40-week, double-blind extension trial. The goal of the COMPOSUR study is to evaluate vibegron in a real-world setting to assess patient treatment satisfaction, tolerability, safety, duration of treatment, and persistence. Methods This is a 12-month, prospective, observational, real-world study, with an optional 12-month extension to 24 months, in the US assessing adults ≥ 18 years old starting a new course of vibegron. Patients must be previously diagnosed with OAB with or without UUI, symptomatic for ≥ 3 months before enrollment, and receive prior treatment with an anticholinergic, with mirabegron, or with a combination of an anticholinergic and mirabegron. Enrollment is performed by the investigator following exclusion and inclusion criteria guided by US product labeling, reinforcing a real-world approach. Patients complete the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q) monthly and the OAB Questionnaire short form (OAB-q-SF) and Work Productivity and Activity Impairment Questionnaire (WPAI:US) at baseline and monthly for 12 months. Patients are followed up via phone call, in-person visits, or telehealth (ie, virtual) visits. The primary endpoint is patient treatment satisfaction as determined by the OAB-SAT-q satisfaction domain score. Secondary endpoints include percent positive responses to individual OAB-SAT-q questions, additional OAB-SAT-q domain scores, and safety. Exploratory endpoints include adherence and persistence. Discussion OAB leads to a significant decrease in quality of life, as well as impairment of work activities and productivity. Persistence with OAB treatments can be challenging, often due to lack of efficacy and adverse effects. COMPOSUR is the first study to provide long-term, prospective, pragmatic treatment data for vibegron in the US and the resultant effect on quality of life among patients with OAB in a real-world clinical setting. Trial registration ClinicalTrials.gov identifier: NCT05067478; registered: October 5, 2021.

Sepsis, an amplified immune response to systemic infection, is characterized by a transient cytokine storm followed by chronic immune dysfunction. Consequently, sepsis survivors are highly susceptible to newly introduced infections, suggesting sepsis can influence the function and composition of the naïve CD8 T cell pool and resulting pathogen-induced primary CD8 T cell responses. Here, we explored the extent to which sepsis induces phenotypic and functional changes within the naïve CD8 T cell pool. To interrogate this, the cecal ligation and puncture (CLP) mouse model of polymicrobial sepsis was used. In normal, non-septic mice, we show type-I interferon (IFN I)-mediated signaling plays an important role in driving the phenotypic and functional heterogeneity in the naïve CD8 T cell compartment leading to increased representation of Ly6C+ naïve CD8 T cells. In response to viral infection after sepsis resolution, naïve Ly6C+ CD8 T cells generated more primary effector and memory CD8 T cells with slower conversion to a central memory CD8 T cell phenotype (Tcm) than Ly6C- naïve CD8 T cells. Importantly, as a potent inducer of cytokine storm and IFN I production, sepsis leads to increased representation of Ly6C+ naïve CD8 T cells that maintained their heightened ability to respond (i.e., effector and memory CD8 T cell accumulation and cytokine production) to primary LCMV infection. Lastly, longitudinal analyses of peripheral blood samples obtained from septic patients revealed profound changes in CD8 T cell subset composition and frequency compared to healthy controls. Thus, sepsis has the capacity to alter the composition of naïve CD8 T cells, directly influencing primary CD8 T cell responses to newly introduced infections.

Abstract Background Genome-wide association studies (GWAS) have identified > 200 loci associated with breast cancer risk. The majority of candidate causal variants are in non-coding regions and likely modulate cancer risk by regulating gene expression. However, pinpointing the exact target of the association, and identifying the phenotype it mediates, is a major challenge in the interpretation and translation of GWAS. Results Here, we show that pooled CRISPR screens are highly effective at identifying GWAS target genes and defining the cancer phenotypes they mediate. Following CRISPR mediated gene activation or suppression, we measure proliferation in 2D, 3D, and in immune-deficient mice, as well as the effect on DNA repair. We perform 60 CRISPR screens and identify 20 genes predicted with high confidence to be GWAS targets that promote cancer by driving proliferation or modulating the DNA damage response in breast cells. We validate the regulation of a subset of these genes by breast cancer risk variants. Conclusions We demonstrate that phenotypic CRISPR screens can accurately pinpoint the gene target of a risk locus. In addition to defining gene targets of risk loci associated with increased breast cancer risk, we provide a platform for identifying gene targets and phenotypes mediated by risk variants.

Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy.

A substantial proportion of HER2+ breast cancer patients do not benefit from HER2-targeted therapy. Here, the authors identify a population of cancer-associated fibroblasts involved in the suppression of trastuzumab-induced ADCC that can be pharmacologically targeted to raise treatment effectiveness in unresponsive tumors.

Abstract In some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the α‐thalassemia/mental retardation syndrome X‐linked (ATRX) gene is mutated leading to the conclusion that the ATRX complex represses ALT. Here, we report that most high‐grade pediatric osteosarcomas maintain their telomeres by ALT, and that the majority of these ALT tumors are ATRX wild‐type (wt) and instead carry an amplified 17p11.2 chromosomal region containing TOP3A. We found that TOP3A was overexpressed in the ALT‐positive ATRX‐wt tumors consistent with its amplification. We demonstrated the functional significance of these results by showing that TOP3A overexpression in ALT cancer cells countered ATRX‐mediated ALT inhibition and that TOP3A knockdown disrupted the ALT phenotype in ATRX‐wt cells. Moreover, we report that TOP3A is required for proper BLM localization and promotes ALT DNA synthesis in ALT cell lines. Collectively, our results identify TOP3A as a major ALT player and potential therapeutic target.

