The first human infected with the Covid-19 virus was traced to a seafood market in Wuhan, China. Research shows that there are comparable types of viruses found in different and mutually distant ...areas. This raises several questions: what if the virus originated in another location? How will future waves of epidemics behave if they originate from different locations with a smaller/larger population than Wuhan? To explore these questions, we implement an agent-based model within fractal cities. Cities radiate gravitational social attraction based on their Zipfian population. The probability and predictability of contagion events are analyzed by examining fractal dimensions and lacunarity. Results show that weak gravitational forces of small locations help dissipate infections across country quicker if the pathogen had originated from that location. Gravitational forces of large cities help contain infections within them if they are the starting locations for the pathogen. Greater connectedness and symmetry allow for a more predictable epidemic outcome since there are no obstructions to spreading. To test our hypothesis, we implement datasets from two countries, Sierra Leone and Liberia, and two diseases, Ebola and Covid-19, and obtain the same results.
(1) Purpose: To improve the capability of EfficientNet, including developing a cropping method called Random Center Cropping (RCC) to retain the original image resolution and significant features on ...the images' center area, reducing the downsampling scale of EfficientNet to facilitate the small resolution images of RPCam datasets, and integrating attention and Feature Fusion (FF) mechanisms with EfficientNet to obtain features containing rich semantic information. (2) Methods: We adopt the Convolutional Neural Network (CNN) to detect and classify lymph node metastasis in breast cancer. (3) Results: Experiments illustrate that our methods significantly boost performance of basic CNN architectures, where the best-performed method achieves an accuracy of 97.96% ± 0.03% and an Area Under the Curve (AUC) of 99.68% ± 0.01% on RPCam datasets, respectively. (4) Conclusions: (1) To our limited knowledge, we are the only study to explore the power of EfficientNet on Metastatic Breast Cancer (MBC) classification, and elaborate experiments are conducted to compare the performance of EfficientNet with other state-of-the-art CNN models. It might provide inspiration for researchers who are interested in image-based diagnosis using Deep Learning (DL). (2) We design a novel data augmentation method named RCC to promote the data enrichment of small resolution datasets. (3) All of our four technological improvements boost the performance of the original EfficientNet.
A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is ...an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARSCoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substratebinding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.
This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, ...including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 n = 8, 10 n = 31, or 20 n = 6 mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at www.clinicaltrials.gov as #NCT02283775.
•Isatuximab combined with pomalidomide/dexamethasone has a manageable safety profile with promising clinical activity.•Isatuximab 10 mg/kg (4 weekly doses followed by dosing every 2 weeks thereafter) has been selected for future combination studies.
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This paper proposes a multi-objective integrated container terminal scheduling problem considering three key components: berth allocation, quay cranes assignment and containers transportation in port ...operation process. In the suggested problem, one of the objectives is to shorten service time of ships with by coordinating of quay cranes, and the other is to reduce operating costs of quay cranes and yard trucks. Then, a Multi-objective Bacterial Colony Optimization algorithm (MOBCO) incorporating concepts of multi-swarm, topology, personal best and global best, named Multi-objective BCO with ring topology (MORBCO), is designed to handle the resulting problem. The extension of standard MOBCO to the MORBCO involves the addition of three specialized strategies: global chemotaxis operation, elite reproduction strategy and personal best archive with neighborhood communication mechanism. In order to test the performance of the MORBCO, benchmark tests are performed and compared with traditional MOBCO and three other well-known multi-objective algorithms first. The computational results indicate that the proposed algorithm can outperform other rivals and efficiently solve a variety of multi-objective problems in most of cases. Subsequently, MORBCO and two best performing algorithms from the previous test are applied to three instances generated by the proposed model. Judging by quality and diversity of obtained non-dominant solutions, we find that MORBCO has superior performance, especially for large instances of the container terminal problem.
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•The first transcriptome and metabolome network was established in arsenic-exposed mice.•Developmental arsenic disrupted mitochondrial fatty acid β-oxidation in mice.•Arsenic ...accumulation and pathological changes were found in liver and intestine.•Disrupted human serum metabolites linked with metabolic toxicity in mice.•L-palmitoylcarnitine was critical player in metabolic toxicity and late-life NAFLD development.
