Differential Modulation Research Articles

GnRH-driven FTO-mediated RNA m6A modification promotes gonadotropin synthesis and secretion

BackgroundGonadotropin precisely controls mammalian reproductive activities. Systematic analysis of the mechanisms by which epigenetic modifications regulate the synthesis and secretion of gonadotropin can be useful for more precise regulation of the animal reproductive process. Previous studies have identified many differential m6A modifications in the GnRH-treated adenohypophysis. However, the molecular mechanism by which m6A modification regulates gonadotropin synthesis and secretion remains unclear.ResultsHerein, it was found that GnRH can promote gonadotropin synthesis and secretion by promoting the expression of FTO. Highly expressed FTO binds to Foxp2 mRNA in the nucleus, exerting a demethylation function and reducing m6A modification. After Foxp2 mRNA exits the nucleus, the lack of m6A modification prevents YTHDF3 from binding to it, resulting in increased stability and upregulation of Foxp2 mRNA expression, which activates the cAMP/PKA signaling pathway to promote gonadotropin synthesis and secretion.ConclusionsOverall, the study reveals the molecular mechanism of GnRH regulating the gonadotropin synthesis and secretion through FTO-mediated m6A modification. The results of this study allow systematic interpretation of the regulatory mechanism of gonadotropin synthesis and secretion in the pituitary at the epigenetic level and provide a theoretical basis for the application of reproductive hormones in the regulation of animal artificial reproduction.

Abstract PO1-23-11: Differential m6A modification identified by direct RNA sequencing in endocrine- resistant and sensitive breast cancer cells

Abstract A major limitation of current adjuvant treatments for the ~ 70% of breast cancer patients with estrogen receptor α–expressing (ER+) primary breast tumors is the development of acquired and adaptive endocrine therapy (ET) resistance and metastatic spread. Chemical modifications of transcribed RNAs alters their cellular location, stability, and, for mRNAs, translation into proteins. N-6 methyladenosine (m6A) is the most common modification of mRNA. We tested the hypothesis that m6A epitranscriptomic changes alters the transcriptome resulting in changes in targets in pathways contributing to the metastatic cascade in ET-resistant breast cancer cells. We used an unbiased approach of direct mRNA sequencing using the Oxford Nanopore MinION platform on polyA-selected mRNA from MCF-7 luminal A breast cancer cells and ER+, ET-resistant LCC9 breast cancer cells treated with vehicle control or 100 nM 4-hydroxytamoxifen (4-OHT) for 24 h. In addition, MCF-7 cells were treated with the METTL3 (the catalytic methyltransferase that adds the methyl group from S-adenosylmethionine (SAM) to the adenosine on the N6 position) inhibitor STM2457 to identify m6A positions and transcripts directly regulated by METTL3 activity. Computational analysis directly identified m6A locations in transcripts. We examined the differential modification rate (DMR) between MCF-7 cells +/STM2457 treatment, between MCF-7 and LCC9 cells with vehicle control treatment or with 4-OHT treatment and within each cell line with 4-OHT treatment. We identified 183 and 3,097 genes with m6A DMRs between vehicle-treated and 4-OHT-treated MCF-7 and LCC9 cells, respectively. For 4-OHT-treated cells, we identified 2,401 and 2,638 genes with m6A DMRs in MCF-7 and LCC9 cells respectively with 1,760 genes in common. We identified many genes with multiple m6A modifications, e.g., AMIGO2 appeared to have 14 m6A sites at DRACH motifs in MCF-7 cells, but none were m6A modified in LCC9 cells. Enrichment by Pathway Maps, Process Networks, and GO Processes were performed. Overall, our data suggest a role for altered m6A positions in transcripts and pathways involved in ET-resistance in breast cancer. Citation Format: Belinda Petri, Bailey Valdes, Kellianne Piell, Eric Rouchka, Carolyn Klinge. Differential m6A modification identified by direct RNA sequencing in endocrine- resistant and sensitive breast cancer cells [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-23-11.

