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Ovarian cancer is the most lethal female reproductive system tumour. Despite the great advances in surgery and systemic chemotherapy over the past two decades, almost all patients in stages III and IV relapse and develop resistance to chemotherapy after first-line treatment. Ovarian cancer has an extraordinarily complex immunosuppressive tumour microenvironment in which immune checkpoints negatively regulate T cells activation and weaken antitumour immune responses by delivering immunosuppressive signals. Therefore, inhibition of immune checkpoints can break down the state of immunosuppression. Indeed, Immune checkpoint inhibitors (ICIs) have revolutionised the therapeutic landscape of many solid tumours. However, ICIs have yielded modest benefits in ovarian cancer. Therefore, a more comprehensive understanding of the mechanistic basis of the immune checkpoints is needed to improve the efficacy of ICIs in ovarian cancer. In this review, we systematically introduce the mechanisms and expression of immune checkpoints in ovarian cancer. Moreover, this review summarises recent updates regarding ICI monotherapy or combined with other small-molecule-targeted agents in ovarian cancer.
The subduction model of the Neo-Tethys during the Early Cretaceous has always been a controversial topic, and the scarcity of Early Cretaceous magmatic rocks in the southern part of the Gangdese batholith is the main cause of this debate. To address this issue, this article presents new zircon U–Pb chronology, zircon Hf isotope, whole-rock geochemistry and Sr–Nd isotope data for the Early Cretaceous quartz diorite dykes with adakite affinity in Liuqiong, Gongga. Zircon U–Pb dating of three samples yielded ages of c. 141–137 Ma, indicating that the Liuqiong quartz diorite was emplaced in the Early Cretaceous. The whole-rock geochemical analysis shows that the Liuqiong quartz diorite is enriched in large-ion lithophile elements (LILEs) and light rare-earth elements (LREEs) and is depleted in high-field-strength elements (HFSEs), which are related to slab subduction. Additionally, the Liuqiong quartz diorite has high SiO2, Al2O3 and Sr contents, high Sr/Y ratios and low heavy rare-earth element (HREE) and Y contents, which are compatible with typical adakite signatures. The initial 87Sr/86Sr values of the Liuqiong adakite range from 0.705617 to 0.705853, and the whole-rock ϵNd(t) values vary between +5.78 and +6.24. The zircon ϵHf(t) values vary from +11.5 to +16.4. Our results show that the Liuqiong adakite magma was derived from partial melting of the Neo-Tethyan oceanic plate (mid-ocean ridge basalt (MORB) + sediment + fluid), with some degree of subsequent peridotite interaction within the overlying mantle wedge. Combining regional data, we favour the interpretation that the Neo-Tethyan oceanic crust was subducted at a low angle beneath the Gangdese during the Early Cretaceous.
Sporadic clusters of healthcare-associated coronavirus disease 2019 (COVID-19) occurred despite intense rostered routine surveillance and a highly vaccinated healthcare worker (HCW) population, during a community surge of the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) B.1.617.2 δ (delta) variant. Genomic analysis facilitated timely cluster detection and uncovered additional linkages via HCWs moving between clinical areas and among HCWs sharing a common lunch area, enabling early intervention.
Bistabilities of two equilibrium states discovered in the coupled side-by-side Kármán wakes are investigated through Floquet analysis and direct numerical simulation (DNS) with different initial conditions over a range of gap-to-diameter ratio ($g^*= 0.2\text {--}3.5$) and Reynolds number ($Re = 47\text {--}100$). Two bistabilities are found in the transitional $g^*-Re$ regions from in-phase (IP) to anti-phase (AP) vortex shedding states. By initialising the flow in DNS with zero initial conditions, the flow in the first bistable region (i.e. bistable IP/FF$_C$ at $g^*= 1.4 \text {--} 2.0$, where FF$_C$ denotes the conditional flip-flop flow) attains flip-flop (FF) flow, it settles into the IP state by initialising the flow with an IP flow. The second bistability is observed between cylinder-scale IP and AP states at large $g^*$ ($=$ 2.0–3.5). The transition from the FF$_C$ to IP is dependent on initial conditions and irreversible over the parameter space, meaning that the flow cannot revert back to the FF$_C$ state once it jumps to the IP state irrespective of the direction of $Re$ variations. Its counterpart for the bistable IP/AP state is reversible. We also found that the FF$_C$ flow in the first bistable region is primarily bifurcated from synchronised AP with cluster-scale features, possibly because the cluster-scale AP flow is inherently unstable to FF flow instabilities. It is demonstrated that the irreversible bistability exists in other interacting wakes around multiple cylinders. A good understanding of flow bistabilities is pivotal to flow control applications and the interpretation of desynchronised flow features observed at high $Re$ values.
