Miracle-dz/UniFAR-FTUs huggingface dataset:
Illuminating the dark phosphoproteome

Identifying the targets of “dark” kinases will provide new biological and disease insights. Gloss Protein phosphorylation is a posttranslational modification that regulates protein function. Many biological processes require phosphorylation, and its dysregulation is a hallmark of several complex diseases. Major developments in mass spectrometry now enable the measurement of thousands of changes in phosphorylation and mapping them to exact sites on specific proteins. More than 100,000 phosphorylation sites have been reported, but the kinases regulating these events are currently known only for a small fraction of these sites, and even fewer sites are linked to specific functions. A small subset of kinases dominates the annotated phosphosites, whereas many kinases have no known target proteins. Functional experiments linking human disease genes and mouse knockouts with kinases suggest that these lesser-studied kinases may also be important in health. This Review, with 4 figures, 4 videos, 3 data files, and 205 references, discusses how identifying regulatory kinases and functions of phosphorylated proteins will reveal mechanistic insights into biological function in healthy and disease contexts, point to new therapeutic targets, and enhance our understanding of drug action. Protein phosphorylation is a major regulator of protein function and biological outcomes. This was first recognized through functional biochemical experiments, and in the past decade, major technological advances in mass spectrometry have enabled the study of protein phosphorylation on a global scale. This rapidly growing field of phosphoproteomics has revealed that more than 100,000 distinct phosphorylation events occur in human cells, which likely affect the function of every protein. Phosphoproteomics has improved the understanding of the function of even the most well-characterized protein kinases by revealing new downstream substrates and biology. However, current biochemical and bioinformatic approaches have only identified kinases for less than 5% of the phosphoproteome, and functional assignments of phosphosites are almost negligible. Notably, our understanding of the relationship between kinases and their substrates follows a power law distribution, with almost 90% of phosphorylation sites currently assigned to the top 20% of kinases. In addition, more than 150 kinases do not have a single known substrate. Despite a small group of kinases dominating biomedical research, the number of substrates assigned to a kinase does not correlate with disease relevance as determined by pathogenic human mutation prevalence and mouse model phenotypes. Improving our understanding of the substrates targeted by all kinases and functionally annotating the phosphoproteome will be broadly beneficial. Advances in phosphoproteomics technologies, combined with functional screening approaches, should make it feasible to illuminate the connectivity and functionality of the entire phosphoproteome, providing enormous opportunities for discovering new biology, therapeutic targets, and possibly diagnostics.
Acute exacerbations in chronic obstructive pulmonary disease: should we use antibiotics and if so, which ones?

Purpose of review Acute exacerbations are a major cause of morbidity and mortality in chronic obstructive pulmonary disease (COPD) with evidence suggesting at least 50% of exacerbations involve bacteria that benefit from antibiotic treatment. Here, we review the most relevant data regarding the use of antibiotics in exacerbations of COPD and provide insights on the selection of initial antibiotic therapy for their treatment. Recent findings Identification of bacterial exacerbations still relies on clinical assessment rather than laboratory biomarkers. Several recent studies, including a meta-analysis and placebo-controlled trials, demonstrate improved outcomes with antibiotics in all but mild exacerbations of COPD, including both inpatient and outpatient. A broader antibiotic regimen should be used for patients who have risk factors for poor outcomes. A risk-stratification approach can guide antibiotic choice, although the stratification algorithm still needs to be validated in a randomized controlled trial. Summary The use of antibiotics for the treatment of moderate-to-severe suspected bacterial exacerbations in COPD is supported by published trials and evidence-based systematic reviews. Recent trials also show differences in outcomes based on antibiotic choice. More research is necessary to evaluate risk stratification approaches when selecting initial antibiotic therapy.
Contributions of innate lymphocytes to allergic responses