Research on Frequency Discrimination Method Using Multiplicative-Integral and Linear Transformation Network

In this paper, a frequency discrimination method using a multiplicative-integral and linear transformation network is proposed. In this method, two preset differential frequency signals and frequency modulation signals are transformed by multiplication and integration, and then the instantaneous frequency parameters of the frequency modulation signal are accurately analyzed by the linear transformation network to restore the original modulation signal. Compared with the phase discriminator, the simulation results show that this method has a higher frequency discrimination bandwidth. In addition, this method has better anti-noise performance, and the frequency discrimination distortion caused by noise with a different Signal-to-Noise Ratio is reduced by 33.80% on average compared with the phase discriminator. What is more, the carrier center frequency error has little influence on the frequency discrimination quality of this method, which solves the problem that most common frequency discriminators are seriously affected by the carrier center frequency error. This method requires a low accuracy of carrier center frequency, which makes it extremely suitable for digital frequency discrimination technology and can meet the needs of various frequency discrimination occasions.

Ratiometric Sensing of Azithromycin and Sulfide Using Dual Emissive Carbon Dots: A Turn On-Off-On Approach.

A novel ratiometric fluorescence probe was developed for the determination of azithromycin (AZM) and sulfide ions based on the differential modulation of red emissive carbon dots (R-N@CDs) and blue emissive carbon dots (B-NS@CDs). The addition of sulfide anion selectively quenched the red emission of R-N@CDs while the blue emission of B-NS@CDs unaffected. Upon subsequent introduction of AZM to this R-N@CDs@sulfide system, the quenched red fluorescence was restored. Comprehensive characterization of the CDs was performed using UV-Vis, fluorescence, FTIR spectroscopy, XPS, and TEM. The proposed method exhibited excellent sensitivity and selectivity, with limits of detection of 0.33 µM for AZM and 0.21 µM for sulfide. Notably, this approach enabled direct detection of sulfide without requiring prior modulation of the CDs with metal ions, as is common in other reported methods. The ratiometric probe was successfully applied for the determination of AZM in biological fluids and sulfide in environmental water samples with high selectivity. This work presents the first fluorometric method for the detection of AZM in biological fluids.

Thapsigargin and Tunicamycin Block SARS-CoV-2 Entry into Host Cells via Differential Modulation of Unfolded Protein Response (UPR), AKT Signaling, and Apoptosis

Background: SARS-Co-V2 infection can induce ER stress-associated activation of unfolded protein response (UPR) in host cells, which may contribute to the pathogenesis of COVID-19. To understand the complex interplay between SARS-Co-V2 infection and UPR signaling, we examined the effects of acute pre-existing ER stress on SARS-Co-V2 infectivity. Methods: Huh-7 cells were treated with Tunicamycin (TUN) and Thapsigargin (THA) prior to SARS-CoV-2pp transduction (48h p.i.) to induce ER stress. Pseudo-typed particles (SARS-CoV-2pp) entry into host cells was measured by Bright GloTM luciferase assay. Cell viability was assessed by cell titer Glo® luminescent assay. The mRNA and protein expression was evaluated by RT-qPCR and Western Blot. Results: TUN (5 µg/ml) and THA (1 µM) efficiently inhibited the entry of SARS-CoV-2pp into host cells without any cytotoxic effect. TUN and THA's attenuation of virus entry was associated with differential modulation of ACE2 expression. Both TUN and THA significantly reduced the expression of stress-inducible ER chaperone GRP78/BiP in transduced cells. In contrast, the IRE1-XBP1s and PERK-eIF2α-ATF4-CHOP signaling pathways were downregulated with THA treatment, but not TUN in transduced cells. Insulin-mediated glucose uptake and phosphorylation of Ser307 IRS-1 and downstream p-AKT were enhanced with THA in transduced cells. Furthermore, TUN and THA differentially affected lipid metabolism and apoptotic signaling pathways. Conclusions: These findings suggest that short-term pre-existing ER stress prior to virus infection induces a specific UPR response in host cells capable of counteracting stress-inducible elements signaling, thereby depriving SARS-Co-V2 of essential components for entry and replication. Pharmacological manipulation of ER stress in host cells might provide new therapeutic strategies to alleviate SARS-CoV-2 infection.

