Population flow drives spatio-temporal distribution of COVID-19 in China.

Sudden, large-scale and diffuse human migration can amplify localized outbreaks of disease into widespread epidemics1-4. Rapid and accurate tracking of aggregate population flows may therefore be epidemiologically informative. Here we use 11,478,484 counts of mobile phone data from individuals leaving or transiting through the prefecture of Wuhan between 1 January and 24 January 2020 as they moved to 296 prefectures throughout mainland China. First, we document the efficacy of quarantine in ceasing movement. Second, we show that the distribution of population outflow from Wuhan accurately predicts the relative frequency and geographical distribution of infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) until 19 February 2020, across mainland China. Third, we develop a spatio-temporal 'risk source' model that leverages population flow data (which operationalize the risk that emanates from epidemic epicentres) not only to forecast the distribution of confirmed cases, but also to identify regions that have a high risk of transmission at an early stage. Fourth, we use this risk source model to statistically derive the geographical spread of COVID-19 and the growth pattern based on the population outflow from Wuhan; the model yields a benchmark trend and an index for assessing the risk of community transmission of COVID-19 over time for different locations. This approach can be used by policy-makers in any nation with available data to make rapid and accurate risk assessments and to plan the allocation of limited resources ahead of ongoing outbreaks.

Novel recombinant human thyroid-stimulating hormone in aiding postoperative assessment of patients with differentiated thyroid cancer-phase I/II study.

PURPOSE: Thyroid hormone withdrawal (THW) inevitably induced hypothyroidism in patients with differentiated thyroid cancer (DTC), and we aimed to evaluate the safety and efficacy of a novel recombinant human thyroid-stimulating hormone (rhTSH, ZGrhTSH) as an alternative of THW in China. METHODS: Totally, 64 DTC patients were enrolled with 24 in the dose-escalation cohort equally grouped into 0.9 mg × 1 day, 0.9 mg × 2 day, 1.8 mg × 1 day, and 1.8 mg × 2 day dosage, and 40 further enrolled into 0.9 mg × 2 day dose-expansion cohort. All patients underwent both ZGrhTSH phase and levothyroxine (L-T4) withdrawal phase for self-comparison in terms of TSH levels, the radioactive iodine (RAI) uptake, stimulated thyroglobulin level, and the quality of life (QoL). RESULTS: In ZGrhTSH phase, no major serious adverse events were observed, and mild symptoms of headache were observed in 6.3%, lethargy in 4.7%, and asthenia in 3.1% of the patients, and mostly resolved spontaneously within 2 days. Concordant RAI uptake was noticed in 89.1% (57/64) of the patients between ZGrhTSH and L-T4 withdrawal phases. The concordant thyroglobulin level with a cut-off of 1 µg/L was noticed in 84.7% (50/59) of the patients without the interference of anti-thyroglobulin antibody. The QoL was far better during ZGrhTSH phase than L-T4 withdrawal phase, with lower Billewicz (- 51.30 ± 4.70 vs. - 39.10 ± 16.61, P < 0.001) and POMS (91.70 ± 16.70 vs. 100.40 ± 22.11, P = 0.011) scores which indicate the lower the better. Serum TSH level rose from basal 0.11 ± 0.12 mU/L to a peak of 122.11 ± 42.44 mU/L 24 h after the last dose of ZGrhTSH. In L-T4 withdrawal phase, a median of 23 days after L-T4 withdrawal was needed, with the mean TSH level of 82.20 ± 31.37 mU/L. The half-life for ZGrhTSH clearance was about 20 h. CONCLUSION: The ZGrhTSH held the promise to be a safe and effective modality in facilitating RAI uptake and serum thyroglobulin stimulation, with better QoL of patients with DTC compared with L-T4 withdrawal.

Design and synthesis of a novel class EGFR/HER2 dual inhibitors containing tricyclic oxazine fused quinazolines scaffold.

Two series of novel tricyclic oxazine and oxazepine fused quinazolines have been designed, synthesized and evaluated for their inhibitory activity against EGFR and HER2. Structure-activity relationship (SAR) of these compounds was discussed. From the SAR studies, we found that intramolecular cyclization which possessed a functional Michael acceptor group can enhance the antitumor activities. Compounds 1e and 1h were identified as lead compounds which displayed almost 3-4 times more potent inhibition of EGFR and HER2 than the approved drug lapatinib. The satisfactory physicochemical properties of these compounds were also supported by ACD labs. The results presented here will promote the development of newer dual inhibitors of EGFR and HER2.

The Role of Hedonic Behavior in Reducing Perceived Risk.