Sarcoma is a rare and complex disease comprising over 80 malignant subtypes that is frequently characterized by poor prognosis. Challenges in clinical management include uncertainties in diagnosis and disease classification, limited prognostic and predictive biomarkers, incompletely understood disease heterogeneity among and within subtypes, lack of effective treatment options, and limited progress in identifying new drug targets and novel therapeutics. Proteomics refers to the study of the entire complement of proteins expressed in specific cells or tissues. Advances in proteomics have included the development of quantitative mass spectrometry (MS)-based technologies which enable analysis of large numbers of proteins with relatively high throughput, enabling proteomics to be studied on a scale that has not previously been possible. Cellular function is determined by the levels of various proteins and their interactions, so proteomics offers the possibility of new insights into cancer biology. Sarcoma proteomics therefore has the potential to address some of the key current challenges described above, but it is still in its infancy. This review covers key quantitative proteomic sarcoma studies with findings that pertain to clinical utility. Proteomic methodologies that have been applied to human sarcoma research are briefly described, including recent advances in MS-based proteomic technology. We highlight studies that illustrate how proteomics may aid diagnosis and improve disease classification by distinguishing sarcoma histologies and identify distinct profiles within histological subtypes which may aid understanding of disease heterogeneity. We also review studies where proteomics has been applied to identify prognostic, predictive and therapeutic biomarkers. These studies traverse a range of histological subtypes including chordoma, Ewing sarcoma, gastrointestinal stromal tumors, leiomyosarcoma, liposarcoma, malignant peripheral nerve sheath tumors, myxofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, osteosarcoma, and undifferentiated pleomorphic sarcoma. Critical questions and unmet needs in sarcoma which can potentially be addressed with proteomics are outlined.

The presence of urgency urinary incontinence (U/UUI) after sling surgery is a common reason for dissatisfaction and imposition on quality of life. We aimed to evaluate and analyze the pathophysiology, evaluation, and treatment of U/UUI after sling surgery. A MEDLINE review was performed for relevant, English-language articles relating to storage and emptying symptoms after sling surgery. U/UUI may persist, be improved, or worsen in women with preoperative mixed urinary incontinence and may appear de novo in those women originally presenting with pure stress urinary incontinence (SUI). While the exact mechanism is not clear, partial bladder outlet obstruction (BOO) should always be suspected, especially in those women with worsened or de novo symptoms soon after sling surgery. Initial workup should elucidate the temporality, quality, and bother associated with symptoms and to evaluate the woman for urinary tract infection (UTI), pelvic organ prolapse (POP), or perforation of the lower urinary tract. The utility of urodynamics in attaining a definitive diagnosis of BOO is inconclusive. Treatment options include reevaluation of the patient after sling incision or after addressing UTI, POP, and perforation of the bladder or urethra. Women also typically undergo a multitiered approach to storage lower urinary tract symptoms outlined in the American Urological Association/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction Overactive Bladder Guidelines. While improvement is typically seen with multimodality treatment, all women should be counseled regarding need for additional treatment for U/UUI, BOO, and SUI in the future.

Abstract In well‐buffered modern soils, higher annual rainfall is associated with enhanced soil ferrimagnetic mineral content, especially of ultrafine particles that result in distinctive rock magnetic properties. Hence, paleosol magnetism has been widely used as a paleoprecipitation proxy. Identifying the dominant mechanism(s) of magnetic enhancement in a given sample is critical for reliable inference of paleoprecipitation. Here, we use high‐resolution magnetic field and electron microscopy to identify the grain‐scale setting and formation pathway of magnetic enhancement in two modern soils developed in higher (∼580 mm/y) and lower (∼190 mm/y) precipitation settings from the Qilianshan Range, China. We found that both soils contain 1–30 μm aeolian Fe‐oxide grains with indistinguishable rock magnetic properties, while the higher‐precipitation soil contains an additional population of ultrafine (

Chemoresistance in colorectal cancer initiating cells (CICs) involves the sustained activation of multiple drug resistance (MDR) and WNT/β-catenin signaling pathways, as well as of alternatively spliced-isoforms of CD44 containing variable exon-6 (CD44v6). In spite of its importance, mechanisms underlying the sustained activity of WNT/β-catenin signaling have remained elusive. The presence of binding elements of the β-catenin-interacting transcription factor TCF4 in the MDR1 and CD44 promoters suggests that crosstalk between WNT/β-catenin/TCF4-activation and the expression of the CD44v6 isoform mediated by FOLFOX, a first-line chemotherapeutic agent for colorectal cancer, could be a fundamental mechanism of FOLFOX resistance. Our results identify that FOLFOX treatment induced WNT3A secretion, which stimulated a positive feedback loop coupling β‐catenin signaling and CD44v6 splicing. In conjunction with FOLFOX induced WNT3A signal, specific CD44v6 variants produced by alternative splicing subsequently enhance the late wave of WNT/β-catenin activation to facilitate cell cycle progression. Moreover, we revealed that FOLFOX-mediated sustained WNT signal requires the formation of a CD44v6-LRP6-signalosome in caveolin microdomains, which leads to increased FOLFOX efflux. FOLFOX-resistance in colorectal CICs occurs in the absence of tumor-suppressor disabled-2 (DAB2), an inhibitor of WNT/β-catenin signaling. Conversely, in sensitive cells, DAB2 inhibition of WNT-signaling requires interaction with a clathrin containing CD44v6-LRP6-signalosome. Furthermore, full-length CD44v6, once internalized through the caveolin-signalosome, is translocated to the nucleus where in complex with TCF4, it binds to β-catenin/TCF4-regulated MDR1, or to CD44 promoters, which leads to FOLFOX-resistance and CD44v6 transcription through transcriptional-reprogramming. These findings provide evidence that targeting CD44v6-mediated LRP6/β-catenin-signaling and drug efflux may represent a novel approach to overcome FOLFOX resistance and inhibit tumor progression in colorectal CICs. Thus, sustained drug resistance in colorectal CICs is mediated by overexpression of CD44v6, which is both a functional biomarker and a therapeutic target in colorectal cancer.