Differential Modulation by Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) of Mesenteric Fat and Macrophages and T Cells in Adipose Tissue of Obese fa/fa Zucker Rats

Polyunsaturated fatty acids (PUFAs) can alter adipose tissue function; however, the relative effects of plant and marine n3-PUFAs are less clear. Our objective was to directly compare the n3-PUFAs, plant-based α-linolenic acid (ALA) in flaxseed oil, and marine-based eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in high-purity oils versus n6-PUFA containing linoleic acid (LA) for their effects on the adipose tissue and oral glucose tolerance of obese rats. Male fa/fa Zucker rats were assigned to faALA, faEPA, faDHA, and faLA groups and compared to baseline fa/fa rats (faBASE) and lean Zucker rats (lnLA). After 8 weeks, faEPA and faDHA had 11–14% lower body weight than faLA. The oral glucose tolerance and total body fat were unchanged, but faEPA had less mesenteric fat. faEPA and faDHA had fewer large adipocytes compared to faLA and faALA. EPA reduced macrophages in the adipose tissue of fa/fa rats compared to ALA and DHA, while faLA had the greatest macrophage infiltration. DHA decreased (~10-fold) T-cell infiltration compared to faBASE and faEPA, whereas faALA and faLA had an ~40% increase. The n3-PUFA diets attenuated tumour necrosis factor-α in adipose tissue compared to faBASE, while it was increased by LA in both genotypes. In conclusion, EPA and DHA target different aspects of inflammation in adipose tissue.

Cryptosporidium life cycle small molecule probing implicates translational repression and an Apetala 2 transcription factor in macrogamont differentiation.

The apicomplexan parasite Cryptosporidium is a leading cause of childhood diarrhea in developing countries. Current treatment options are inadequate and multiple preclinical compounds are being actively pursued as potential drugs for cryptosporidiosis. Unlike most apicomplexans, Cryptosporidium spp. sequentially replicate asexually and then sexually within a single host to complete their lifecycles. Anti-cryptosporidial compounds are generally identified or tested through in vitro phenotypic assays that only assess the asexual stages. Therefore, compounds that specifically target the sexual stages remain unexplored. In this study, we leveraged the ReFRAME drug repurposing library against a newly devised multi-readout imaging assay to identify small-molecule compounds that modulate macrogamont differentiation and maturation. RNA-seq studies confirmed selective modulation of macrogamont differentiation for 10 identified compounds (9 inhibitors and 1 accelerator). The collective transcriptomic profiles of these compounds indicates that translational repression accompanies Cryptosporidium sexual differentiation, which we validated experimentally. Additionally, cross comparison of the RNA-seq data with promoter sequence analysis for stage-specific genes converged on a key role for an Apetala 2 (AP2) transcription factor (cgd2_3490) in differentiation into macrogamonts. Finally, drug annotation for the ReFRAME hits indicates that an elevated supply of energy equivalence in the host cell is critical for macrogamont formation.

Multiple cholinergic receptor subtypes coordinate dual modulation of acetylcholine on anterior and posterior paraventricular thalamic neurons.

Paraventricular thalamus (PVT) plays important roles in the regulation of emotion and motivation through connecting many brain structures including the midbrain and the limbic system. Although acetylcholine (ACh) neurons of the midbrain were reported to send projections to PVT, little is known about how cholinergic signaling regulates PVT neurons. Here, we used both RNAscope and slice patch-clamp recordings to characterize cholinergic receptor expression and ACh modulation of PVT neurons in mice. We found ACh excited a majority of anterior PVT (aPVT) neurons but predominantly inhibited posterior PVT (pPVT) neurons. Compared to pPVT with more inhibitory M2 receptors, aPVT expressed higher levels of all excitatory receptor subtypes including nicotinic α4, α7, and muscarinic M1 and M3. The ACh-induced excitation was mimicked by nicotine and antagonized by selective blockers for α4β2 and α7 nicotinic ACh receptor (nAChR) subtypes as well as selective antagonists for M1 and M3 muscarinic ACh receptors (mAChR). The ACh-induced inhibition was attenuated by selective M2 and M4 mAChR receptor antagonists. Furthermore, we found ACh increased the frequency of excitatory postsynaptic currents (EPSCs) on a majority of aPVT neurons but decreased EPSC frequency on a larger number of pPVT neurons. In addition, ACh caused an acute increase followed by a lasting reduction in inhibitory postsynaptic currents (IPSCs) on PVT neurons of both subregions. Together, these data suggest that multiple AChR subtypes coordinate a differential modulation of ACh on aPVT and pPVT neurons.

