Miracle-dz/UniFAR-FTUs huggingface dataset:
Sensory Perception in Bacterial Cyclic Diguanylate Signal Transduction

Cyclic diguanylate (c-di-GMP) signal transduction systems provide bacteria with the ability to sense changing cell status or environmental conditions and then execute suitable physiological and social behaviors in response. In this review, we provide a comprehensive census of the stimuli and receptors that are linked to the modulation of intracellular c-di-GMP. ABSTRACT Cyclic diguanylate (c-di-GMP) signal transduction systems provide bacteria with the ability to sense changing cell status or environmental conditions and then execute suitable physiological and social behaviors in response. In this review, we provide a comprehensive census of the stimuli and receptors that are linked to the modulation of intracellular c-di-GMP. Emerging evidence indicates that c-di-GMP networks sense light, surfaces, energy, redox potential, respiratory electron acceptors, temperature, and structurally diverse biotic and abiotic chemicals. Bioinformatic analysis of sensory domains in diguanylate cyclases and c-di-GMP-specific phosphodiesterases as well as the receptor complexes associated with them reveals that these functions are linked to a diverse repertoire of protein domain families. We describe the principles of stimulus perception learned from studying these modular sensory devices, illustrate how they are assembled in varied combinations with output domains, and summarize a system for classifying these sensor proteins based on their complexity. Biological information processing via c-di-GMP signal transduction not only is fundamental to bacterial survival in dynamic environments but also is being used to engineer gene expression circuitry and synthetic proteins with à la carte biochemical functionalities.
Technical aspects and operative nuances using a high-definition 4K-3-dimensional exoscope for carotid endarterectomy surgery.

PURPOSE Carotid endarterectomy (CEA) is effective in treating carotid artery stenosis to prevent stroke. Historically, this operation has been performed utilizing loupe magnification with or without the operating microscope (OM). However, there remains a need for continued improvement in operative visualization and surgical ergonomics. Recently, newly developed digital 'exoscope' has provided the surgeon with unique lighting and magnification as well as improvements in surgical ergonomics and working angle. We sought to review our cumulative experience using a novel 4K high-definition (4K-HD) 3-dimensional (3D) exoscope (EX) for CEA surgery. METHODS All CEA surgery cases at our institution between 2013 and 2019 using the 4K-HD 3D EX were reviewed. Operative parameters, patient outcome and operator's assessment of the EX compared to OM-assisted cases was conducted. RESULTS 28 patients were treated, 10 of which were operated using the EX. All procedures were performed without perioperative complications, or significant differences in operative parameters (blood loss <20 cm3 and 164 ± 49.5 minutes) compared to OM-assisted cases. Operators reported improved level of comfort performing 'high' bifurcation surgery and improved visualization and posture during inspection of the distal ICA lumen as primary advantages of EX-assisted CEA over OM-assisted CEA. CONCLUSIONS The ORBEYE EX, albeit a learning curve necessitating a short period of the OR team, provided safety and outcome comparable to OM-assisted surgery. Potential advantages noted were improved visualization and ergonomics specifically for when extreme working angles were required. Our experience suggests that the exoscope may become a valuable alternative to standard magnification tools in CEA surgery.
Density of CD3+ and CD8+ Cells in the Microenvironment of Colorectal Cancer according to Prediagnostic Physical Activity

Background: Physical activity is associated not only with a decreased risk of developing colorectal cancer but also with improved survival. One putative mechanism is the infiltration of immune cells in the tumor microenvironment. Experimental findings suggest that physical activity may mobilize immune cells to the tumor. We hypothesized that higher levels of physical activity prior to colorectal cancer diagnosis are associated with higher densities of tumor-infiltrating T-lymphocytes in colorectal cancer patients. Methods: The study setting was a northern Swedish population-based cohort, including 109,792 participants with prospectively collected health- and lifestyle-related data. For 592 participants who later developed colorectal cancer, archival tumor tissue samples were used to assess the density of CD3+ and CD8+ cytotoxic T cells by IHC. Odds ratios for associations between self-reported, prediagnostic recreational physical activity and immune cell infiltration were estimated by ordinal logistic regression. Results: Recreational physical activity >3 times per week was associated with a higher density of CD8+ T cells in the tumor front and center compared with participants reporting no recreational physical activity. Odds ratios were 2.77 (95% CI, 1.21–6.35) and 2.85 (95% CI, 1.28–6.33) for the tumor front and center, respectively, after adjustment for sex, age at diagnosis, and tumor stage. The risk estimates were consistent after additional adjustment for several potential confounders. For CD3, no clear associations were found. Conclusions: Physical activity may promote the infiltration of CD8+ immune cells in the tumor microenvironment of colorectal cancer. Impact: The study provides some evidence on how physical activity may alter the prognosis in colorectal cancer.
Assessment of programmed death-ligand 1 receptor immunohistochemical expression and its association with tumor-infiltrating lymphocytes and p53 status in triple-negative breast cancer