Emerging evidence has linked arsenic exposure and metabolic homeostasis, but the mechanism is incompletely understood, especially at relatively low concentrations. In this study, we used a mouse model to evaluate the health impacts and metabolic toxicity of arsenic exposure in drinking water at environmentally relevant levels (0.25 and 1.0 ppm). Our results indicated that arsenic damaged intestinal barrier and induced arsenic accumulation, oxidative stress, and pathological changes in the liver and illum. Interestingly, arsenic increased the hepatic triglyceride (TG) and total cholesterol (TC), while reduced serum TG and TC levels. The liver transcriptome found that arsenic exposure caused transcriptome perturbation and promoted hepatic lipid accumulation by regulating the exogenous fatty acids degradation and apolipoproteins related genes. The serum metabolomics identified 74 and 88 differential metabolites in 0.25 and 1.0 ppm, respectively. The KEGG disease and subcellular location analysis indicated that arsenic induced liver and intestinal diseases, and the mitochondrion might be the target organelle for arsenic-induced toxicity. Co-enrichment of transcriptome and metabolome identified 24 metabolites and 9 genes as metabolic toxicity biomarkers. Moreover, 40 male (20 nonalcoholic fatty liver disease (NAFLD) cases and 20 healthy controls) was further selected to validate our findings. Importantly, the significantly changed L-palmitoylcarnitine, 3-hydroxybutyric acid, 2-hydroxycaproic acid and 6 genes of Hadha, Acadl, Aldh3a2, Cpt1a, Cpt2, and Acox1 were found in the NAFLD cases. The results from integrated multi-omics and chemical-protein network analysis indicated that L-palmitoylcarnitine played a critical role in metabolic toxicity by regulating mitochondrial fatty acids β-oxidation genes (Cpt1a, Cpt2). In conclusion, these findings provided new clues for the metabolic toxicity of arsenic exposure at environmentally relevant levels, which involved in the late-life NAFLD development. Our results also contribute to understanding the human responses and phenotypic changes to this hazardous material exposure in the environment.
Type 2 diabetes mellitus (T2DM) has become a global health problem with no cure. Despite lifestyle modifications and various pharmaceutical options, the achievement of stable and durable glucose ...control along with effective prevention of T2DM-related cardiovascular complications remains a challenging task in clinical management. With its selective high abundance in metabolic tissues (adipose tissue, liver, and pancreas), β-Klotho is the essential component of fibroblast growth factor (FGF) receptor complexes. It is essential for high-affinity binding of endocrine FGF19 and FGF21 to evoke the signaling cascade actively involved in homeostatic maintenance of glucose metabolism and energy expenditure. In this Review, we discuss the biological function of β-Klotho in the regulation of glucose metabolism and offer mechanistic insights into its involvement in the pathophysiology of T2DM. We review our current understanding of the endocrine axis comprised of β-Klotho and FGFs (FGF19 and FGF21) and its regulatory effects on glucose metabolism under physiological and T2DM conditions. We also highlight advances in the development and preclinical validation of pharmacological compounds that target β-Klotho and/or the β-Klotho-FGFRs complex for the treatment of T2DM. Given the remarkable advances in this field, we also discuss outstanding research questions and the many challenges in the clinical development of β-Klotho-based therapies.
Stroke remains the leading cause of long-term disability worldwide. Rehabilitation training is essential for motor function recovery following stroke. Specifically, limb linkage rehabilitation ...training can stimulate motor function in the upper and lower limbs simultaneously. This study aimed to investigate limb linkage rehabilitation task-related changes in cortical activation and effective connectivity (EC) within a functional brain network after stroke by using functional near-infrared spectroscopy (fNIRS) imaging. Thirteen stroke patients with either left hemiparesis (L-H group, n = 6) and or right hemiparesis (R-H group, n = 7) and 16 healthy individuals (control group) participated in this study. A multichannel fNIRS system was used to measure changes in cerebral oxygenated hemoglobin (delta HbO
) and deoxygenated hemoglobin (delta HHb) in the bilateral prefrontal cortices (PFCs), motor cortices (MCs), and occipital lobes (OLs) during (1) the resting state and (2) a motor rehabilitation task with upper and lower limb linkage (first 10 min task_S1, last 10 min task_S2). The frequency-specific EC among the brain regions was calculated based on coupling functions and dynamic Bayesian inference in frequency intervals: high-frequency I (0.6-2 Hz) and II (0.145-0.6 Hz), low-frequency III (0.052-0.145 Hz), and very-low-frequency IV (0.021-0.052 Hz). The results showed that the stroke patients exhibited an asymmetric (greater activation in the contralesional versus ipsilesional motor region) cortical activation pattern versus healthy controls. Compared with the healthy controls, the stroke patients showed significantly lower EC (p < 0.025) in intervals I and II in the resting and task states. The EC from the MC and OL to the right PFC in interval IV was significantly higher in the R-H group than in the control group during the resting and task states (p < 0.025). Furthermore, the L-H group showed significantly higher EC from the MC and OL to the left PFC in intervals III and IV during the task states compared with the control group (p < 0.025). The significantly increased influence of the MC and OL on the contralesional PFC in low- and very-low-frequency bands suggested that plastic reorganization of cognitive resources severed to compensate for impairment in stroke patients during the motor rehabilitation task. This study can serve as a basis for understanding task-related reorganization of functional brain networks and developing novel assessment techniques for stroke rehabilitation.