Purpose of review Allergic diseases represent a growing global health concern, especially among pediatric populations. Current strategies for the treatment of allergies and asthma focus on limiting the severity of the symptoms; however, additional research investigating the mechanisms promoting inflammation in the context of allergic reactions may lead to the development of more effective therapeutic strategies. Recent findings Novel studies have highlighted the contributions of innate lymphocytes to the induction of inflammatory responses to allergens. Remarkably, neuron-derived signals, hormones, and even vitamins have been suggested to modulate the activity of innate lymphocytes, opening new windows of opportunity for the treatment of allergic inflammation. Summary These studies highlight the complex interactions of the nervous, endocrine, and immune system that promote pathology in the context of allergic inflammation. Further studies are required to understand these interactions in order to aid in the development of novel and much-needed therapies to treat allergic conditions.
Imaging of Metastatic Cancer Cells in Sentinel Lymph Nodes using Affibody Probes and Possibility of a Theranostic Approach

The accurate detection of lymph node metastases is essential for treatment success in early-stage malignant cancer. Sentinel lymph node (SLN) biopsy is the most effective procedure for detecting small or micrometastases that are undetectable by conventional imaging modalities. To demonstrate a new approach for developing a more efficient SLN biopsy procedure, we reported a two-stage imaging method combining lymphoscintigraphy and near-infrared (NIR) fluorescence imaging to depict metastatic cancer cells in SLNs in vivo. Furthermore, the theranostic potential of the combined procedure was examined by cell culture and xenograft mouse model. Anti-HER2 and anti-epidermal growth factor receptor (EGFR) affibody probes were used for NIR fluorescence imaging. Strong NIR fluorescence signal intensity of the anti-EGFR affibody probe was observed in SAS cells (EGFR positive). Radioactivity in the SLNs was clearly observed in the in vivo studies. High anti-EGFR affibody NIR fluorescence intensity was observed in the metastatic lymph nodes in mice. The addition of the IR700-conjugated anti-EGFR affibody to the culture medium decreased the proliferation of SAS cells. Decreased proliferation was shown in Ki-67 immunohistochemistry in xenograft tumors. Our data suggest that a two-stage combined imaging method using lymphoscintigraphy and affibody probes may offer the direct visualization of metastatic lymph nodes as an easily applied technique in SLN biopsy. Although further animal studies are required to assess the effect of treating lymphatic metastasis in this approach, our study results provide a foundation for the further development of this promising imaging and treatment strategy for earlier lymph node metastasis detection and treatment.
Functional Brain Network Estimation with Time Series Self-scrubbing

Functional brain network (FBN) has been becoming an increasingly important measurement for exploring the cerebral working mechanism and mining informative biomarkers for assisting diagnosis of some neurodegenerative disorders. Despite its potential performance in discovering the valuable patterns hidden in the brains, the estimated FBNs are often heavily influenced by the quality of the observed data (e.g., BOLD signal series). In practice, a preprocessing pipeline is usually employed for improving the data quality prior to the FBN estimation; but, even so, some data points in the time series are still not clean enough, possibly including original artifacts (e.g., micro head motion), non-resting functional disturbing (e.g., mind-wandering), and new “noises” caused by the preprocessing pipeline per se. Therefore, not all data points in the time series can contribute to the subsequent FBN estimation. To address this issue, in this paper, we propose a novel FBN estimation method by introducing a latent variable as an indicator of the data quality, and develop an alternating optimization algorithm for scrubbing the data and estimating FBN simultaneously in a single framework. As a result, we can obtain more accurate FBNs with the self-scrubbing data. To illustrate the effectiveness of the proposed method, we conduct experiments on two publicly available datasets to identify mild cognitive impairment (MCI) patients from normal control (NC) subjects based on the estimated FBNs. Experimental results show that the proposed FBN modelling method can achieve higher classification accuracy, significantly outperforming the baseline methods.
A Precautionary Approach to Guide the Use of Transition Metal-Based Nanotechnology to Prevent Orthopedic Infections