Understanding how human populations naturally respond to and cope with risk is important for fields ranging from psychology to public health. We used geophysical and individual-level mobile-phone data (mobile-apps, telecommunications, and Web usage) of 157,358 victims of the 2013 Ya'an earthquake to diagnose the effects of the disaster and investigate how experiencing real risk (at different levels of intensity) changes behavior. Rather than limiting human activity, higher earthquake intensity resulted in graded increases in usage of communications apps (e.g., social networking, messaging), functional apps (e.g., informational tools), and hedonic apps (e.g., music, videos, games). Combining mobile data with a field survey ( N = 2,000) completed 1 week after the earthquake, we use an instrumental-variable approach to show that only increases in hedonic behavior reduced perceived risk. Thus, hedonic behavior could potentially serve as a population-scale coping and recovery strategy that is often missing in risk management and policy considerations.

Synthesis and evaluation of a novel class Hsp90 inhibitors containing 1-phenylpiperazine scaffold.

Previously, we identified 1-(2-(4-bromophenoxy)ethoxy)-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol (1) as a novel Hsp90 inhibitor with moderate activity through virtual screening. In this study, we report the optimization process of 1. A series of analogues containing the 1-phenylpiperazine core scaffold were synthesized and evaluated. The structure-activity relationships (SAR) for these compounds was also discussed for further molecular design. This effort afforded the most active inhibitor 13f with improved activity in not only target-based level, but also cell-based level compared with the original hit 1.

Discovery and design of tricyclic scaffolds as protein kinase CK2 (CK2) inhibitors through a combination of shape-based virtual screening and structure-based molecular modification.

Protein kinase CK2 (CK2), a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates, serves as an attractive anticancer target. One of its most potent inhibitors, CX-4945, has entered a phase I clinical trial. Herein we present an integrated workflow combining shape-based virtual screening for the identification of novel CK2 inhibitors. A shape-based model derived from CX-4945 was built, and the subsequent virtual screening led to the identification of several novel scaffolds with high shape similarity to that of CX-4945. Among them two tricyclic scaffolds named [1,2,4]triazolo[4,3-c]quinazolin and [1,2,4]triazolo[4,3-a]quinoxalin attracted us the most. Combining strictly chemical similarity analysis, a second-round shape-based screening was performed based on the two tricyclic scaffolds, leading to 28 derivatives. These compounds not only targeted CK2 with potent and dose-dependent activities but also showed acceptable antiproliferative effects against a series of cancer cell lines. Our workflow supplies a high efficient strategy in the identification of novel CK2 inhibitors. Compounds reported here can serve as ideal leads for further modifications.

Emergency communications after earthquake reveal social network backbone of important ties.

Social networks provide a basis for collective resilience to disasters. Combining the quasi-experimental context of a major earthquake in Ya'an, China, with anonymized mobile telecommunications records regarding 91,839 Ya'an residents, we use initial bursts of postdisaster communications (e.g. choice of alter, order of calls, and latency) to reveal the "important ties" that form the social network backbone. We find that only 26.8% of important ties activated during the earthquake were the strongest ties during normal times. Many important ties were hitherto latent and weak, only to become persistent and strong after the earthquake. We show that which ties activated during a sudden disaster are best predicted by the interaction of embeddedness and tie strength. Moreover, a backbone of important ties alone (without the inclusion of weak ties ordinarily seen as important to bridge communities) is sufficient to generate a hierarchical structure of social networks that connect a disaster zone's disparate communities.

A general urban spreading pattern of COVID-19 and its underlying mechanism.

Currently, the global situation of COVID-19 is aggravating, pressingly calling for efficient control and prevention measures. Understanding the spreading pattern of COVID-19 has been widely recognized as a vital step for implementing non-pharmaceutical measures. Previous studies explained the differences in contagion rates due to the urban socio-political measures, while fine-grained geographic urban spreading pattern still remains an open issue. Here, we fill this gap by leveraging the trajectory data of 197,808 smartphone users (including 17,808 anonymous confirmed cases) in nine cities in China. We find a general spreading pattern in all cities: the spatial distribution of confirmed cases follows a power-law-like model and the spreading centroid human mobility is time-invariant. Moreover, we reveal that long average traveling distance results in a high growth rate of spreading radius and wide spatial diffusion of confirmed cases in the fine-grained geographic model. With such insight, we adopt the Kendall model to simulate the urban spreading of COVID-19 which can well fit the real spreading process. Our results unveil the underlying mechanism behind the spatial-temporal urban evolution of COVID-19, and can be used to evaluate the performance of mobility restriction policies implemented by many governments and to estimate the evolving spreading situation of COVID-19.