Abstract Activation of a telomere length maintenance mechanism (TMM), including telomerase and alternative lengthening of telomeres (ALT), is essential for replicative immortality of tumor cells, although its regulatory mechanisms are incompletely understood. We conducted a microRNA (miRNA) microarray analysis on isogenic telomerase positive (TEP) and ALT cancer cell lines. Amongst nine miRNAs that showed difference in their expression in TEP and ALT cancer cells in array analysis, miR-708 was selected for further analysis since it was consistently highly expressed in a large panel of ALT cells. miR-708 in TEP and ALT cancer cells was not correlated with C-circle levels, an established feature of ALT cells. Its overexpression induced suppression of cell migration, invasion, and angiogenesis in both TEP and ALT cells, although cell proliferation was inhibited only in TEP cells suggesting that ALT cells may have acquired the ability to escape inhibition of cell proliferation by sustained miR-708 overexpression. Further, cell proliferation regulation in TEP cells by miR708 appears to be through the CARF-p53 pathway. We demonstrate here that miR-708 (i) is the first miRNA shown to be differentially regulated in TEP and ALT cancer cells, (ii) possesses tumor suppressor function, and (iii) deregulates CARF and p21WAF1-mediated signaling to limit proliferation in TEP cells.

Cancer-initiating cells (CICs) drive colorectal tumor growth by their supportive niches where CICs interact with multiple cell types within the microenvironment, including cancer-associated fibroblasts (CAFs). We investigated the interplay between the CICs and the clinically relevant chemotherapeutic FOLFOX that creates the persistent tumorigenic properties of colorectal CICs, and stimulates the microenvironmental factors derived from the CAFs. We found that the CICs expressing an immunophenotype (CD44v6[+]) promote FOLFOX-resistance and that the CIC-immunophenotype was enhanced by factors secreted by CAFs after FOLFOX treatment These secreted factors included periostin, IL17A and WNT3A, which induced CD44v6 expression by activating WNT3A/β-catenin signaling. Blocking the interaction between CICs with any of these CAF-derived factors through tissue-specific conditional silencing of CD44v6 significantly reduced colorectal tumorigenic potential. To achieve this, we generated two unique vectors (floxed-pSico-CD44v6 shRNA plus Fabpl-Cre) that were encapsulated into transferrin coated PEG-PEI/(nanoparticles), which when introduced in vivo reduced tumor growth more effectively than using CD44v6-blocking antibodies. Notably, this tissue-specific conditional silencing of CD44v6 resulted in long lasting effects on self-renewal and tumor growth associated with a positive feedback loop linking WNT3A signaling and alternative-splicing of CD44. These findings have crucial clinical implications suggesting that therapeutic approaches for modulating tumor growth that currently focus on cell-autonomous mechanisms may be too limited and need to be broadened to include mechanisms that recognize the interplay between the stromal factors and the subsequent CIC-immunophenotype enrichment. Thus, more specific therapeutic approaches may be required to block a chemotherapy induced remodeling of a microenvironment that acts as a paracrine regulator to enrich CD44v6 (+) in colorectal CICs

AimsThis study assessed gender differences in a debilitating urologic pain condition, interstitial cystitis/bladder pain syndrome (IC/BPS). We aimed to (1) evaluate how pain, symptom, and distress profiles of IC/BPS may differ between genders and (2) obtain in-depth firsthand accounts from patients to provide additional insight into their experiences that may explain potential gender differences.MethodsA mixed methods approach combined validated patient-reported outcome measures with a single timepoint 90-min focus group. Tests of summary score group differences between men and women were assessed across questionnaires measuring urologic symptoms, pain, emotional functioning, and diagnostic timeline. Qualitative analysis applied an inductive-deductive approach to evaluate and compare experiences of living with IC/BPS Group narratives were coded and evaluated thematically by gender using the biopsychosocial model, providing insight into the different context of biopsychosocial domains characterizing the male and female experience of IC/BPS.ResultsThirty-seven participants [women (n = 27) and men (n = 10)] completed measures and structured focus group interviews across eight group cohorts conducted from 8/2017 to 3/2019. Women reported greater pain intensity (p = 0.043) and extent (p = 0.018), but not significantly greater impairment from pain (p = 0.160). Levels of psychological distress were significantly elevated across both genders. Further, the duration between time of pain symptom onset and time to diagnosis was significantly greater for women than men (p = 0.012). Qualitative findings demonstrated key distinctions in experiences between genders. Men appeared not to recognize or to deter emotional distress while women felt overwhelmed by it. Men emphasized needing more physiological treatment options whilst women emphasized needing more social and emotional support. Interactions with medical providers and the healthcare system differed substantially between genders. While men reported feeling supported and involved in treatment decisions, women reported feeling dismissed and disbelieved.ConclusionThe findings indicate different pain experiences and treatment needs between genders in persons experiencing urologic pain and urinary symptoms, with potential intervention implications. Results suggest gender health inequality in medical interactions in this urologic population needing further investigation.

Abstract Telomere biology disorders (TBDs), including dyskeratosis congenita (DC), are a group of rare inherited diseases characterized by very short telomeres. Mutations in the components of the enzyme telomerase can lead to insufficient telomere maintenance in hematopoietic stem cells, resulting in the bone marrow failure that is characteristic of these disorders. While an increasing number of genes are being linked to TBDs, the causative mutation remains unidentified in 30‐40% of patients with DC. There is therefore a need for whole genome sequencing (WGS) in these families to identify novel genes, or mutations in regulatory regions of known disease‐causing genes. Here we describe a family in which a partial deletion of the 3′ untranslated region (3′ UTR) of DKC1, encoding the protein dyskerin, was identified by WGS, despite being missed by whole exome sequencing. The deletion segregated with disease across the family and resulted in reduced levels of DKC1 mRNA in the proband. We demonstrate that the DKC1 3′ UTR contains two polyadenylation signals, both of which were removed by this deletion, likely causing mRNA instability. Consistent with the major function of dyskerin in stabilization of the RNA subunit of telomerase, hTR, the level of hTR was also reduced in the proband, providing a molecular basis for his very short telomeres. This study demonstrates that the terminal region of the 3′ UTR of the DKC1 gene is essential for gene function and illustrates the importance of analyzing regulatory regions of the genome for molecular diagnosis of inherited disease.