Breast cancer (BC) is the second most frequent type of cancer for both sexes combined, after lung cancer. Triple-negative BC (TNBC) molecular subtype is characterized by lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) immunoexpression or amplification and represent 10–20% of all BC cases. The issue of the present study was to analyze the associations between programmed death-ligand 1 (PD-L1) immunoexpression and distribution of stromal tumor-infiltrating lymphocytes (stTILs) combined with clinico-morphological features of patients with TNBC. Secondly, our research evaluated PD-L1 immunoexpression as a prognostic factor and its correlation with p53 immunoexpression. Thirty cases with primary TNBC without prior neoadjuvant therapy were included in this research. stTILs were identified in all cases, most of them with low distribution (66.7%). A positive immunoreaction for PD-L1 was observed in 40% of cases. The PD-L1 immunoexpression was statistically significant associated with age, pathological tumor size, lymphovascular invasion, stTILs level, the presence of cluster of differentiation 8-positive (CD8+) TILs and p53 immunoexpression. In the present study, a positive PD-L1 immunoexpression was associated with a worse distant metastasis free survival (DMFS). We also found not only that high stTILs level were associated with a better DMFS but also that there was a statistically significant association between stTILs level and PD-L1 immunoexpression. Our results bring new insights to the fine connections between tumor microenvironment and molecular changes of TNBC. It helps us to better understand these aggressive tumors to identify the more useful biomarkers for predicting the response to adjuvant therapy and can represent a method for selecting the most suitable patients for immunotherapy.
Music-reading expertise associates with face but not Chinese character processing ability

A growing number of behavioural and neuroimaging studies have investigated the cognitive mechanisms and neural substrates underlying various forms of visual expertise, such as face and word processing. However, it remains poorly understood whether and to what extent the acquisition of one form of expertise would be associated with that of another. The current study examined the relationship between music-reading expertise and face and Chinese character processing abilities. In a series of experiments, music experts and novices performed discrimination and recognition tasks of musical notations, faces, and words. Results consistently showed that musical experts responded more accurately to musical notations and faces, but not to words, than did musical novices. More intriguingly, the music expert’s age of training onset could well predict their face but not word processing performance: the earlier musical experts began musical notation reading, the better their face processing performance. Taken together, our findings provide preliminary and converging evidence that music-reading expertise links with face, but not word, processing, and lend support to the notion that the development of different types of visual expertise may not be independent, but rather interact with each other during their acquisition.
Accelerating compressed sensing reconstruction of subsampled radial k-space data using geometrically-derived density compensation