We focus on the population dynamics driven by two classes of truncated $\alpha$-stable processes with Markovian switching. Almost necessary and sufficient conditions for the ergodicity of the proposed models are provided. Also, these results illustrate the impact on ergodicity and extinct conditions as the parameter $\alpha$ tends to 2.
Staff surveillance is crucial during the containment phase of a pandemic to help reduce potential healthcare-associated transmission and sustain good staff morale. During an outbreak of SARS-COV-2 with community transmission, our institution used an integrated strategy for early detection and containment of COVID-19 cases among healthcare workers (HCWs).
Methods:
Our strategy comprised 3 key components: (1) enforcing reporting of HCWs with acute respiratory illness (ARI) to our institution’s staff clinic for monitoring; (2) conducting ongoing syndromic surveillance to obtain early warning of potential clusters of COVID-19; and (3) outbreak investigation and management.
Results:
Over a 16-week surveillance period, we detected 14 cases of COVID-19 among HCWs with ARI symptoms. Two of the cases were linked epidemiologically and thus constituted a COVID-19 cluster with intrahospital HCW–HCW transmission; we also detected 1 family cluster and 2 clusters among HCWs who shared accommodation. No transmission to HCWs or patients was detected after containment measures were instituted. Early detection minimized the number of HCWs requiring quarantine, hence preserving continuity of service during an ongoing pandemic.
Conclusions:
An integrated surveillance strategy, outbreak management, and encouraging individual responsibility were successful in early detection of clusters of COVID-19 among HCWs. With ongoing local transmission, vigilance must be maintained for intrahospital spread in nonclinical areas where social mingling of HCWs occurs. Because most individuals with COVID-19 have mild symptoms, addressing presenteeism is crucial to minimize potential staff and patient exposure.
Patients with COVID-19 may present with respiratory syndromes indistinguishable from those caused by common viruses. Early isolation and containment is challenging. Although screening all patients with respiratory symptoms for COVID-19 has been recommended, the practicality of such an effort has yet to be assessed.
Methods:
Over a 6-week period during a SARS-CoV-2 outbreak, our institution introduced a “respiratory surveillance ward” (RSW) to segregate all patients with respiratory symptoms in designated areas, where appropriate personal protective equipment (PPE) could be utilized until SARS-CoV-2 testing was done. Patients could be transferred when SARS-CoV-2 tests were negative on 2 consecutive occasions, 24 hours apart.
Results:
Over the study period, 1,178 patients were admitted to the RSWs. The mean length-of-stay (LOS) was 1.89 days (SD, 1.23). Among confirmed cases of pneumonia admitted to the RSW, 5 of 310 patients (1.61%) tested positive for SARS-CoV-2. This finding was comparable to the pickup rate from our isolation ward. In total, 126 HCWs were potentially exposed to these cases; however, only 3 (2.38%) required quarantine because most used appropriate PPE. In addition, 13 inpatients overlapped with the index cases during their stay in the RSW; of these 13 exposed inpatients, 1 patient subsequently developed COVID-19 after exposure. No patient–HCW transmission was detected despite intensive surveillance.
Conclusions:
Our institution successfully utilized the strategy of an RSW over a 6-week period to contain a cluster of COVID-19 cases and to prevent patient–HCW transmission. However, this method was resource-intensive in terms of testing and bed capacity.
Two-dimensional direct numerical simulations of a cylinder undergoing forced streamwise oscillations in steady approaching flow are conducted over ranges of oscillation amplitude, oscillation frequency and gap distance between the cylinder and the wall at a Reynolds number of 175. The flow characteristics are found to be strongly affected by the gap distance, compared to those observed around an isolated cylinder (Tang et al., J. Fluid Mech., vol. 832, 2017, pp. 146–169). The synchronisation modes are mapped out in the parameter ranges. The existence of the plane wall leads to an increased chance of occurrence of high-order modes with the denominator being an odd number. Two new flow phenomena, namely the period doubling and transition to quasi-periodic states through cascade of period doubling within the primary synchronisation region, are observed. The interaction of the plane-wall boundary layer with vortices shed from the cylinder and the asymmetry of the flow through the gap and around the top side of the cylinder are identified as the primary physical mechanisms responsible for the observed behaviours. The influence of velocity gradient in the plane-wall boundary layer on the two new phenomena is quantified through a numerical test involving linear shear flow around an isolated cylinder. The period-doubling phenomenon occurs only when the velocity gradient is larger than a critical value. The results obtained through three-dimensional simulations suggest that the synchronisation modes identified through two-dimensional simulations are not significantly affected by the three-dimensionality of the flow over the parameter ranges covered in the present study.