Triadic embeddedness structure in family networks predicts mobile communication response to a sudden natural disaster.

Kinship networks are a fundamental social unit in human societies, and like social networks in general, provide social support in times of need. Here, we investigate the impact of sudden environmental shock, the Ms 7.0 2013 Ya'an earthquake, on the mobile communications patterns of local families, which we operationalize using anonymized individual-level mobile telecommunications metadata from family plan subscribers of a major carrier (N = 35,565 people). We demonstrate that families' communications dynamics after the earthquake depended on their triadic embeddedness structure, a structural metric we propose that reflects the number of dyads in a family triad that share social ties. We find that individuals in more embedded family structures were more likely to first call other family plan members and slower in calling non-family ties immediately after the earthquake; these tendencies were stronger at higher earthquake intensity. In the weeks after the event, individuals in more embedded family structures had more reciprocal communications and contacted more social ties in their broader social network. Overall, families that are structurally more embedded displayed higher levels of intra-family coordination and mobilization of non-family social connections.

Predictive diagnosis of major depression using NMR-based metabolomics and least-squares support vector machine.

BACKGROUND: Major depressive (MD) disorder is a serious psychiatric disorder that can result in suicidal behavior if not treated. The MD diagnosis using a standardized instrument instead of a structured interview will be advantageous for treatment and management of the MD, but so far no such technique exists. We developed an integrated analytical method of NMR-based metabolomics and least squares-support vector machine (LS-SVM) for predictive diagnosis of the MD. METHODS: The metabolite profiles in clinical plasma samples obtained from 72 depressive patients and 54 healthy subjects were analyzed by NMR spectroscopy. Then, LS-SVM models with different kernels were trained and tested using 80% and 20% of samples, respectively. RESULTS: We found that the best performance for the MD prediction was achieved by LS-SVM equipped with RBF kernel. Moreover, the predictive performance of the MD using multi-biomarkers was largely improved as compared with that using a single biomarker. In this study, the LS-SVM-RBF using glucose-lipid signaling can achieve the MD prediction with the AUC values of 0.94 (0.89-0.99) in the training set and 0.96 (0.92-1.00) in the test set. CONCLUSION: The LS-SVM-RBF using glucose-lipid signaling obtained from NMR spectroscopy can be used as an auxiliary diagnostic tool for the MD.

CPUY201112, a novel synthetic small-molecule compound and inhibitor of heat shock protein Hsp90, induces p53-mediated apoptosis in MCF-7 cells.

Heat-shock protein 90 (Hsp90) is highly expressed in many tumor cells and is associated with the maintenance of malignant phenotypes. Targeting Hsp90 has had therapeutic success in both solid and hematological malignancies, which has inspired more studies to identify new Hsp90 inhibitors with improved clinical efficacy. Using a fragment-based approach and subsequent structural optimization guided by medicinal chemistry principles, we identified the novel compound CPUY201112 as a potent Hsp90 inhibitor. It binds to the ATP-binding pocket of Hsp90 with a kinetic dissociation (Kd) constant of 27 ± 2.3 nM. It also exhibits potent in vitro antiproliferative effects in a range of solid tumor cells. In MCF-7 cells with high Hsp90 expression, CPUY201112 induces the degradation of Hsp90 client proteins including HER-2, Akt, and c-RAF. We prove that treating MCF-7 cells with CPUY201112 results in cell cycle arrest and apoptosis through the wild-type (wt) p53 pathway. CPUY201112 also synergizes with Nutlin-3a to induce cancer cell apoptosis. CPUY201112 significantly inhibited the growth of MCF-7 xenografts in nude mice without apparent body weight loss. These results demonstrate that CPUY201112 is a novel Hsp90 inhibitor with potential use in treating wild-type p53 related cancers.

Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90.

Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.

One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer's disease.

This study is to explore whether there is presenilin 1 (PS1) gene mutation in Chinese familial Alzheimer's disease (FAD). There has been no such systemic research before in China. Using polymerase chain reaction, single strand conformation polymorphism (PCR-SSCP), followed by denaturing high performance liquid chromatograph (DHPLC) and DNA sequencing, we analyzed a Chinese family with early onset AD. The patients in this family showed a novel missense mutation in exon 4 of the PS1 gene (G to T change in codon 97), altering valine to leucine acid substitution. Because the change occurred in conserved domains of this gene, and is not present in normal controls, this novel mutation is likely to be causative of Chinese FAD.

Metabonomic analysis of potential biomarkers and drug targets involved in diabetic nephropathy mice.