The quest for neuroprotective factors that can prevent or slow down the progression of retinal degeneration is still ongoing. Acute hypoxic stress has been shown to provide transient protection against subsequent damage in the retina. Stanniocalcins – STC1 and STC2 – are secreted glycoproteins that are hypoxia-regulated and were shown to be cytoprotective in various in vitro studies. Hence, we investigated the expression of stanniocalcins in the normal, degenerating and hypoxic retina. We show that the expression of Stc1 and Stc2 in the retina was detectable as early as postnatal day 10 and persisted during aging. Retinal expression of Stc2, but not Stc1, was induced in mice in an in vivo model of acute hypoxia and a genetic model of chronic hypoxia. Furthermore, we show that HIF1, not HIF2, is responsible for regulating Stc2 in cells with the molecular response to hypoxia activated due to the absence of von Hippel Lindau protein. Surprisingly, Stc2 was not normally expressed in photoreceptors but in the inner retina, as shown by laser capture microdissection and immunofluorescence data. The expression of both Stc1 and Stc2 remained unchanged in the degenerative retina with an almost complete loss of photoreceptors, confirming their expression in the inner retina. However, the absence of either Stc1 or Stc2 had no effect on retinal architecture, as was evident from retinal morphology of the respective knockout mice. Taken together our data provides evidence for the differential regulation of STC1 and STC2 in the retina and the prospect of investigating STC2 as a retinal neuroprotective factor.

Nanofluids have been presented as media to enhance the heat transfer capabilities of thermal control systems and devices of both single and two-phase heat transfer modes. Since the addition of solid nanoparticles in a base fluid can significantly increase the thermal and transport properties of a given working fluid, it impacts other properties that require a proper evaluation before applying the nanofluid in a thermal system. Successful application of nanofluids in liquid cooling systems including single-phase convection in heat exchangers and two-phase systems like heat pipes and thermosyphon have indicated the potential in using such a novel working fluid to improve their thermal efficiency. An evaluation related to the performance enhancement using nanofluids in two-phase cooling systems is presented, which aims to show how nanofluids’ can play an important role in current and future thermal control devices' design and operation.

Nanofluids have consistently gained attention over the last decades due to their capability in improving the heat transfer efficiency of thermal devices. This improvement is related to the increase in the working fluid's thermal conductivity when adding solid nanoparticles, also presenting an undesirable influence on other transport properties, such as the increase of the fluid's density, viscosity, etc. To better assess the influence of a certain solid nanoparticle in a base fluid, the obtained data has been used to generate models applied to predict the nanofluids' properties. However, reliability in those models is still a concern as they can show different results for the same characteristics of solid nanoparticles and base fluid, which can generate unreliable data upon applying them in more complex and broad thermal models. A review related to the thermophysical properties of nanofluids is important to offer the basis of analysis for accurate numerical simulation of thermal systems where nanofluids are applied.

Clinical proteomics critically depends on the ability to acquire highly reproducible data over an extended period of time. Here, the authors assess reproducibility over four months across different mass spectrometers and develop a computational approach to mitigate variation among instruments over time.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating condition carrying substantial psychosocial burden. Psychological treatment for IC/BPS is little studied, and there are barriers to its use in clinical management. Whether psychological treatments benefit patients with IC/BPS is unclear and we do not know whether such treatments would meet patient needs. Aims: Incorporating patient-reported needs and acknowledging diversity in pain experiences can inform patient-centered interventions for IC/BPS. This project characterized the experience of living with IC/BPS and patient perceptions of needs in its treatment, with the goal of informing patient-centered treatment for IC/BPS. Methods: Using both quantitative and qualitative methods, 27 females with IC/BPS participated in a focus group and completed validated self-report assessments evaluating urinary symptoms, pain, and emotional functioning. Focus groups were audio recorded and transcribed and then coded and analyzed using an iterative inductive/deductive approach. Linear regression models evaluated the relationship between psychological functioning and symptom severity. Results: We conducted six focus groups between August and December 2017. Five major themes emerged from qualitative analysis: managing physical symptoms, emotional symptoms, impact on daily life and socio-contextual factors, responding to illness, and addressing needs in treatment. The physiological and emotional consequences of IC/BPS were reported, highlighting their impact on interpersonal relationships and challenges in obtaining appropriate treatment for IC/BPS. Quantitative analysis showed that depression levels were significantly associated with worsened IC/BPS symptomology, after controlling for known confounding factors. Conclusion: Individuals with IC/BPS could benefit from tailored psychological interventions focusing on pain management, emotion regulation, communications skills, along with sexual dysfunction and intimacy fears.

HER2-enriched breast cancers within the HER2-positive subtype are addicted to the HER2 pathway. Here, the authors analyse gene expression before, during, and after treatment with anti-HER2-based therapies in the phase II PAMELA clinical trial, finding phenotypic changes induced by treatment.

Background: A considerable proportion of acute ischemic stroke patients treated with endovascular thrombectomy (EVT) are dead or severely disabled at 3 months despite successful reperfusion. Ischemic core imaging biomarkers may help to identify patients who are more likely to have a poor outcome after endovascular thrombectomy (EVT) despite successful reperfusion. We studied the association of CT perfusion-(CTP), CT angiography-(CTA), and non-contrast CT-(NCCT) based imaging markers with poor outcome in patients who underwent EVT in daily clinical practice.Methods: We included EVT-treated patients (July 2016–November 2017) with an anterior circulation occlusion from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry with available baseline CTP, CTA, and NCCT. We used multivariable binary and ordinal logistic regression to analyze the association of CTP ischemic core volume, CTA-Collateral Score (CTA-CS), and Alberta Stroke Program Early CT Score (ASPECTS) with poor outcome (modified Rankin Scale score (mRS) 5-6) and likelihood of having a lower score on the mRS at 90 days.Results: In 201 patients, median core volume was 13 (IQR 5-41) mL. Median ASPECTS was 9 (IQR 8-10). Most patients had grade 2 (83/201; 42%) or grade 3 (28/201; 14%) collaterals. CTP ischemic core volume was associated with poor outcome [aOR per 10 mL 1.02 (95%CI 1.01–1.04)] and lower likelihood of having a lower score on the mRS at 90 days [aOR per 10 mL 0.85 (95% CI 0.78–0.93)]. In multivariable analysis, neither CTA-CS nor ASPECTS were significantly associated with poor outcome or the likelihood of having a lower mRS.Conclusion: In our population of patients treated with EVT in daily clinical practice, CTP ischemic core volume is associated with poor outcome and lower likelihood of shift toward better outcome in contrast to either CTA-CS or ASPECTS.

