Miracle-dz/UniFAR-FTUs huggingface dataset:
Multiplexed chromatin imaging reveals predominantly pairwise long-range coordination between Drosophila Polycomb genes

Polycomb (Pc) group proteins are transcriptional regulators with key roles in development, cell identity and differentiation. Pc-bound chromatin regions form repressive domains that interact in 3D to assemble repressive nuclear compartments. Here, we used multiplexed chromatin imaging to investigate whether Pc compartments involve the clustering of multiple Pc domains during Drosophila development. Notably, 3D proximity between Pc targets is rare and involves predominantly pairwise interactions. These 3D proximities are particularly enhanced in segments where Pc genes are co-repressed. In addition, segment-specific expression of Hox Pc targets leads to their spatial segregation from Pc repressed genes. Finally, non-Hox Pc targets are proximal in regions where they are co-expressed. These results indicate that long-range Pc interactions are temporally and spatially regulated during differentiation and development but do not involve clustering of multiple distant Pc genes.
Near-Stream Computing: General and Transparent Near-Cache Acceleration

Data movement and communication have become the primary bottlenecks in large multicore systems. The near-data computing paradigm provides a solution: move computation to where the data resides on-chip. Two challenges keep near-data computing from the mainstream: lack of programmer transparency and applicability. Programmer transparency requires providing sequential memory semantics with distributed computation, which requires burdensome coordination. Broad applicability requires support for combinations of address patterns (e.g. affine, indirect, multi-operand) and computation types (loads, stores, reductions, atomics). We find that streams – coarse grain memory access patterns – are a powerful ISA abstraction for near data offloading. Tracking data access at stream-granularity heavily reduces the burden of coordination for providing sequential semantics. Decomposing the problem using streams means that arbitrary combinations of address and computation patterns can be combined for broad generality.With this insight, we develop a paradigm called near-stream computing, comprising a compiler, CPU ISA extension, and a microarchitecture that facilitate programmer transparent computation offloading to shared caches. We evaluate our system on OpenMP kernels that stress broad addressing and compute behavior, and find that 46% of dynamic instructions can be offloaded to remote banks, reducing the network traffic by 76%. Overall it achieves 2.13× speedup over a state-of-the-art near-data computing technique, with a 1.90× energy efficiency gain.
Automatic Pain Intensity Estimation based on Electrocardiogram and Demographic Factors

: Automatic pain intensity estimation possess signiﬁcant importance for reliable and complete pain management. The accurate and continuous monitoring is essential in order to attain objective insight about the condition of the patient. In this work, we elaborate physiological signals in order to estimate the pain intensity and investigate the impact of demographic factors. Speciﬁcally, we exploit electrocardiography signals, adopting the Pan-Tompkins algorithm to extract important features and apply well-validated classiﬁcation methods, while we explore the correlation of gender and age with the pain manifestation.
Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease

In the existing stages of diabetic kidney disease (DKD), the first stage of DKD is called the preclinical stage, characterized by glomerular hyperfiltration, an abnormally elevated glomerular filtration rate. Glomerular hyperfiltration is an independent risk factor for accelerated deterioration of renal function and progression of nephropathy, which is associated with a high risk for metabolic and cardiovascular disease. It is imperative to understand hyperfiltration and identify potential treatments to delay DKD progress. This paper summarizes the current mechanisms of hyperfiltration in early DKD. We pay close attention to the effect of glucose reabsorption mediated by sodium–glucose cotransporters and renal growth on hyperfiltration in DKD patients, as well as the mechanisms of nitric oxide and adenosine actions on renal afferent arterioles via tubuloglomerular feedback. Furthermore, we also focus on the contribution of the atrial natriuretic peptide, cyclooxygenase, renin–angiotensin–aldosterone system, and endothelin on hyperfiltration. Proposing potential treatments based on these mechanisms may offer new therapeutic opportunities to reduce the renal burden in this population.
Treatment of Refractory/High-Risk Pregnancies With Antiphospholipid Syndrome: A Systematic Review of the Literature