The increase of multidrug-resistant bacteria remains a global concern. Among the proposed strategies, the use of nanoparticles (NPs) alone or associated with orthopedic implants represents a promising solution. NPs are well-known for their antimicrobial effects, induced by their size, shape, charge, concentration and reactive oxygen species (ROS) generation. However, this non-specific cytotoxic potential is a powerful weapon effective against almost all microorganisms, but also against eukaryotic cells, raising concerns related to their safe use. Among the analyzed transition metals, silver is the most investigated element due to its antimicrobial properties per se or as NPs; however, its toxicity raises questions about its biosafety. Even though it has milder antimicrobial and cytotoxic activity, TiO2 needs to be exposed to UV light to be activated, thus limiting its use conjugated to orthopedic devices. By contrast, gold has a good balance between antimicrobial activity as an NP and cytocompatibility because of its inability to generate ROS. Nevertheless, although the toxicity and persistence of NPs within filter organs are not well verified, nowadays, several basic research on NP development and potential uses as antimicrobial weapons is reported, overemphasizing NPs potentialities, but without any existing potential of translation in clinics. This analysis cautions readers with respect to regulation in advancing the development and use of NPs. Hopefully, future works in vivo and clinical trials will support and regulate the use of nano-coatings to guarantee safer use of this promising approach against antibiotic-resistant microorganisms.
Prognostic impact of pleural effusion in EGFR‐mutant non‐small cell lung cancer patients without brain metastasis

In epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC), brain metastasis is known as a poor prognosis factor. However, prognostic factors in the patients without brain metastasis remain unclear. In this study, we aimed to clarify the differences between metastatic site and prognosis in common EGFR‐mutant NSCLC patients without brain metastasis.
Prevalence and Factors of Concurrent Multiple Male Sex Partnership Among Men Who Have Sex With Men With Regular Sex Partners in Beijing, China

Abstract This study was to test whether the cognitive factors of the theory of planned behavior were associated with concurrent multiple male sex partnership (CMMSP) status (past three months) and intention to have CMMSP (next six months) among 251 men who have male regular sex partners in Beijing, China. The prevalence of having had CMMSP and intention to do so was 48.2% and 28.7%, respectively. Positive attitudes toward CMMSP, injunctive norm for not having CMMSP, and behavioral control for not having CMMSP were significantly associated with behavioral intention. Descriptive norm and perceived behavioral control were significant factors for CMMSP status.
Genome-Wide Identification and Expression Profiling of Sugar Transporter Protein (STP) Family Genes in Cabbage (Brassica oleracea var. capitata L.) Reveals their Involvement in Clubroot Disease Responses

Sugar transporter protein (STP) genes are involved in multiple biological processes, such as plant responses to various stresses. However, systematic analysis and functional information of STP family genes in Brassica oleracea are very limited. A comprehensive analysis was carried out to identify BoSTP genes and dissect their phylogenetic relationships and to investigate the expression profiles in different organs and in response to the clubroot disease. A total of 22 BoSTP genes were identified in the B. oleracea genome and they were further classified into four clades based on the phylogenetic analysis. All the BoSTP proteins harbored the conserved sugar transporter (Sugar_tr, PF00083) domain, and the majority of them contained 12 transmembrane helices (TMHs). Rates of synonymous substitution in B. oleracea relative to Arabidopsis thaliana indicated that STP genes of B. oleracea diverged from those of A. thaliana approximately 16.3 million years ago. Expression profiles of the BoSTP genes in different organs derived from RNA-Seq data indicated that a large number of the BoSTP genes were expressed in specific organs. Additionally, the expression of BoSTP4b and BoSTP12 genes were induced in roots of the clubroot-susceptible cabbage (CS-JF1) at 28 days after inoculation with Plasmodiophora brassicae, compared with mock-inoculated plants. We speculated that the two BoSTPs might be involved in monosaccharide unloading and carbon partitioning associated with P. brassicae colonization in CS-JF1. Subcellular localization analysis indicated that the two BoSTP proteins were localized in the cell membrane. This study provides insights into the evolution and potential functions of BoSTPs.
Non-Isothermal Crystallisation Kinetics of Carbon Black- Graphene-Based Multimodal-Polyethylene Nanocomposites