Objective. To accelerate compressed sensing (CS) reconstruction of subsampled radial k-space data using a geometrically-derived density compensation function (gDCF) without significant loss in image quality. Approach. We developed a theoretical framework to calculate a gDCF based on Nyquist distance along the radial and circumferential directions of a discrete polar coordinate system. Our gDCF was compared against standard DCF (e.g. ramp filter) and another commonly used DCF (modified Shepp–Logan (SL) filter). The resulting image quality produced by each DCF was quantified using normalized root-mean-square-error (NRMSE), blur metric (1 = blurriest; 0 = sharpest), and structural similarity index (SSIM; 1 = perfect match; 0 = no match) compared with the reference. For filtered backprojection (FBP) of phantom data obtained at the Nyquist sampling rate, Cartesian k-space sampling was used as the reference. For CS reconstruction of subsampled cardiac magnetic resonance imaging datasets (real-time cardiac cine data with 11 projections per frame, n = 20 patients; cardiac perfusion data with 30 projections per frame, n = 19 patients), CS reconstruction without DCF was used as the reference. Main results. The NRMSE, SSIM, and blur metrics of the phantom data were good for all DCFs, confirming that our gDCF produces uniform densities at the upper limit (Nyquist). For CS reconstruction of subsampled real-time cine and cardiac perfusion datasets, the image quality metrics (SSIM, NRMSE) were significantly (p < 0.05) higher for our gDCF than other DCFs, and the reconstruction time was significantly (p < 0.05) faster for our gDCF (reference) than no DCF (11.9%–52.9% slower), standard DCF (23.9%–57.6% slower), and modified SL filter (13.5%–34.8% slower). Significance. The proposed gDCF accelerates CS reconstruction of subsampled radial k-space data without significant loss in image quality compared with no DCF as the reference.
Primary Sclerosing Cholangitis–Associated Cholangiocarcinoma Demonstrates High Intertumor and Intratumor Heterogeneity

INTRODUCTION: Intertumor and intratumor heterogeneity may explain the diagnostic challenge and limited efficacy of chemotherapy for primary sclerosing cholangitis–associated cholangiocarcinoma (PSC-CCA). In this study, tumor heterogeneity was assessed through p53 and p16 protein expression analysis and next-generation sequencing (NGS) of TP53 and CDKN2A genetic alterations in PSC-associated CCA. METHODS: Formalin-fixed paraffin-embedded tissue samples from resection material of patients with PSC-CCA or patients with PSC diagnosed with biliary dysplasia were selected. Sections with CCA and foci with dysplastic epithelium were identified by 2 independent gastrointestinal pathologists. Immunohistochemical evaluation of p53 and p16 protein expression and NGS of TP53 and CDKN2A genetic alterations were performed. RESULTS: A total of 49 CCA and 21 dysplasia samples were identified in the resection specimens of 26 patients. P53 protein expression showed loss of expression, wild type, and overexpression in 14%, 63%, and 23% CCA and in 19%, 62%, and 19% dysplasia samples, respectively. P16 protein expression showed negative, heterogeneous, and positive results in 31%, 57%, and 12% CCA and in 33%, 53%, and 14% dysplasia samples, respectively. NGS showed high intertumor and intratumor heterogeneity of TP53 mutations and CDKN2A loss. Nearly 70% of the samples with a TP53 missense mutation demonstrated p53 overexpression, whereas all samples with a TP53 nonsense mutation demonstrated loss of p53 protein expression. DISCUSSION: PSC-associated CCA is characterized by high intertumor and intratumor heterogeneity of both p53/p16 protein expression and genetic alterations in TP53/CDKN2A, indicating that these tumors consist of multiple subclones with substantially different genetic makeup. The high intertumor and intratumor heterogeneity in PSC-CCA should be acknowledged during the development of diagnostic and therapeutic strategies.
Podoplanin promotes tumor growth, platelet aggregation, and venous thrombosis in murine models of ovarian cancer

Podoplanin (PDPN) is a sialylated membrane glycoprotein that binds to C‐type lectin‐like receptor 2 on platelets resulting in platelet activation. PDPN is expressed on lymphatic endothelial cells, perivascular fibroblasts/pericytes, cancer cells, cancer‐associated fibroblasts, and tumor stromal cells. PDPN's expression on malignant epithelial cells plays a role in metastasis. Furthermore, the expression of PDPN in brain tumors (high‐grade gliomas) was found to correlate with an increased risk of venous thrombosis.
Releasing incompatible males drives strong suppression across populations of wild and Wolbachia-carrying Aedes aegypti in Australia