Diabetic nephropathy (DN) is one of the lethal manifestations of diabetic systemic microvascular disease. Elucidation of characteristic metabolic alterations during diabetic progression is critical to understand its pathogenesis and identify potential biomarkers and drug targets involved in the disease. In this study, (1)H nuclear magnetic resonance ((1)H NMR)-based metabonomics with correlative analysis was performed to study the characteristic metabolites, as well as the related pathways in urine and kidney samples of db/db diabetic mice, compared with age-matched wildtype mice. The time trajectory plot of db/db mice revealed alterations, in an age-dependent manner, in urinary metabolic profiles along with progression of renal damage and dysfunction. Age-dependent and correlated metabolite analysis identified that cis-aconitate and allantoin could serve as biomarkers for the diagnosis of DN. Further correlative analysis revealed that the enzymes dimethylarginine dimethylaminohydrolase (DDAH), guanosine triphosphate cyclohydrolase I (GTPCH I), and 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) were involved in dimethylamine metabolism, ketogenesis and GTP metabolism pathways, respectively, and could be potential therapeutic targets for DN. Our results highlight that metabonomic analysis can be used as a tool to identify potential biomarkers and novel therapeutic targets to gain a better understanding of the mechanisms underlying the initiation and progression of diseases.

Differential acetylcholine and choline concentrations in the cerebrospinal fluid of patients with Alzheimer's disease and vascular dementia.

BACKGROUND: An important aspect of Alzheimer's disease (AD) is loss or impairment of cholinergic neurons. It is controversial whether there is a similar cholinergic impairment and cerebral deficit of acetylcholine (ACh) in the case of vascular dementia (VD). The purpose of this study was to explore the levels of ACh and choline (Ch) in the cerebrospinal fluid (CSF) of patients with AD and VD, and their possible relationship with cognitive impairment. METHODS: Twenty-two AD patients, twenty-two VD patients, and twenty normal controls were recruited and scored with a Mini-Mental State Examination (MMSE). CSF concentrations of ACh and Ch were measured using high-performance liquid chromatography with an electrochemical detector (HPLC-ECD) and the results were then compared to cognitive status. RESULTS: ACh concentrations in CSF of AD patients [(10.7 +/- 5.1) nmol/L] and VD patients [(16.8 +/- 7.4) nmol/L] were both significantly lower than in controls [(34.5 +/- 9.0) nmol/L, t = 10.67, P < 0.001; t = 6.91, P < 0.001]. Both results correlated positively with MMSE scores (rs = 0.88 and rs = 0.85, respectively, P < 0.01). The CSF concentration of Ch was significantly higher in VD patients [(887.4 +/- 187.4) nmol/L] compared to AD patients [(627.6 +/- 145.1) nmol/L, t = 6.4, P < 0.001] and controls [(716.0 +/- 159.4) nmol/L, t = 4.2, P = 0.002]. CSF Ch concentration showed no difference between AD patients and normal controls, nor did it correlate with MMSE score in any of the three groups. CONCLUSIONS: The positive correlation between ACh deficit and cognitive impairment suggests that ACh is an important neurotransmitter for memory. The similar decrease in ACh concentration in AD and VD patients may imply a similar pathogenesis for the process of cognitive impairment involved in these two disorders. The elevated CSF levels of Ch in VD patients compared to AD patients may be useful diagnostically. Cholinesterase inhibitors may be helpful not only for AD patients, but also for VD patients.

[Relationship between learning ability and memory and free radical in hippocampus of old rats].