Converging lines of evidence show that protoplanetary disks are complex environments hosting spatial and temporal variability at multiple scales. Here we reanalyze paleomagnetic estimates of solar nebula magnetic field strengths using a Bayesian framework that tests for recording bias due to chondrule motion and explicitly accounts for time-varying ambient fields. We find that LL and CO group chondrule paleointensities likely rotated during cooling ( p = 0.79–0.99), validating assumptions in previous paleomagnetic studies. Chondrule rotation also suggests low gas density formation environments beyond 2 and 4 au for LL and CO chondrules, respectively. Our recomputed paleointensities for LL and CO chondrules imply either: (1) temporally constant magnetic fields of ${34}_{-14}^{+36}$ μ T and ${106}_{-18}^{+88}$ μ T, respectively; or (2) time-varying magnetic fields with peak amplitudes between ${49}_{-21}^{+97}$ μ T and ${128}_{-11}^{+307}$ μ T. Considering the known mechanisms for sustaining magnetic field gradients and high-amplitude temporal magnetic fluctuations in the solar nebula, we find that magnetic field flux concentrations in disk gaps or time-varying magnetic fields, for example due to the Hall shear instability, are most compatible with the existing data. Using this statistical framework, future paleointensity studies of chondrules can be used to directly test for the variability of magnetic fields in the solar system protoplanetary disk and to distinguish between these scenarios.

Changes observed in the current climate and projected for the future significantly concern researchers, decision-makers, and the general public. Climate indices of extreme rainfall events are a trend assessment tool to detect climate variability and change signals, which have an average reliability at least in the short term and given climatic inertia. This paper shows 12 climate indices of extreme rainfall events for annual and seasonal scales for 12 climate stations between 1969 to 2019 in the Metropolitan area of Cali (southwestern Colombia). The construction of the indices starts from daily rainfall time series, which although have between 0.5% and 5.4% of missing data, can affect the estimation of the indices. Here, we propose a methodology to complete missing data of the extreme event indices that model the peaks in the time series. This methodology uses an artificial neural network approach known as Non-Linear Principal Component Analysis (NLPCA). The approach reconstructs the time series by modulating the extreme values of the indices, a fundamental feature when evaluating extreme rainfall events in a region. The accuracy in the indices estimation shows values close to 1 in the Pearson's Correlation Coefficient and in the Bi-weighting Correlation. Moreover, values close to 0 in the percent bias and RMSE-observations standard deviation ratio. The database provided here is an essential input in future evaluation studies of extreme rainfall events in the Metropolitan area of Cali, the third most crucial urban conglomerate in Colombia with more than 3.9 million inhabitants.

The concern over x-ray exposure risks can overshadow the potential benefit of radiography, especially in cases where manual therapy is employed. Spinal malalignment cannot be accurately visualized without imaging. Manual therapy and the load tolerances of injured spinal tissues raise different criteria for the use of x-rays for spinal disorders than in medical practice. Current regulatory bodies rely on radiography risk assessments based on Linear-No-Threshold (LNT) risk models. There is a need to consider radiography guidelines for chiropractic which are different from those for medical practice. Radiography practice guidelines are summaries dominated by frequentist interpretations in the analysis of data from studies. In contrast, clinicians often employ a pseudo-Bayesian form of reasoning during the clinical decision-making process. The overrepresentation of frequentist perspectives in evidence-based practice guidelines alter decision-making away from practical assessment of a patient’s needs, toward an overly cautious standard applied to patients without regard to their risk/benefit likelihoods relating to radiography. Guidelines for radiography in chiropractic to fully assess the condition of the spine and spinal alignment prior to manual therapy, especially with high velocity, low amplitude spinal manipulation (HVLA-SM), should necessarily differ from those used in medical practice.

Abstract Magnetic fields in the early solar system may have driven the inward accretion of the protoplanetary disk (PPD) and generated instabilities that led to the formation of planets and ring and gap structures. The Allende carbonaceous chondrite meteorite records a strong early solar system magnetic field that has been interpreted to have a PPD, dynamo, or impact‐generated origin. Using high‐resolution magnetic field imaging to isolate the magnetization of individual grain assemblages, we find that only Fe‐sulfides carry a coherent magnetization. Combined with rock magnetic analyses, we conclude that Allende carries a magnetization acquired during parent body chemical alteration at ~3.0–4.2 My after calcium aluminum‐rich inclusions in an >40 µT magnetic field. This early age strongly favors a magnetic field of nebular origin instead of dynamo or solar wind alternatives. When compared to other paleomagnetic data from meteorites, this strong intensity supports a central role for magnetic instabilities in disk accretion and the presence of temporal variations or spatial heterogeneities in the disk, such as ring and gap structures.