Different treatment protocols have been employed to manage heparin/low-dose aspirin refractory or high-risk pregnancies in antiphospholipid antibody syndrome (APS) pregnancies. A systematic review of the literature on additional treatments used in refractory and/or high-risk APS pregnancies was conducted. Records from February 2006 to October 2021 were retrieved from PubMed, Web of Science, Cochrane, and the www.clinicaltrials. gov platform. Twenty-one studies met our eligibility criteria. Live birth rate is this study’s primary endpoint, while pregnancy complications and adverse events are secondary endpoints. A total of 434 pregnancies, 162 (37.3%) refractory and 272 (62.7%) high-risk/refractory pregnancies, were included. Both IVIG <2 gr/kg/monthly/HCQ/LDS and PEX/IA ± LDS led to 100% viable infants in refractory APS. Furthermore, HCQ 200–400 mg showed a higher live birth rate than HCQ + LDS (88.6% vs. 82.7%). Following treatment protocol with HCQ 200–400 mg and IVIG <2 gr/kg/monthly/HCQ/LDS, pregnancy complications rates of 16.7 and 83.3% were registered, respectively. Pravastatin 20 mg, IA weekly + IVIG 2 gr/monthly, and PEX weekly + IVIg 2 gr/kg/monthly showed higher live birth rates in high-risk APS pregnancies of 100, 100 and 92%, respectively, whereas the lower severe pregnancy complications were reported in pregnancies treated with PEX weekly + IVIg 2 gr/kg/monthly (11.1%). One (0.6%) case of dermatitis during treatment with HCQ was observed. The results of this study showed that HCQ 200–400 mg and PEX weekly + IVIG 2 gr/kg/monthly achieved a higher live birth rate in refractory APS and high-risk/refractory APS, respectively. The results presented provide clinicians with up-to-date knowledge in the management of APS pregnancies according to risk stratification.
Expression of Functional Molecule on Plasmacytoid Dendritic Cells Is Associated With HBsAg Loss in HBeAg-Positive Patients During PEG-IFN α-2a Treatment

Objective The ideal endpoint of antiviral therapy in chronic hepatitis B (CHB) patients is to clear hepatitis B surface antigen (HBsAg). This study aimed to evaluate whether the expression of functional molecules on plasmacytoid dendritic cells (pDCs) is associated with HBsAg loss in HBeAg-positive patients during peginterferon alpha-2a (PEG IFN α-2a) therapy. Methods A single-center prospective cohort study was performed in HBeAg-positive CHB patients who were treated with PEG-IFN α-2a and followed up for 4 years. HBsAg clearance, HBeAg loss and undetectable HBV DNA achieved by PEG-IFN α-2a therapy was considered as functional cure. The frequencies of pDC and CD86+ pDC in peripheral blood, and the mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDC were measured at starting therapy, after 12 and 24 weeks of therapy. Results Of 63 patients enrolled, 17 patients achieved HBsAg loss. The baseline HBV DNA load in Non-functional-cure group was significantly higher than that in Functional cure group, and the CD86+ pDC% was significantly lower in patients without functional cure. HBV DNA load (OR=0.146, P = 0.002) and CD86+ pDC% (OR=1.183, P = 0.025) were independent factors associated with functional cure confirmed by binary logistic regression analysis. In the Functional cure group, HBsAg, HBeAg, and HBV DNA loads decreased remarkably after 12 weeks and 24 weeks of treatment compared to baseline. In Non-functional-cure group, CD86+ pDC% and CD86MFI increased significantly from baseline after 12 weeks of treatment. In the Functional cure group, compared with baseline, pDC% increased significantly at 24 weeks, while CD86MFI increased significantly after 24 weeks of treatment. Conclusion The lower the baseline HBV DNA load and the more the baseline CD86+ pDC%, the easier it is for patients to obtain functional cure.
Mycobacterium tuberculosis-Induced Upregulation of the COX-2/mPGES-1 Pathway in Human Macrophages Is Abrogated by Sulfasalazine