Significance With over 40% of humans at risk from mosquito-borne diseases such as dengue, yellow fever, chikungunya, and Zika, the development of environmentally friendly mosquito-control tools is critical. The release of reproductively incompatible male mosquitoes carrying a Wolbachia bacterium can drive mating events that kill the eggs. Through replicated treatment and control experiments in northern Australia, regular releases of Aedes aegypti males infected with a Wolbachia from Aedes albopictus was shown to drive strong population suppression in mosaic populations of wild-type (no Wolbachia) and wMel-Wolbachia–carrying Ae. aegypti. In a demonstration of bidirectional incompatibility between different Wolbachia strains in the field, we also demonstrate that one season’s suppression experiment can also show an ongoing effect into the following season. Releasing sterile or incompatible male insects is a proven method of population management in agricultural systems with the potential to revolutionize mosquito control. Through a collaborative venture with the “Debug” Verily Life Sciences team, we assessed the incompatible insect technique (IIT) with the mosquito vector Aedes aegypti in northern Australia in a replicated treatment control field trial. Backcrossing a US strain of Ae. aegypti carrying Wolbachia wAlbB from Aedes albopictus with a local strain, we generated a wAlbB2-F4 strain incompatible with both the wild-type (no Wolbachia) and wMel-Wolbachia Ae. aegypti now extant in North Queensland. The wAlbB2-F4 strain was manually mass reared with males separated from females using Verily sex-sorting technologies to obtain no detectable female contamination in the field. With community consent, we delivered a total of three million IIT males into three isolated landscapes of over 200 houses each, releasing ∼50 males per house three times a week over 20 wk. Detecting initial overflooding ratios of between 5:1 and 10:1, strong population declines well beyond 80% were detected across all treatment landscapes when compared to controls. Monitoring through the following season to observe the ongoing effect saw one treatment landscape devoid of adult Ae. aegypti early in the season. A second landscape showed reduced adults, and the third recovered fully. These encouraging results in suppressing both wild-type and wMel-Ae. aegypti confirms the utility of bidirectional incompatibility in the field setting, show the IIT to be robust, and indicate that the removal of this arbovirus vector from human-occupied landscapes may be achievable.
The novel repressor Rce2 competes with Ace3 to regulate cellulase gene expression in the filamentous fungus Trichoderma reesei

The filamentous fungus Trichoderma reesei is widely used for industrial cellulase production. In T. reesei, cellulase gene expression is tightly controlled by a regulatory network involving multiple transcription factors. Here, we isolated a novel protein, Rce2, using a pull‐down assay and mass spectrometry analysis, from a partial carbon catabolite de‐repression mutant, T. reesei Rut‐C30, cultured under glucose‐repressing conditions. Deletion and overexpression of Rce2 in T. reesei wild‐type QM6a and mutant Rut‐C30 revealed that Rce2 acts as a repressor of cellulase gene expression. DNase I footprinting assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays revealed that Rce2 was located in the nucleus and bound to the consensus sequences 5′‐(T/A)NNNNCCG‐3′ and 5′‐CGGNNNN(T/A)‐3′ in the promoters of cellulase‐related genes to repress their transcription. Additionally, Rce2 antagonized Ace3 binding to the cbh1 promoter to repress its transcription. However, Rce2 was not involved in Cre1‐mediated carbon catabolite repression. These results demonstrate the mechanism through which Rce2 represses the expression of cellulase genes and provide novel insights into the regulatory system of cellulases and methods that can be used for the regulation of gene expression in T. reesei.
A software approach for identifying the effect of dental caries on dentin–enamel junction

Dental decay is the most prevalent oral disease worldwide since more than 2.4 billion people suffer from caries of permanent teeth. Therefore, any details about its progression into the hard-dental tissues could contribute to unravelling the mechanisms underlying this process. We have analyzed dental tissue sections with and without caries in order to detect structure differences corelating them with clinical aspects observable from the tooth surface. Our working hypothesis was based on finding a link between the process of tertiary dentin laying (as a response to coronal caries) and the subsequent obliteration of dentin tubules. We have selected N=10 extracted teeth with/without coronal caries, resin-embedded and sectioned them. A specific software was used to digitally quantify the density of unobliterated dentin tubules reaching the dentin–enamel junction (DEJ), considering as positive threshold criteria the presence of the odontoblast process inside the analyzed tubule. This study showed the differences between the healthy and carious-affected hard-dental coronal tissues. More odontoblast processes reached the DEJ in unaffected teeth. Using specific software, we have quantified their density decrease near a lesion. We have studied the dynamics of the carious study and measured the consequent structural modifications of the dentin. In conclusion, there is a significant difference between the number of dentin tubules containing odontoblast processes that reach the DEJ in healthy/altered tissues. The tooth reacts not only by production of tertiary dentin to protect the pulp chamber, but also by obliteration of dentin tubules, thus reducing the number of odontoblast processes reaching the DEJ. This pilot study could serve as the starting point in developing a dedicated software that could deliver a personalized pattern for decay progression by analyzing one single tooth and extrapolate the result to all the patient’s remaining ones.
Depression, Anxiety, and Daily Activity Among Adolescents Before and During the COVID-19 Pandemic: Cross-sectional Survey Study