Evaluating the Nutritional Composition of Unripe Citrus and Its Effect on Inhibiting Adipogenesis and Adipocyte Differentiation.

Citrus fruits offer a range of health benefits due to their rich nutritional profile, including vitamin C, flavonoids, carotenoids, and fiber. It is known that unripe citrus has higher levels of vitamin C, dietary fiber, polyphenols, and flavonoids compared to mature fruits. In this study, we assessed the nutritional components of unripe citrus peel and pressed juices, as well as their anti-obesity potential through the modulation of adipocyte differentiation and the expression of adipogenesisrelated genes, specifically PPARγ and C/EBPα, in 3T3-L1 preadipocytes. Our analysis revealed that unripe citrus peel exhibited elevated levels of fiber and protein compared to pressed juice, with markedly low levels of free sugar, particularly sucrose. The content of hesperidin, a representative flavonoid in citrus fruits, was 3,157.6 mg/kg in unripe citrus peel and 455.5 mg/kg in pressed juice, indicating that it was approximately seven times higher in unripe citrus peel compared to pressed juice. Moreover, we observed that the peel had a dose-dependently inhibitory effect on adipocyte differentiation, which was linked to a significant downregulation of adipogenesis-related gene expression. Thus, our findings suggest that unripe citrus possesses anti-obesity effects by impeding adipogenesis and adipocyte differentiation, with the peel demonstrating a more pronounced effect compared to pressed juice.

DMSO and Its Role in Differentiation Impact Efficacy of Human Adenovirus (HAdV) Infection in HepaRG Cells.

Differentiated HepaRG cells are popular in vitro cell models for hepatotoxicity studies. Their differentiation is usually supported by the addition of dimethyl sulfoxide (DMSO), an amphipathic solvent widely used in biomedicine, for example, in potential novel therapeutic drugs and cryopreservation of oocytes. Recent studies have demonstrated drastic effects, especially on epigenetics and extracellular matrix composition, induced by DMSO, making its postulated inert character doubtful. In this work, the influence of DMSO and DMSO-mediated modulation of differentiation on human adenovirus (HAdV) infection of HepaRG cells was investigated. We observed an increase in infectivity of HepaRG cells by HAdVs in the presence of 1% DMSO. However, this effect was dependent on the type of medium used for cell cultivation, as cells in William's E medium showed significantly stronger effects compared with those cultivated in DMEM. Using different DMSO concentrations, we proved that the impact of DMSO on infectability was dose-dependent. Infection of cells with a replication-deficient HAdV type demonstrated that the mode of action of DMSO was based on viral entry rather than on viral replication. Taken together, these results highlight the strong influence of the used cell-culture medium on the performed experiments as well as the impact of DMSO on infectivity of HepaRG cells by HAdVs. As this solvent is widely used in cell culture, those effects must be considered, especially in screening of new antiviral compounds.

Comprehensive analysis of m6A modification in immune infiltration, metabolism and drug resistance in hepatocellular carcinoma

N6-methyladenosine (m6A) is important in regulating mRNA stability, splicing, and translation, and it also contributes to tumor development. However, there is still limited understanding of the comprehensive effects of m6A modification patterns on the tumor immune microenvironment, metabolism, and drug resistance in hepatocellular carcinoma (HCC). In this study, we utilized unsupervised clustering based on the expression of 23 m6A regulators to identify m6A clusters. We identified differential m6A modification patterns and characterized m6A-gene-cluster A, which exhibited poorer survival rates, a higher abundance of Treg cells, and increased expression of TGFβ in the tumor microenvironment (TME). Additionally, m6A-gene-cluster A demonstrated higher levels of glycolysis activity, cholesterol metabolism, and fatty acid biosynthesis. We also found that the m6A score was associated with prognosis and drug resistance. Patients with a low m6A score experienced worse prognoses, which were linked to an abundance of Treg cells, upregulation of TGFβ, and increased metabolic activity. HCC patients with a higher m6A score showed improved prognosis following sorafenib treatment and immunotherapy. In conclusion, we reveals the association between m6A modification patterns and the tumor immune microenvironment, metabolism, and drug resistance in HCC. Furthermore, the m6A score holds potential as a predictive factor for the efficacy of targeted therapy and immunotherapy in HCC.