Despite accumulating evidence on the role of glial cells and their associated chemicals in mechanisms of pain, few studies have addressed the potential role of chemokines in the descending ...facilitation of chronic pain. We aimed to study the hypothesis that CXCL1/CXCR2 axis in the periaqueductal gray (PAG), a co-restructure of the descending nociceptive system, is involved in descending pain facilitation.
Intramedullary injection of Walker 256 mammary gland carcinoma cells of adult female Sprague Dawley rats was used to establish a bone cancer pain (BCP) model. RT-PCR, Western blot, and immunohistochemistry were performed to detect pNfkb, Cxcl1, and Cxcr2 and their protein expression in the ventrolateral PAG (vlPAG). Immunohistochemical co-staining with NeuN, GFAP, and CD11 were used to examine the cellular location of pNFκB, CXCL1, and CXCR2. The effects of NFκB and CXCR2 antagonists and CXCL1 neutralizing antibody on pain hypersensitivity were evaluated by behavioral testing.
BCP induced cortical bone damage and persistent mechanical allodynia and increased the expression of pNFκB, CXCL1, and CXCR2 in vlPAG. The induced phosphorylation of NFκB was co-localized with GFAP and NeuN, but not with CD11. Micro-injection of BAY11-7082 attenuated BCP and reduced CXCL1 increase in the spinal cord. The expression level of CXCL1 in vlPAG showed co-localization with GFAP, but not with CD11 and NeuN. Micro-administration of CXCL1 neutralizing antibody from 6 to 9 days after inoculation attenuated mechanical allodynia. Furthermore, vlPAG application of CXCL1 elicited pain hypersensitivity in normal rats. Interestingly, CXCR2 was upregulated in vlPAG neurons (not with CD11 and GFAP) after BCP. CXCR2 antagonist SB225002 completely blocked the CXCL1-induced mechanical allodynia and attenuated BCP-induced pain hypersensitivity.
The NFκB-dependent CXCL1-CXCR2 signaling cascade played a role in glial-neuron interactions and in descending facilitation of BCP.
Bone cancer pain (BCP) remains a serious complication of malignancy, which is an intractable clinical problem due to the gap in knowledge of its underlying mechanisms. Recent studies have ...demonstrated that the major involvement of neuroinflammation, particularly high-mobility group box 1 (HMGB1), which was identified as a late mediator of inflammation, in a number of pain conditions. However, the underlying mechanisms and functions of HMGB1 release in spinal cord, and its contributions to the development of BCP as well, are poorly understood. In the present study, we examined the theory that PKC activation lead to nuclear translocation and cytosolic HMGB1 secretion, which subsequently induces spinal neuro inflammatory responses (cytokine release) causing hyperalgesia. Our results showed that PKC activation and HMGB1 release in spinal neurons as well as mechanical allodynia in BCP rats, were all attenuated by intrathecal administration of the PKC inhibitor Gö6983 and aggravated by its activator PMA. Intrathecal administration of anti-HMGB1 antibody also alleviated hypersensitivity caused by BCP. Meanwhile, phospho-PKC and cellular HMGB1 were found co-localized in neurons, but not in microglia and astrocytes, of the spinal dorsal horns of tumor-bearing rats. Additionally, we found that HMGB1 translocation from nuclei to cytoplasm may be the consequence of PKC translocation into the nuclei, which occurred 9 days after tumor inoculation. Total p-HMGB1 as well as nuclear and cytoplasmic HMGB1 expression levels were tested in response to broad-spectrum PKC inhibitor Gö6983 or activator PMA in BCP rats. Together, these findings suggest that bone cancer related hyperalgesia is driven by PKC induced phosphorylation of HMGB1, which results in its translocation from the nucleus, and releasing from the cytosol of the dorsal horn, and the activation of spinal pro-inflammatory mediators.
•The levels of HMGB1 and related proinflammatory cytokine expression were elevated.•Nuclear HMGB1 translocation and PKC activation primarily occurred in neurons.•PKC activation caused HMGB1 translocation via a phosphorylation-dependent mechanism.•HMGB1 release enhanced the expression of proinflammatory mediators.
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