Macrophages are the primary human host cells of intracellular Mycobacterium tuberculosis (M.tb) infection, where the magnitude of inflammatory reactions is crucial for determining the outcome of infection. Previously, we showed that the anti-inflammatory drug sulfasalazine (SASP) significantly reduced the M.tb bactericidal burden and histopathological inflammation in mice. Here, we asked which genes in human inflammatory macrophages are affected upon infection with M.tb and how would potential changes impact the functional state of macrophages. We used a flow cytometry sorting system which can distinguish the dead and alive states of M.tb harbored in human monocyte-derived macrophages (MDM). We found that the expression of cyclooxygenase-2 and microsomal prostaglandin E2 synthase (mPGES)-1 increased significantly in tagRFP+ MDM which were infected with alive M.tb. After exposure of polarized M1-MDM to M.tb (H37Rv strain)-conditioned medium (MTB-CM) or to the M.tb-derived 19-kD antigen, the production of PGE2 and pro-inflammatory cytokines increased 3- to 4-fold. Upon treatment of M1-MDM with SASP, the MTB-CM-induced expression of COX-2 and the release of COX products and cytokines decreased. Elevation of PGE2 in M1-MDM upon MTB-CM stimulation and modulation by SASP correlated with the activation of the NF-κB pathway. Together, infection of human macrophages by M.tb strongly induces COX-2 and mPGES-1 expression along with massive PGE2 formation which is abrogated by the anti-inflammatory drug SASP.
Water-Soluble Trichogin GA IV-Derived Peptaibols Protect Tomato Plants From Botrytis cinerea Infection With Limited Impact on Plant Defenses

Peptaibols are non-ribosomal linear peptides naturally produced by a wide variety of fungi and represent the largest group of peptaibiotic molecules produced by Trichoderma species. Trichogin GA IV is an 11-residue lipopeptaibol naturally produced by Trichoderma longibrachiatum. Peptaibols possess the ability to form pores in lipid membranes or perturb their surface, and have been studied as antibiotics or anticancer drugs in human medicine, or as antimicrobial molecules against plant pathogens. When applied to plants, peptaibols may also elicit defense responses. A major drawback to the exploitation and application of peptaibols in agriculture is their poor water solubility. In a previous study, we designed water-soluble Lys-containing Trichogin GA IV analogs, which were able to inhibit the growth of several fungal plant pathogens in vitro. In the present study, we shed light on the mechanism underpinning their efficacy on plants, focusing on six Trichogin GA IV analogs. Our results highlighted peptide hydrophilicity, rather than helix stability, as the major determinant of their activity against B. cinerea infection in tomato leaves. The peptides showed preventive but not curative efficacy against infection, and lack of translaminar activity, with results reproducible on two tomato cultivars, Marmande and Micro-Tom. Reactive oxygen species (ROS) detection analysis in tomato and Arabidopsis, and expression of defense genes in tomato, highlighted a transient and limited impact of the peptides on the plant defense system. The treatment did not result in significant modulation of defense genes or defense priming. The antimicrobial effect thus emerges as the only mechanism behind the plant protection ability exerted by water-soluble Trichogin GA IV analogs, and limited effects on the plant metabolism are expected to occur.
Sequential Prefrontal and Temporoparietal Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment of Tinnitus With and Without Comorbid Depression: A Case Series and Systematic Review

Background Tinnitus distress is related to both the loudness and intrusiveness of the tinnitus percept. Treatment approaches targeting both attentional/limbic and auditory systems may better alleviate tinnitus distress than approaches targeting the auditory system alone. Materials and Methods Ten subjects with chronic tinnitus received sequential rTMS treatment involving: 1) excitatory stimulation administered to the left dorsolateral prefrontal cortex (DLPFC) or inhibitory stimulation administered to the right DLPFC, followed by 2) inhibitory stimulation administered to primary auditory cortex (Heschel's gyrus or HG). A systematic literature review was performed to evaluate the existing literature on sequential repetitive Transcranial Magnetic Stimulation (rTMS) treatment approaches for tinnitus. Results of the case series are interpreted in the context of tinnitus neurobiology and the extant literature. Results Subjects experienced a significant decrease (average 21.7%) in symptoms on the Tinnitus Functional Index (TFI). Those with tinnitus alone experienced a greater mean symptom reduction than those with comorbid MDD (27.7 vs. 17.0%, respectively). Adverse effects were transient and minor. Literature review confirmed that sequential approaches had some advantages compared to single site rTMS; in general, the addition of 1 Hz treatment at DLPFC was superior to single site rTMS in the short term (1–12 weeks), while the addition of 20 Hz treatment at DLPFC appeared superior in the long term (90–180 days). Conclusions Sequential rTMS approaches for the treatment of tinnitus—particularly those administering low-frequency treatment at left DLPFC—merit further investigation.
The Role of Testosterone in Spermatogenesis: Lessons From Proteome Profiling of Human Spermatozoa in Testosterone Deficiency