A 930 m/180 Gbps*User Underwater Coherent Optical Code-Division Multiple-Access Network Based on Hybrid 256-Differential Pulse Position Modulation and Weighted Modified Prime Code Sequence

Currently, there are three types of optical communication networks based on the communication channel between the transmitter and receiver: the optical fiber channel, visible light channel, and optical wireless channel networks. The last type has several advantages for underwater communication, wireless sensors, and military communication networks. However, this type of optical network suffers from weather conditions in free-space communications and attenuation owing to the scattering and absorption mechanisms for underwater communication. In this study, we present a new transceiver architecture of a coherent optical code-division multiple-access (OCDMA) system based on a hybrid M-ary differential pulse position modulation scheme and a spreading code sequence called weighted modified prime code for underwater communication to minimize channel dispersion, increase the transmission rate per second, enhance the network bit error rate (BER) performance, and improve network security. Using an OCDMA system, we can simultaneously expand the network coverage area and increase the number of users sharing the network over the same channel bandwidth. The simulation results in this study proved that the proposed system can accommodate 1310 active users and a network throughput of 180 Gbps*user over a transmission distance of 930 m without any repeater at a 10−9 BER performance, compared to the 45 Gbps*user network throughput and 100 m transmission distance reported in the literature.

Two criteria for quasihomogeneity

Let ( R , m R , k ) (R,\mathfrak {m}_R,\mathbb {k}) be a one-dimensional complete local reduced k \mathbb {k} -algebra over a field of characteristic zero. The ring R R is said to be quasihomogeneous if there exists a surjection Ω R ↠ m \Omega _R\twoheadrightarrow \mathfrak {m} where Ω R \Omega _R denotes the module of differentials. We present two characterizations of quasihomogeniety of R R in the case when R R is a domain. The first one on the valuation semigroup of R R and the other on the trace ideal of the module Ω R \Omega _R .

Impact of Burial Dissolution on the Development of Ultra‐deep Fault‐controlled Carbonate Reservoirs: Insights from High‐temperature and High‐pressure Dissolution Kinetic Simulation

AbstractBurial dissolution is a critical diagenetic process influencing ultra‐deep carbonate reservoir development and preservation. Artificial carbonate samples with different internal structures were prepared, and high‐temperature and high‐pressure dissolution kinetic simulations were conducted. The results demonstrate that the intensity of burial dissolution is controlled by temperature and pressure, while tectonic‐fluid activity influences the development pattern of burial dissolution, ultimately determining the direction of its differential modification. Extensive burial dissolution is likely to occur primarily at relatively shallow depths, significantly influencing reservoir formation, preservation, modification, and adjustment. The development of faults facilitates the maintenance of the intensity of burial dissolution. The maximum intensity of burial dissolution occurs at the tips and overlap zones of faults and intersections of multiple faults. The larger the scale of the faults, the more conducive it is to the development of burial dissolution. Burial dissolution fosters the formation of fault networks characterized by enhanced reservoir capacity and permeability. Burial dissolution controlled by episodic tectonic‐fluid activity is a plausible explanation for forming the Tarim Basin's ultra‐deep fault‐controlled “string‐bead‐like” reservoirs.

TiTDet: A tiny text detector with scale-sensitive loss and effective fusion factor

The text in natural scenes is often smaller compared to artificially designed text. Due to the small proportion of pixels, low resolution, less semantic information, and susceptibility to complex scenes, tiny text detection often results in many missed detections. To address this issue, this paper draws inspiration from small object detection methods and proposes TiTDet, a detection algorithm more suitable for tiny text. Due to the small proportion of pixels, low resolution, less semantic information, and susceptibility to complex scenes, tiny text detection often results in many missed detections. To address this issue, this paper draws inspiration from small object detection methods and proposes TiTDet, a detection algorithm more suitable for tiny text. Firstly, this paper incorporates a context extraction module and an attention-guided module. These modules guide contextual information learning through a self attention mechanism, while eliminating the possible negative impact caused by redundant information. Regarding multi-scale feature fusion, this paper proposes a fine-grained effective fusion factor, making the fusion process emphasize small object learning more and highlight the feature expression of tiny texts. In terms of post-processing, this paper proposes a differentiable binarization module, incorporating the binarization process into model training. Leveraging the implicit information in the data to drive model improvement can enhance the post-processing effect. Lastly, this paper proposes a scale-sensitive loss, which can handle tiny texts more fairly, fully considering the positional relationship between the predicted and real regions, and better guiding the model training. This paper proves that TiTDet exhibits high sensitivity and accuracy in detecting tiny texts, achieving an 86.0% F1-score on ICDAR2015. The paper also compares the superiority of the method on CTW1500 and Total-Text.