Abstract Our objective was to determine whether inclusion of industrial egg residue (IER) in the diets of laying hens would replace calcitic limestone without interfering with productive efficiency, egg quality or digestibility. In a first study (Experiment I), we used 30% IER in the diets of laying hens and found that the apparent digestibility coefficients were 51.6%, 42.8%, 51.6% and 17.8% for dry matter, crude protein, calcium and phosphorus, respectively. In the second study (Experiment II), we compared a control diet containing calcitic limestone with four diets containing increasing levels of IER, in proportions of 25%, 50%, 75% and 100%. During the first cycle (day 1–28), there was no difference between treatments in terms of productive performance or egg quality. During the second production cycle (day 29–56), we observed less food consumption by birds that ingested the highest levels of IER (100% substitution) than in controls. During the third cycle (day 57–84), we found that the inclusion of IER negatively affected performance, particularly lower production numbers, lower egg mass and higher feed conversion. Finally, during the third cycle, chickens broke and ingested their eggs shortly after laying. We conclude that the use of industrial egg residue cannot replace limestone in the feed of commercial laying hens, because it reduces performance and affects egg quality.

ALT telomeres experience DNA damage that may drive recombination-based telomere elongation. Here, the authors reveal that FANCM plays a critical role in the suppression of ALT activity through its interaction with the BTR (BLM-TOP3A-RMI) complex.

Abstract Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy and immune-mediated mechanisms of a novel HER2-targeting ADC bearing a potent anthracycline derivate as payload (T-PNU) in a human HER2-expressing syngeneic breast cancer model resistant to trastuzumab and ado-trastuzumab emtansine. Mechanistically, the anthracycline component of the novel ADC induced immunogenic cell death leading to exposure and secretion of danger-associated molecular signals. RNA sequencing derived immunogenomic signatures and TCRβ clonotype analysis of tumor-infiltrating lymphocytes revealed a prominent role of the adaptive immune system in the regulation of T-PNU mediated anti-cancer activity. Depletion of CD8 T cells severely reduced T-PNU efficacy, thus confirming the role of cytotoxic T cells as drivers of the T-PNU mediated anti-tumor immune response. Furthermore, T-PNU therapy promoted immunological memory formation in tumor-bearing animals protecting those from tumor rechallenge. Finally, the combination of T-PNU and checkpoint inhibition, such as α-PD1, significantly enhanced tumor eradication following the treatment. In summary, a novel PNU-armed, HER2-targeting ADC elicited long-lasting immune protection in a murine orthotopic breast cancer model resistant to other HER2-directed therapies. Our findings delineate the therapeutic potential of this novel ADC payload and support its clinical development for breast cancer patients and potentially other HER2 expressing malignancies.

Rituximab plus chemotherapy induction followed by rituximab maintenance for up to 2 years confers a long-term benefit in terms of progression-free survival in patients with indolent non-Hodgkin lymphoma. It is not known whether further prolonged maintenance with rituximab provides additional benefit. The phase III MabCute study enrolled 692 patients with relapsed or refractory indolent non-Hodgkin lymphoma. Patients who responded to induction with rituximab plus chemotherapy and were still responding after up to 2 years’ initial maintenance with subcutaneous rituximab were randomized to extended maintenance with subcutaneous rituximab (n=138) or observation only (n=138). The primary endpoint of investigator-assessed progression-free survival in the randomized population was un-addressed by the end of study because of an insufficient number of events (129 events were needed for 80% power at 5% significance if approximately 330 patients were randomized). In total, there were 46 progression-free survival events, 19 and 27 in the rituximab and observation arms, respectively (P=0.410 by stratified log-rank test; hazard ratio 0.76 [95% confidence interval: 0.37– 1.53]). The median progression-free survival was not reached in either randomized arm. There were no new safety signals; however, adverse events were seen slightly more frequently with rituximab than with observation during extended maintenance. Maintenance for up to 2 years with rituximab after response to initial induction therefore remains the standard of care in patients with relapsed or refractory indolent non- Hodgkin lymphoma. (Clinicaltrials.gov identifier: NCT01461928).

BackgroundDiscoveries in the identification of transcription factors, growth factors and extracellular signaling molecules have led to the detection of downstream targets that modulate valvular tissue organization that occurs during development, aging, or disease. Among these, matricellular protein, periostin, and cytoskeletal protein filamin A are highly expressed in developing heart valves. The phenotype of periostin null indicates that periostin promotes migration, survival, and differentiation of valve interstitial cushion cells into fibroblastic lineages necessary for postnatal valve remodeling/maturation. Genetically inhibiting filamin A expression in valve interstitial cushion cells mirrored the phenotype of periostin nulls, suggesting a molecular interaction between these two proteins resulted in poorly remodeled valve leaflets that might be prone to myxomatous over time. We examined whether filamin A has a cross-talk with periostin/signaling that promotes remodeling of postnatal heart valves into mature leaflets.ResultsWe have previously shown that periostin/integrin-β1 regulates Pak1 activation; here, we revealed that the strong interaction between Pak1 and filamin A proteins was only observed after stimulation of VICs with periostin; suggesting that periostin/integrin-β-mediated interaction between FLNA and Pak1 may have a functional role in vivo. We found that FLNA phosphorylation (S2152) is activated by Pak1, and this interaction was observed after stimulation with periostin/integrin-β1/Cdc42/Rac1 signaling; consequently, FLNA binding to Pak1 stimulates its kinase activity. Patients with floppy and/or prolapsed mitral valves, when genetically screened, were found to have point mutations in the filamin A gene at P637Q and G288R. Expression of either of these filamin A mutants failed to increase the magnitude of filamin A (S2152) expression, Pak1-kinase activity, actin polymerization, and differentiation of VICs into mature mitral valve leaflets in response to periostin signaling.ConclusionPN-stimulated bidirectional interaction between activated FLNA and Pak1 is essential for actin cytoskeletal reorganization and the differentiation of immature VICs into mature valve leaflets.

Abstract Eugenia uniflora, known as the “Brazilian cherry”, is an economically important neotropical Myrtaceae in the cosmetics and pharmaceutical industries due the production of essential oils with antioxidant activity. On account of its significant genetic variability, genotype evaluations are needed in order to identify genetic features related to the essential oil production that meet the industry requirements. The main objective of the present study was to evaluate the yield, composition, and antioxidant activity of essential oils isolated from the leaves of 36 genotypes of E. uniflora. Essential oil samples were obtained by hydrodistillation, and their composition was determined by gas chromatography coupled with mass spectrometry. A variation of 0.22% to 1.68% in the essential oil yield was observed, in which 78 compounds, namely oxygenated sesquiterpenes, were identified. According to the cluster analysis of the major compounds, six groups were revealed. The observed diversity demonstrates the genetic variability of the species. Also, the antioxidant activity was affected by the composition of the essential oils, ranging from 176.66 to 867.57 µM TEAC.