Testosterone is essential to maintain qualitative spermatogenesis. Nonetheless, no studies have been yet performed in humans to analyze the testosterone-mediated expression of sperm proteins and their importance in reproduction. Thus, this study aimed to identify sperm protein alterations in male hypogonadism using proteomic profiling. We have performed a comparative proteomic analysis comparing sperm from fertile controls (a pool of 5 normogonadic normozoospermic fertile men) versus sperm from patients with secondary hypogonadism (a pool of 5 oligozoospermic hypogonadic patients due to isolated LH deficiency). Sperm protein composition was analyzed, after peptide labelling with Isobaric Tags, via liquid chromatography followed by tandem mass spectrometry (LC-MS/MS) on an LTQ Velos-Orbitrap mass spectrometer. LC-MS/MS data were analyzed using Proteome Discoverer. Criteria used to accept protein identification included a false discovery rate (FDR) of 1% and at least 1 peptide match per protein. Up to 986 proteins were identified and, of those, 43 proteins were differentially expressed: 32 proteins were under-expressed and 11 were over-expressed in the pool of hypogonadic patients compared to the controls. Bioinformatic analyses were performed using UniProt Knowledgebase, and the Gene Ontology Consortium database based on PANTHER. Notably, 13 of these 43 differentially expressed proteins have been previously reported to be related to sperm function and spermatogenesis. Western blot analyses for A-Kinase Anchoring Protein 3 (AKAP3) and the Prolactin Inducible Protein (PIP) were used to confirm the proteomics data. In summary, a high-resolution mass spectrometry-based proteomic approach was used for the first time to describe alterations of the sperm proteome in secondary male hypogonadism. Some of the differential sperm proteins described in this study, which include Prosaposin, SMOC-1, SERPINA5, SPANXB1, GSG1, ELSPBP1, fibronectin, 5-oxoprolinase, AKAP3, AKAP4, HYDIN, ROPN1B, ß-Microseminoprotein and Protein S100-A8, could represent new targets for the design of infertility treatments due to androgen deficiency.
CRISRP/Cas9-Mediated Targeted Mutagenesis of Tomato Polygalacturonase Gene (SlPG) Delays Fruit Softening

Polygalacturonase (PG) gene has been documented as a key candidate for the improvement of fruit firmness, which is a target trait for tomato production because it facilitates transportation and storage. To reduce the expression of the PG gene, most of the elite commercial tomato varieties were obtained by RNA interference technology. However, this approach of producing commercialized tomatoes by integration of the exogenous gene is controversial. In this work, CRISPR/Cas9 technology was used to induce the targeted mutagenesis of the SlPG gene to delay the softening of tomato fruit. Results showed that the SlPG gene was frameshift mutated by 4 bp deletion, 10 bp deletion, and 1 bp insertion, which generated premature translation termination codons. Compared with wild-type (WT), homozygous T1-generation tomato plants exhibited late fruit softening under natural conditions. Consistent with this phenomenon, the firmness value of WT fruit was lower in slpg mutant fruit, and the physiological loss of water was higher. Collectively, these data demonstrate that the mutation of the SlPG gene delays tomato fruit softening. More importantly, 8 out of 20 transgene-free tomato plants, which were homozygous for null alleles of SlPG, were separated in the T3-generation of line slpgT2-#2. This transgene-free slpg may provide materials for more in-depth research of SlPG functions and the molecular mechanism of fruit softening in tomatoes.
Data-Driven Modeling of Dissolved Iron in the Global Ocean

The importance of dissolved Fe (dFe) in regulating ocean primary production and the carbon cycle is well established. However, the large-scale distribution and temporal dynamics of dFe remain poorly constrained in part due to incomplete observational coverage. In this study, we use a compilation of published dFe observations (n=32,344) with paired environmental predictors from contemporaneous satellite observations and reanalysis products to build a data-driven surface-to-seafloor dFe climatology with 1°×1° resolution using three machine-learning approaches (random forest, supper vector machine and artificial neural network). Among the three approaches, random forest achieves the highest accuracy with overall R2 and root mean standard error of 0.8 and 0.3 nmol L-1, respectively. Using this data-driven climatology, we explore the possible mechanisms governing the dFe distribution at various depth horizons using statistical metrics such as Pearson correlation coefficients and the rank of predictors importance in the model construction. Our results are consistent with the critical role of aeolian iron supply in enriching surface dFe in the low latitude regions and suggest a far-reaching impact of this source at depth. Away from the surface layer, the strong correlation between dFe and apparent oxygen utilization implies that a combination of regeneration, scavenging and large-scale ocean circulation are controlling the interior distribution of dFe, with hydrothermal inputs important in some regions. Finally, our data-driven dFe climatology can be used as an alternative reference to evaluate the performance of ocean biogeochemical models. Overall, the new global scale climatology of dFe achieved in our study is an important step toward improved representation of dFe in the contemporary ocean and may also be used to guide future sampling strategies.
The Role of M1/M2 Macrophage Polarization in Rheumatoid Arthritis Synovitis