NMR Metabolomics of Primary Ovarian Cancer Cells in Comparison to Established Cisplatin-Resistant and -Sensitive Cell Lines.

Cancer cell lines are frequently used in metabolomics, such as in vitro tumor models. In particular, A2780 cells are commonly used as a model for ovarian cancer to evaluate the effects of drug treatment. Here, we compare the NMR metabolomics profiles of A2780 and cisplatin-resistant A2780 cells with those of cells derived from 10 patients with high-grade serous ovarian carcinoma (collected during primary cytoreduction before any chemotherapeutic treatment). Our analysis reveals a substantial similarity among all primary cells but significant differences between them and both A2780 and cisplatin-resistant A2780 cells. Notably, the patient-derived cells are closer to the resistant A2780 cells when considering the exo-metabolome, whereas they are essentially equidistant from A2780 and A2780-resistant cells in terms of the endo-metabolome. This behavior results from dissimilarities in the levels of several metabolites attributable to the differential modulation of underlying biochemical pathways. The patient-derived cells are those with the most pronounced glycolytic phenotype, whereas A2780-resistant cells mainly diverge from the others due to alterations in a few specific metabolites already known as markers of resistance.

Differential modulation of local field potentials in the primary and premotor cortices during ipsilateral and contralateral reach to grasp in macaque monkeys.

Hand movements are associated with modulations of neuronal activity across several interconnected cortical areas, including the primary motor cortex (M1), and the dorsal and ventral premotor cortices (PMd and PMv). Local field potentials (LFPs) provide a link between neuronal discharges and synaptic inputs. Our current understanding of how LFPs vary in M1, PMd, and PMv during contralateral and ipsilateral movements is incomplete. To help reveal unique features in the pattern of modulations, we simultaneously recorded LFPs in these areas in two macaque monkeys performing reach and grasp movements with either the right or left hand. The greatest effector-dependent differences were seen in M1, at low (≤ 13 Hz) and gamma frequencies. In premotor areas, differences related to hand use were only present in low frequencies. PMv exhibited the greatest increase in low frequencies during instruction cues and the smallest effector-dependent modulation during movement execution. In PMd, delta oscillations were greater during contralateral reach and grasp, and beta activity increased during contralateral grasp. In contrast, beta oscillations decreased in M1 and PMv. These results suggest that while M1 primarily exhibits effector-specific LFP activity, premotor areas compute more effector-independent aspects of the task requirements, particularly during movement preparation for PMv and production for PMd. The generation of precise hand movements likely relies on the combination of complementary information contained in the unique pattern of neural modulations contained in each cortical area. Accordingly, integrating LFPs from premotor areas and M1 could enhance the performance and robustness of brain-machine interfaces.Significance Statement We compared local field potentials (LFPs) from the primary motor cortex (M1), the dorsal and ventral premotor cortices (PMd and PMv) while monkeys performed reach and grasp with the contralateral or ipsilateral hand. In general, hand-related differences were greater in M1 than in premotor areas. During both contralateral and ipsilateral trials, LFPs were more similar when comparing the two premotor areas than comparing M1 to PMd or PMv. However, the pattern of modulations in each area had unique features. The combination of these signals is likely essential to support the flexibility and complexity of unilateral hand movements. Our results help to understand the neural substrate that allows cortical areas to concurrently contribute to different aspects of movement planning and production.