OBJECTIVE: To study the relationship between the amount of free radical in hippocampus and the learning ability and memory in old rats. METHODS: Morris water maze was used for 10 days to examine the learning scores, latency scores, and the loci of movement in the maze among 46 old rats (aged 20 months), 36 young rats (aged 6 months), and 34 adult rats (aged 12 months). Salicylate was injected intraperitoneally and hippocampus dialysis was performed. Chromatography was used to measure the basic values of 2,3DHBA and 2,5DHBA in dialysis fluid chemiluminometry was used to measure the superoxide dismutrase (SOD) in the sample. The rats were killed and their brains were taken out. Histological examination was conducted to calculate the number of neurons in CA1, CA4, and PM regions in hippocampus. RESULTS: The learning scores on the first, fifth, and tenth days were 36.5 +/- 5.9 sec, 38.6 +/- 5.9 sec, and 39.4 +/- 6.9 sec (P > 0.05) in the old rats; 60.2 +/- 5.4 sec, 156.8 +/- 5.8 sec, and 165.1 +/- 6.8 sec in the young rats; and 61.7 +/- 5.8 sec, 152.3 +/- 6.9 sec, and 168.7 +/- 6.5 sec in adult rats. The learning scores at any time point of old rats were significantly lower than those of the young and adults rats (all P < 0.01). The latency scores of the first, fifth, and tenth days were 25.7 +/- 1.2 sec, 27.5 +/- 1.9 sec, and 27.7 +/- 1.9 sec in the old rats without significant difference between any two of these values (P > 0.05), however, the 3 latency scores of the old rats were all significantly larger than those of the young and adult rats (21.8 +/- 1.7 sec, 5.9 +/- 1.0 sec, and 3.6 +/- 0.6 sec, and 21.8 +/- 1.6 sec, 5.0 +/- 0.9 sec, and 4.8 +/- 0.7 sec respectively, all P < 0.01). The basic value of 2,3DHBA after intraperitoneal injection of salicylate was 20.7 +/- 0.3 pmol/ml in the old rats, 5 times that of the young rats and 6 times that of the adult rats (P < 0.01). The basic value of 2,5DHBA after intraperitoneal injection of salicylate was 60.12 pmol/ml in the old rats, 6 times that of the young rats and 5.8 times that of the adult rats (P < 0.01). The SOD activity was 410 U x g(-1) x min(-1) +/- 50 U x g(-1) x min(-1), significantly lower than those in the young and adult rats (880 U x g(-1) x min(-1) +/- 62 U x g(-1) x min(-1) and 860 U x g(-1) x min(-1) +/- 60 U x g(-1) x min(-1) (both P < 0.01). The values of neuron density in CA1, CA4, and PM regions of the old rats were all significantly lower than those of the young and adult rats (all P < 0.01). CONCLUSION: The decrease of learning ability in old rat is positively correlated with the increase of free radicals and loss of neurons in hippocampus.

Discovery and Bioevaluation of Novel Pyrazolopyrimidine Analogs as Competitive Hsp90 Inhibitors Through Shape-Based Similarity Screening.

Hsp90 as a promising therapeutic target for the treatment of cancer has received great attention. Many Hsp90 inhibitors such as BIIB021 and CUDC-305 have been in clinical. In this paper shape-based similarity screening through ROCS overlays on the basis of CUDC-305, BIIB021, PU-H71 and PU-3 were performed to discover HSP90 inhibitors. A set of 19 novel pyrazolopyrimidine analogues was identified and evaluated on enzyme level and cell-based level as Hsp90 inhibitors. The compound HDI4-04 with IC50 0.35 µM in the Hsp90 ATP hydrolysis assay exhibited potent cytotoxicity against five human cancer cell lines. Western blot analysis and Hsp70 luciferase reporter assay further confirmed that HDI4-04 targeted the Hsp90 protein folding machinery. And according to the biological assay, the SAR was discussed and summarized, which will guide us for further optimization of these compounds.

Hybrids of the Benzofuran Core from Natural Products and the 2,4-Dihydroxy-5-isopropylbenzene Fragment as Potent Hsp90 Inhibitors: Design, Synthesis and Bioevaluation.

Several chemical fragments have been confirmed as highly efficient cores for the design of Hsp90 inhibitors. Molecular hybridization of potent fragments has been widely used as a rational drug discovery strategy. In this study, a novel class of hybrids of benzofuran, a privileged core from natural products, and 2,4-dihydroxy-5-isopropyl phenyl, an efficient fragment in Hsp90 inhibitors, were designed and synthesized. Subsequent evaluation confirmed they inhibited cell proliferation and regulated the level of client proteins through Hsp90 inhibition. Some of the hybrids can serve as leads to obtain novel chemotypes of Hsp90 inhibitors. The methods reported here may expand the range of known structural types accommodated by the ATP binding site of Hsp90.

Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening.

Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 ± 0.01 µM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization.

Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium channel inhibitors (part I).

Kv1.5 potassium channel is an efficacious and safe therapeutic target for the treatment of atrial fibrillation (AF), the most common arrhythmia that threatens human. Herein, by modifying the hit compound 7k from an in-house database, 48 derivatives were synthesized for the assay of their Kv1.5 inhibitory effects by whole cell patch clamp technique. Six compounds which showed better potency than the positive compound dronedarone were selected for the next evaluation of their drug-like properties. Compound 8 exhibited balanced solubility and permeability. It also showed acceptable pharmacodynamics profile with very low acute toxicity. Taking all these data into account, compound 8 can serve as a promising lead for the development of novel therapeutic agent for the treatment of AF.