Innate and adaptive immunity represent a harmonic counterbalanced system involved in the induction, progression, and possibly resolution of the inflammatory reaction that characterize autoimmune rheumatic diseases (ARDs), including rheumatoid arthritis (RA). Although the immunopathophysiological mechanisms of the ARDs are not fully clarified, they are often associated with an inappropriate macrophage/T-cell interaction, where classical (M1) or alternative (M2) macrophage activation may influence the occurrence of T-helper (Th)1 or Th2 responses. In RA patients, M1/Th1 activation occurs in an inflammatory environment dominated by Toll-like receptor (TLR) and interferon (IFN) signaling, and it promotes a massive production of pro-inflammatory cytokines [i.e., tumor necrosis factor-α (TNFα), interleukin (IL)-1, IL-12, IL-18, and IFNγ], chemotactic factors, and matrix metalloproteinases resulting in osteoclastogenesis, erosion, and progressive joint destruction. On the other hand, the activation of M2/Th2 response determines the release of growth factors and cytokines [i.e., IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β] involved in the anti-inflammatory process leading to the clinical remission of RA. Several subtypes of macrophages have been described. Five polarization states from M1 to M2 have been confirmed in in vitro studies analyzing morphological characteristics, gene expression of phenotype markers (CD80, CD86, TLR2, TLR4, or CD206, CD204, CD163, MerTK), and functional aspect, including the production of reactive oxygen species (ROS). An M1 and M2 macrophage imbalance may induce pathological consequences and contribute to several diseases, such as asthma or osteoclastogenesis in RA patients. In addition, the macrophage dynamic polarization from M1 to M2 includes the presence of intermediate polarity stages distinguished by the expression of specific surface markers and the production/release of distinct molecules (i.e., nitric oxide, cytokines), which characterize their morphological and functional state. This suggests a “continuum” of macrophage activation states playing an important role during inflammation and its resolution. This review discusses the importance of the delicate M1/M2 imbalance in the different phases of the inflammatory process together with the identification of specific pathways, cytokines, and chemokines involved, and its clinical outcomes in RA. The analysis of these aspects could shed a light on the abnormal inflammatory activation, leading to novel therapeutical approaches which may contribute to restore the M1/M2 balance.
Elevated Serum Lactate in Glioma Patients: Associated Factors

Introduction Serum lactate levels in brain cancer patients correlate with tumor malignancy grading, and serum lactate has been suggested as a potential biomarker and prognostic factor. The purpose of this study was to identify potential sources of elevated serum lactate in patients with brain gliomas by examining factors of importance for serum lactate production and clearance. Methods In this cross-sectional study, data were collected from 261 glioma patients who underwent surgery from March 2011 to June 2015. We recorded patient gender, age, blood serum measures of lactate, glucose, pH, hemoglobin and base excess, patient health status, medications, and tumor characteristics. Patients with elevated and normal serum lactate levels were compared, and we explored if there were correlations between the variables. The association of serum lactate with the measured variables was investigated by simple and multivariable linear regression models. Results and Discussion Patients with elevated serum lactate had higher blood glucose, larger tumor volumes, and more tumor edema; more often needed pressor medication during surgery; and more often received corticosteroid treatment. The investigated variables were highly correlated. Multivariable linear regression indicated that gender, tumor volume, Charlson Comorbidity Index, hyperglycemia, and corticosteroid treatment were associated with serum lactate levels. Histopathology was not an independent factor. In conclusion, comorbidities, hyperglycemia, and presurgical corticosteroid treatment exhibited the strongest association with serum lactate in glioma patients.