Quantum diamond microscope (QDM) magnetic field imaging is a recently developed technique capable of mapping magnetic field sources in geologic samples at 1 micrometer resolution. Applying QDM imaging to speleothems can provide high‐resolution time series of detrital input into the cave environment, which, in turn, can yield useful paleoenvironmental information. Here we map the magnetic field over a speleothem from midwest Brazil over a 174 year timespan with annual to sub-annual resolution and perform backfield remanence acquisition experiments to quantify changes in the magnetic grain population through time. We find that magnetic particles occur in highly enriched layers of 10–100 µm thickness that sample the same detrital source population. Combined with petrographic observations and electron microprobe mapping of Mg and Ca, we conclude that detrital enrichment in our sample is caused by drier conditions leading to slow or halted speleothem growth. This interpretation is compatible with oxygen isotopic data and implies that speleothem magnetism can be used to infer the past occurrence of drought and potentially quantify their duration. Future high-resolution magnetic imaging of speleothems may provide additional insight into the mechanism of detrital enrichment and establish their role as a proxy for local moisture and infiltration.

Abstract We measured the effects of açai oil in the diets of prepartum cows to evaluate health, milk production and quality. Sixteen Holstein cows were divided into two groups: SOY used as control, and AÇAI, test group. Occurred inclusion of 4% soybean or açai oils was provided in the concentrate starting at 20 days prepartum [d -20 to d 0 (partum-day)]. The AÇAI diet increased (P=0.01) milk production (d 10 and 20) and reduced somatic cell count (d 20). In milk, no effects were detected (P≥0.10) for concentration of fat, lactose or protein as well as in terms of serum concentration of calcium, albumin or triglycerides. AÇAI diet tended to increase (P=0.09) serum concentrations of total protein, glutathione transferase (d 4), and total antioxidant capacity (d 4 and 10) and increased (P≤0.05) globulin, gamma-glutamyl transferase, superoxide dismutase and glutathione peroxidase (d 4). Further, AÇAI diet reduced the serum concentration of creatine kinase (P≤0.05) (d 0, 4 and 10), reactive oxygen species (d 0 and 4) and lipoperoxidation (d 0) and tended to reduce aspartate transaminase activity (P=0.07; d 0 and 4). Açai oil in the diets in prepartum cows improved their health as well as milk production and quality.

Amyotrophic lateral sclerosis is a disease characterized by progressive paralysis and death. Most ALS-cases are sporadic (sALS) and patient heterogeneity poses challenges for effective therapies. Applying metabolite profiling on 77-sALS patient-derived-fibroblasts and 43-controls, we found ~25% of sALS cases (termed sALS-1) are characterized by transsulfuration pathway upregulation, where methionine-derived-homocysteine is channeled into cysteine for glutathione synthesis. sALS-1 fibroblasts selectively exhibited a growth defect under oxidative conditions, fully-rescued by N-acetylcysteine (NAC). [U13C]-glucose tracing showed transsulfuration pathway activation with accelerated glucose flux into the Krebs cycle. We established a four-metabolite support vector machine model predicting sALS-1 metabotype with 97.5% accuracy. Both sALS-1 metabotype and growth phenotype were validated in an independent cohort of sALS cases. Importantly, plasma metabolite profiling identified a system-wide cysteine metabolism perturbation as a hallmark of sALS-1. Findings reveal that sALS patients can be stratified into distinct metabotypes with differential sensitivity to metabolic stress, providing novel insights for personalized therapy.

In the aging population, lower urinary tract (LUT) dysfunction is common and often leads to storage and voiding difficulties classified into overlapping symptom syndromes. Despite prevalence and consequences of these syndromes, LUT disorders continue to be undertreated simply because there are few therapeutic options. LUT function and structure were assessed in aged (>25 months) male and female Fischer 344 rats randomized to oral treatment with a purine nucleoside phosphorylase (PNPase inhibitor) 8-aminoguanine (8-AG) or vehicle for 6 weeks. The bladders of aged rats exhibited multiple abnormalities: tactile insensitivity, vascular remodeling, reduced collagen-fiber tortuosity, increased bladder stiffness, abnormal smooth muscle morphology, swelling of mitochondria, and increases in urodamaging purine metabolites. Treatment of aged rats with 8-AG restored all evaluated histological, ultrastructural, and physiological abnormalities toward that of a younger state. 8-AG is an effective treatment that ameliorates key age-related structural and physiologic bladder abnormalities. Because PNPase inhibition blocks metabolism of inosine to hypoxanthine and guanosine to guanine, likely uroprotective effects of 8-AG are mediated by increased bladder levels of uroprotective inosine and guanosine and reductions in urodamaging hypoxanthine and xanthine. These findings demonstrate that 8-AG has translational potential for treating age-associated LUT dysfunctions and resultant syndromes in humans.

Abstract Interest in magnetic fields on the ancient Earth and other planetary bodies has motivated the paleomagnetic analysis of complex rocks such as meteorites that carry heterogeneous magnetizations at <

Summary: Mammary stem and progenitor cells are essential for mammary gland homeostasis and are also candidates for cells of origin of mammary tumors. Here, we have investigated the function of the protein kinase p38α in the mammary gland using mice that delete this protein in the luminal epithelial cells. We show that p38α regulates the fate of luminal progenitor cells through modulation of the transcription factor RUNX1, an important controller of the estrogen receptor-positive cell lineage. We also provide evidence that the regulation of RUNX1 by p38α probably involves the kinase MSK1, which phosphorylates histone H3 at the RUNX1 promoter. Moreover, using a mouse model for breast cancer initiated by luminal cells, we show that p38α downregulation in mammary epithelial cells reduces tumor burden, which correlates with decreased numbers of tumor-initiating cells. Collectively, our results define a key role for p38α in luminal progenitor cell fate that affects mammary tumor formation.