The effect of carbon black (CB) and microwave-induced plasma graphene (g) on the crystallisation kinetics of the multimodal high-density polyethylene was studied under non-isothermal conditions. The non-isothermal crystallisation behaviour of the multimodal-high-density polyethylene (HDPE), containing up to 5 wt. % graphene, was compared with that of neat multimodal-HDPE and its carbon black based nanocomposites. The results suggested that the non-isothermal crystallisation behaviour of polyethylene (PE)-g nanocomposites relied significantly on both the graphene content and the cooling rate. The addition of graphene caused a change in the mechanism of the nucleation and the crystal growth of the multimodal-HDPE, while carbon black was shown to have little effect. Combined Avrami and Ozawa equations were shown to be effective in describing the non-isothermal crystallisation behaviour of the neat multimodal-HDPE and its nanocomposites. The mean activation energy barrier (ΔE), required for the transportation of the molecular chains from the melt state to the growing crystal surface, gradually diminished as the graphene content increased, which is attributable to the nucleating agent effect of graphene platelets. On the contrary, the synergistic effect resulting from the PE-CB nanocomposite decreased the ΔE of the neat multimodal-HDPE significantly at the lowest carbon black content.
Overexpression of the C-domain of angiotensin-converting enzyme reduces melanoma growth by stimulating M1 macrophage polarization

Angiotensin-converting enzyme (ACE) can hydrolyze many peptides and plays a central role in controlling blood pressure. Moreover, ACE overexpression in monocytes and macrophages increases resistance of mice to tumor growth. ACE is composed of two independent catalytic domains. Here, to investigate the specific role of each domain in tumor resistance, we overexpressed either WT ACE (Tg-ACE mice) or ACE lacking N- or C-domain catalytic activity (Tg-NKO and Tg-CKO mice) in the myeloid cells of mice. Tg-ACE and Tg-NKO mice exhibited strongly suppressed growth of B16-F10 melanoma because of increased ACE expression in macrophages, whereas Tg-CKO mice resisted melanoma no better than WT animals. The effect of ACE overexpression reverted to that of the WT enzyme with an ACE inhibitor but not with an angiotensin II type 1 (AT1) receptor antagonist. ACE C-domain overexpression in macrophages drove them toward a pronounced M1 phenotype upon tumor stimulation, with increased activation of NF-κB and signal transducer and activator of transcription 1 (STAT1) and decreased STAT3 and STAT6 activation. Tumor necrosis factor α (TNFα) is important for M1 activation, and TNFα blockade reverted Tg-NKO macrophages to a WT phenotype. Increased ACE C-domain expression increased the levels of reactive oxygen species (ROS) and of the transcription factor C/EBPβ in macrophages, important stimuli for TNFα expression, and decreased expression of several M2 markers, including interleukin-4Rα. Natural ACE C-domain–specific substrates are not well-described, and we propose that the peptide(s) responsible for the striking ACE-mediated enhancement of myeloid function are substrates/products of the ACE C-domain.
Interns' depressive symptoms evolution and training aspects: a prospective cohort study.

OBJECTIVE To study depression symptoms' incidence of medical interns (first year of medical residency) and its correlation with occupational characteristics, satisfaction and stress about their training program. METHODS Prospective Cohort Study conducted at Escola Paulista de Medicina, Universidade Federal de São Paulo. First year residents, N = 166, from a teaching hospital were invited to answer the Beck Depression Inventory (BDI) and an occupational questionnaire in a prospective longitudinal study. BDI score variation was related with socio-demographic aspects and occupational characteristics using linear regression models. RESULTS 111 subjects participated (67%); the BDI-score increased in 8 months (mean = 2.75 ± 3.29 vs. 7.00 ± 5.66; p<0.0001). The depressive symptoms' incidence was 9.01% (score>15). BDI-score variation had mean = 4.25 ± 4.93, ranging from -8 to 28. Residents not satisfied with professional training acquired (β = 3.44; p = 0.004), with their personal life (β = 2.97; p = 0.001), or who felt stressed in the relationship with senior residents (β = 2.91; p = 0.015) presented 3 more points of BDI-score after 8 months comparing to those without these perceptions; and being unsatisfied with the nursing team increased BDI-score after 8 months in 2 more points (β = 1.95; p = 0.025). CONCLUSION Among the factors that interfere with depression in interns is the occupational characteristics, which might be enhanced by the training facility. Addressing these dissatisfaction and stressful issues should help the university provide better care of interns' mental health.
Interpretive Performance and Inter-Observer Agreement on Digital Mammography Test Sets