SSCNet: learning-based subspace clustering

Sparse subspace clustering (SSC), a seminal clustering method, has demonstrated remarkable performance by effectively solving the data sparsity problem. However, it is not without its limitations. Key among these is the difficulty of incremental learning with the original SSC, accompanied by a computationally demanding recalculation process that constrains its scalability to large datasets. Moreover, the conventional SSC framework considers dictionary construction, affinity matrix learning and clustering as separate stages, potentially leading to suboptimal dictionaries and affinity matrices for clustering. To address these challenges, we present a novel clustering approach, called SSCNet, which leverages differentiable programming. Specifically, we redefine and generalize the optimization procedure of the linearized alternating direction method of multipliers (ADMM), framing it as a multi-block deep neural network, where each block corresponds to a linearized ADMM iteration step. This reformulation is used to address the SSC problem. We then use a shallow spectral embedding network as an unambiguous and differentiable module to approximate the eigenvalue decomposition. Finally, we incorporate a self-supervised structure to mitigate the non-differentiability inherent in k-means to achieve the final clustering results. In essence, we assign unique objectives to different modules and jointly optimize all module parameters using stochastic gradient descent. Due to the high efficiency of the optimization process, SSCNet can be easily applied to large-scale datasets. Experimental evaluations on several benchmarks confirm that our method outperforms traditional state-of-the-art approaches.

Differential Modulation of Motor Unit Behaviour when a Fatiguing Contraction is Matched for Torque versus EMG.

When an isometric contraction is sustained at a submaximal torque, activation of the motoneuron pool increases, making it difficult to measure neural excitability alterations. Thus, more recently, isometric contractions with maintained electromyographic activity (matched-EMG) are being used to induce fatigue; however, little is known about the neurophysiological adjustments that occur to satisfy the requirements of the task. For our study, 16 participants performed a 10-min sustained isometric elbow flexion contraction at 20% maximal voluntary contraction (MVC) torque or the level of integrated biceps brachii EMG recorded at 20% MVC torque. Surface EMG was used to assess global median frequency, and four fine-wire electrode pairs were used to obtain motor unit (MU) discharge rate from biceps brachii. Torque or EMG steadiness was also assessed throughout the fatiguing contractions. MU discharge rate increased and torque steadiness decreased during the matched-torque contraction; however, MU discharge rate decreased during the matched-EMG contraction and no changes occurred for EMG steadiness. Data pooled for the two contractions revealed a decrease of global median frequency. Lastly, a greater loss of MVC torque was observed immediately after the matched-torque compared to matched-EMG contraction. These findings indicate that, during a matched-torque fatiguing contraction, the nervous system increases MU discharge rates at the cost of poorer steadiness in order to maintain the requisite torque. In contrast, during a matched-EMG fatiguing contraction, a reduction of MU discharge rates allows for a maintenance of EMG steadiness.

Genome-wide 5-hydroxymethylcytosines in circulating cell-free DNA as noninvasive diagnostic markers for gastric cancer.

5-Hydroxymethylcytosine-enriched gene profiles and regions show tissue-specific and tumor specific. There is a potential value to explore cell-free DNA 5-hydroxymethylcytosine feature biomarkers for early gastric cancer detection. A matched case‒control study design with 50 gastric cancer patients and 50 controls was performed to sequence the different 5-hydroxymethylcytosine modification features of cell free DNA. Significantly differential 5-hydroxymethylcytosine modification genes were identified to construct a gastric cancer diagnostic model. Data set from GEO was used as an external testing set to test the robustness of the diagnostic model. Accounting for more than 90% of 5-hydroxymethylcytosine peaks were distributed in the gene body in both the gastric cancer and control groups. The diagnostic model was developed based on five different 5-hydroxymethylcytosine modification genes, FBXL7, PDE3A, TPO, SNTG2 and STXBP5. The model could effectively distinguish gastric cancer patients from controls in the training (AUC = 0.95, sensitivity = 88.6%, specificity = 94.3%), validation (AUC = 0.87, sensitivity = 73.3%, specificity = 93.3%) and testing (AUC = 0.90, sensitivity = 81.9%, specificity = 90.2%) sets. The risk scores of the controls from the model were significantly lower than those of gastric cancer patients in bothour own data (P < 0.001) and GEO external testing data (P < 0.001), and no significant difference between different TNM stage patients (P = 0.09 and 0.66). Furthermore, there was no significant difference between the healthy control and benign gastric disease patients in the testing set from GEO (P = 0.10). The characteristics of 5-hydroxymethylcytosine in cell free DNA are specific to gastric cancer patients, and the diagnostic model constructed by five genes' 5-hydroxymethylcytosine features could effectively identify gastric cancer patients.