Background The COVID-19 pandemic has resulted in significant changes to adolescents’ daily lives and, potentially, to their mental health. The pandemic has also disproportionately affected historically marginalized and at-risk communities, including people of color, socioeconomically disadvantaged people, people identifying as female, and youth. Objective This study aimed to understand differences in depression and anxiety among 2 groups of adolescents in the United States before and during the COVID-19 pandemic, and to examine demographic and daily activity variables associated with depression and anxiety. Methods Online surveys were distributed in 2019 and 2020. Demographic questions were asked at the time of enrollment, and included participants’ age, gender, race and ethnicity, and socioeconomic status (SES). The 8-item Patient Health Questionnaire was used to assess symptoms of depression, and the 7-item Generalized Anxiety Disorder scale was used to assess symptoms of anxiety. A total of 4 pandemic-specific daily activity questions were asked only of the pandemic group. Analyses of covariance compared depression and anxiety between prepandemic and pandemic groups. Demographic and lifestyle variables were included as covariates. Results The sample comprised a total of 234 adolescents, with 100 participants in the prepandemic group and 134 participants in the pandemic group. Within the pandemic group, 94% (n=126) of adolescents reported being out of school due to the pandemic, and another 85.8% (n=115) and 57.1% (n=76) were prevented from extracurricular activities and exercise, respectively. Higher depression was seen in the pandemic group, with a least-squares adjusted mean of 7.62 (SD 1.36) compared to 6.28 (SD 1.42) in the prepandemic group, although the difference was not significant (P=.08). There was no significant difference in anxiety scores between the 2 groups (least-squares adjusted means 5.52, SD 1.30 vs 5.01, SD 1.36; P=.48). Within the pandemic group, lower SES was predictive of anxiety, such that those in the pandemic group of lower SES were more anxious than their higher-SES peers (least-squares adjusted means 11.17, SD 2.34 vs 8.66, SD 2.16; P=.02). Within the pandemic group, being out of work or school and not partaking in extracurricular activities or exercise due to the pandemic were not associated with higher depression or anxiety scores. Conclusions In this study, neither being in the pandemic group nor experiencing changes in daily activity due to the pandemic was associated with higher depression or anxiety. However, we found that adolescents from lower SES backgrounds experienced significantly more anxiety during the pandemic than their more privileged peers. Both instrumental and mental health interventions for low-income adolescents are imperative.
Relation between Plasminogen Activator Inhibitor-1 and Hepatic Enzyme Concentrations in Hyperlipidemic Patients

Summary Plasminogen activator inhibitor type-1 (PAI-1) is a key determinant of the fibrinolytic capacity. Its activity correlates with most of the characteristic features of insulin resistance syndrome, i. e. obesity, high blood pressure and hyperlipidemia. We measured plasma PAI-1 antigen levels in 131 asymptomatic men (aged 44.2 ± 11 years) who had been referred for hyperlipidemia. Those taking medication and those with a secondary hyperlipidemia were excluded. We confirmed the correlation between PAI-1 levels and the following variables: body mass index, blood pressure, triglyceride concentration, and blood glucose and insulin levels before and after an oral glucose tolerance test. We also found a significant and independent correlation between PAI-1 and the concentration of the hepatic enzymes glutamyl transferase, alanine aminotransferase and aspartate aminotransferase. Mild liver abnormalities (presumably steatosis) may thus be one of the factors accounting for high plasma PAI-1 levels in hyperlipidemic patients.