Objective To evaluate the interpretive performance and inter-observer agreement on digital mammographs among radiologists and to investigate whether radiologist characteristics affect performance and agreement. Materials and Methods The test sets consisted of full-field digital mammograms and contained 12 cancer cases among 1000 total cases. Twelve radiologists independently interpreted all mammograms. Performance indicators included the recall rate, cancer detection rate (CDR), positive predictive value (PPV), sensitivity, specificity, false positive rate (FPR), and area under the receiver operating characteristic curve (AUC). Inter-radiologist agreement was measured. The reporting radiologist characteristics included number of years of experience interpreting mammography, fellowship training in breast imaging, and annual volume of mammography interpretation. Results The mean and range of interpretive performance were as follows: recall rate, 7.5% (3.3–10.2%); CDR, 10.6 (8.0–12.0 per 1000 examinations); PPV, 15.9% (8.8–33.3%); sensitivity, 88.2% (66.7–100%); specificity, 93.5% (90.6–97.8%); FPR, 6.5% (2.2–9.4%); and AUC, 0.93 (0.82–0.99). Radiologists who annually interpreted more than 3000 screening mammograms tended to exhibit higher CDRs and sensitivities than those who interpreted fewer than 3000 mammograms (p = 0.064). The inter-radiologist agreement showed a percent agreement of 77.2–88.8% and a kappa value of 0.27–0.34. Radiologist characteristics did not affect agreement. Conclusion The interpretative performance of the radiologists fulfilled the mammography screening goal of the American College of Radiology, although there was inter-observer variability. Radiologists who interpreted more than 3000 screening mammograms annually tended to perform better than radiologists who did not.
[Effects on cervical spondylosis of neck type treated with Hegu needling and Shu needling techniques at the positive reaction points].

OBJECTIVE To observe the clinical effects on cervical spondylosis of neck type treated with the combined therapy of Hegu needling and Shu needling techniques at the positive reaction points as compared with the conventional acupuncture. METHODS A total of 90 patients of cervical spondylosis of neck type were randomized into an observation group and a control group, 45 cases in each one. In the observation group, the combined therapy of Hegu needling and Shu needling techniques at the positive reaction points was adopted. The positive reaction points were selected in the neck, shoulder and back regions. In the control group, the conventional acupuncture therapy was provided. The main acupoints were Tianzhu (BL 10), Fengchi (GB 20), Quchi (LI 11), Waiguan (TE 5), Neck-Jiaji (EX-B 2) of C4 to C6 and ashi points. The supplementary acupoints were Yinxi (HT 6) and Geshu (BL 17). The treatment was given once every two days, 10 treatments as one course in the two groups. Separately, before treatment, after the 1st treatment and at the end of one course of treatment, the scores of symptoms and physical signs and the scores of visual analogous scale (VAS) were observed in the two groups. The comprehensive clinical effects were compared between the two groups at the end of treatment. RESULTS After the 1st treatment and at the end of treatment, the scores of symptoms and physical signs and VAS scores were reduced obviously as compared with those before treatment in the two groups (all P<0.05). After the 1st treatment, the scores of symptoms and physical signs and VAS scores were not different significantly between the two groups (both P>0.05). At the end of treatment, the scores of symptoms and physical signs and VAS scores in the observation group were reduced more obviously as compared with the control group (both P<0.05). The curative and remarkably effective rate was 84.1% (37/44) in the observation group, better than 65.1% (28/43) in the control group (P<0.05). CONCLUSION Either the combined therapy of Hegu needling and Shu needling techniques at the positive reaction points or the conventional acupuncture is effective in the treatment of cervical spondylosis of neck type. The combined therapy of Hegu needling and Shu needling techniques at the positive reaction points achieves the superior effects as compared with the conventional acupuncture.