Globally, 20% to 40% of medical resources are wasted, which could be avoided through professional audit of health insurance claims. The professional audit can pinpoint excessive use of unnecessary medicines and medical examinations. Taiwan’s National Health Insurance Bureau (TNHIB) deducts the weight that medical resources carry if regarded as unnecessary or abused when examining health insurance claims. The ratio of the deducted weight to the total weight claimed by a hospital is defined as the health insurance claim deduction rate (HICDR). A high HICDR increases the operating expenses of the hospital. In addition, it takes the hospital many resources to prepare and file appeals for the deduction. This study aims to: (1) minimize the weight deducted by the TNHIB for a hospital; and (2) facilitate efficient appeals to claim denials. It is expected that HICDR will be reduced through big data analytics. In this study, evidence-based medicine (EBM) is involved to clarify the debate, dilemmas, conflicts of interests in examining health insurance claims. A natural language method—latent Dirichlet allocation (LDA), was used to analyze patients’ medical records. The topics derived from the LDA are used as factors in the logistic regression model to estimate the probability of each claim to be deducted. The experimental results on various medical departments show that the proposed predictive model can produce accurate results, and lead to more than 41.7% reduction to the deduction of the health insurance claims. It is equivalent to more than a 750 thousand NT dollars saving per year. The efficiency of application is validated compared to the manual process that is time-consuming and labor intensive. Moreover, it is expected that this study will supplement the insufficiency of traditional methods and propose a new and effective solution to reduce the deduction rate.

Eukaryote-like serine/threonine kinases (STKs) and cognate phosphatases (STPs) comprise an important regulatory system in many bacterial pathogens. The complexity of this regulatory system has not been fully understood due to the presence of multiple STKs/STPs in many bacteria and their multiple substrates involved in many different physiological and pathogenetic processes. Streptococci are the best materials for the study due to a single copy of the gene encoding STK and its cognate STP. Although several studies have been done to investigate the roles of STK and STP in zoonotic Streptococcus suis, respectively, few studies were performed on the coordinated regulatory roles of this system. In this study, we carried out a systemic study on STK/STP in S. suis by using a comparative phenotypic, proteomic, and phosphoproteomic analysis. Mouse infection assays revealed that STK played a much more important role in S. suis pathogenesis than STP. The ∆stk and ∆stp∆stk strains, but not ∆stp, showed severe growth retardation. Moreover, both ∆stp and ∆stk strains displayed defects in cell division, but they were abnormal in different ways. The comparative proteomics and phosphoproteomics revealed that deletion of stk or stp had a significant influence on protein expression. Interestingly, more virulence factors were found to be downregulated in ∆stk than ∆stp. In ∆stk strain, a substantial number of the proteins with a reduced phosphorylation level were involved in cell division, energy metabolism, and protein translation. However, only a few proteins showed increased phosphorylation in ∆stp, which also included some proteins related to cell division. Collectively, our results show that both STP and STK are critical regulatory proteins for S. suis and that STK seems to play more important roles in growth, cell division, and pathogenesis.

Cell migration, which is central to a wide variety of life processes, involves integration of the extracellular matrix (ECM) with the internal cytoskeleton and motor proteins via receptors spanning the plasma membrane. Cell migration can be induced by a variety of signals, including gradients of external soluble molecules, differences in ECM composition, or electrical gradients. Current in vitro methods to study cell migration only test one substrate at a time. Here, we present a method for assessing cell adhesion, migration, and differentiation in up to 20 different test conditions simultaneously, using only minute amounts of target substrate. Our system, which we call the linear array of multi-substrate cell migration assay (LAMA), has two configurations for direct comparison of one or two cell types in response to an array of ECM constituents under the same culture conditions. This culture model utilizes only nanogram amounts of test substrates and a minimal number of cells, which maximizes the use of limited and expensive test reagents. Moreover, LAMA can also be used for high-throughput screening of potential pharmaceuticals that target ECM-dependent cell behavior and differentiation.

Industries are always looking for more efficient maintenance systems to minimize machine downtime and productivity liabilities. Among several approaches, artificial intelligence techniques have been increasingly applied to machine diagnosis. Current paper forwards the development of a system for the diagnosis of mechanical faults in the rotating structures of machines, based on fuzzy logic, using rules foregrounded on the full spectrum of the machine´s complex vibration signal. The diagnostic system was developed in Matlab and it was applied to a rotor test rig where different faults were introduced. Results showed that the diagnostic system based on full spectra and fuzzy logic is capable of identifying with precision different types of faults, which have similar half spectrum. The methodology has a great potential to be implemented in predictive maintenance programs in industries and may be expanded to include the identification of other types of faults not covered in the case study under analysis.

Abstract Protein colocalisation is often studied using pixel intensity-based coefficients such as Pearson, Manders, Li or Costes. However, these methods cannot be used to study object-based colocalisations in biological systems. Therefore, a novel method is required to automatically identify regions of fluorescent signal in two channels, identify the co-located parts of these regions, and calculate the statistical significance of the colocalisation. We have developed MatCol to address these needs. MatCol can be used to visualise protein and/or DNA colocalisations and fine tune user-defined parameters for the colocalisation analysis, including the application of median or Wiener filtering to improve the signal to noise ratio. Command-line execution allows batch processing of multiple images. Users can also calculate the statistical significance of the observed object colocalisations compared to overlap by random chance using Student’s t-test. We validated MatCol in a biological setting. The colocalisations of telomeric DNA and TRF2 protein or TRF2 and PML proteins in >350 nuclei derived from three different cell lines revealed a highly significant correlation between manual and MatCol identification of colocalisations (linear regression R2 = 0.81, P