Transition to chaos through a cascade of period doublings of the primary $1/2$ synchronization mode is discovered in steady approaching flow around a forced inline oscillating cylinder near a plane boundary at a Reynolds number $(Re)$ of 175. The transition occurs well within the otherwise synchronized region (known as the Arnold tongue) in the frequency and amplitude space of the oscillating cylinder, creating two parameter strips of desynchronized flows within the Arnold tongue. Five orders of period doublings from mode $1/2$ to mode $16/32$ are revealed by progressively increasing the frequency resolution in the simulation. The ratio of frequency intervals of two successive period-doubling modes asymptotes towards the first Feigenbaum constant, reaching a value of 4.52 at mode of $16/32$. Additional three-dimensional simulations demonstrate the existence of period doubling with a regular spanwise flow structure similar to regular mode B of steady flow around an isolated cylinder. Although transition to chaos through cascades of period doublings is primarily reported for the primary $1/2$ synchronization mode, it is also observed for other synchronization modes $(p/q)$ (Tang et al., J. Fluid Mech., vol. 832, 2017, pp. 146–169), where $p$ and $q$ are integers with a non-reducible $p/q$, such as $2/3$. The physical mechanisms responsible for the present period-doubling bifurcations and transition to chaos through cascades of period doublings are ascribed to the interaction of asymmetric vortex shedding from the cylinder (due to a geometric asymmetry) and the boundary layer developed on the plane boundary, through specifically designed numerical tests.
Several observational studies have investigated the association of insomnia with psychiatric disorders. Such studies yielded mixed results, and whether these associations are causal remains unclear. Thus, we aimed to identify the causal relationships between insomnia and five major psychiatric disorders.
Methods:
The analysis was implemented with six genome-wide association studies; one for insomnia and five for psychiatric disorders (attention-deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder, schizophrenia, and bipolar disorder). A heterogeneity in dependent instrument (HEIDI) approach was used to remove the pleiotropic instruments, Mendelian randomization (MR)-Egger regression was adopted to test the validity of the screened instruments, and bidirectional generalized summary data-based MR was performed to estimate the causal relationships between insomnia and these major psychiatric disorders.
Results:
We observed significant causal effects of insomnia on the risk of autism spectrum disorder and bipolar disorder, with odds ratios of 1.739 (95% confidence interval: 1.217–2.486, p = 0.002) and 1.786 (95% confidence interval: 1.396–2.285, p = 4.02 × 10−6), respectively. There was no convincing evidence of reverse causality for insomnia with these two disorders (p = 0.945 and 0.546, respectively). When insomnia was considered as either the exposure or outcome variable, causal estimates for the remaining three psychiatric disorders were not significant.
Conclusions:
Our results suggest a causal role of insomnia in autism spectrum disorder and bipolar disorder. Future disease models should include insomnia as a factor for these two disorders to develop effective interventions. More detailed mechanism studies may also be inspired by this causal inference.
Androgenetic embryonic stem (AgES) cells offer a possible tool for patient-specific pluripotent stem cells that will benefit genomic imprinting studies and clinic applications. However, the difficulty in producing androgenetic embryos and the unbalanced expression of imprinted genes make the therapeutic applicability of AgES cells uncertain. In this study, we produced androgenetic embryos by injecting two sperm into an enucleated metaphase II (MII) oocyte. By this method, 88.48% of oocytes survived after injection, and 20.24% of these developed to the blastocyst stage. We successfully generated AgES cell lines from the androgenetic embryos and assayed the expression of imprinted genes in the cell lines. We found that the morphological characteristics of AgES cells were similar to that of fertilized embryonic stem cells (fES), such as expression of key pluripotent markers, and generation of cell derivatives representing all three germ layers following in vivo and in vitro differentiation. Furthermore, activation of paternal imprinted genes was detected, H19, ASC12 and Tss3 in AgES cell activation levels were lower while other examined genes showed no significant difference to that of fES cells. Interestingly, among examined maternal imprinted genes, only Mest and Igf2 were significantly increased, while levels of other detected genes were no different to that of fES cells. These results demonstrated that activation of some paternal imprinted genes, as well as recovery of maternal imprinted genes, was present in AgES cells. We differentiated AgES cells into a beating embryoid body in vitro, and discovered that the AgES cells did not show significant higher efficiency in myocardial differentiation potential.
Oscillatory flow around a cluster of four circular cylinders in a diamond arrangement is investigated using two-dimensional direct numerical simulation over Keulegan–Carpenter numbers (KC) ranging from 4 to 12 and Reynolds numbers (Re) from 40 to 230 at four gap-to-diameter ratios (G) of 0.5, 1, 2 and 4. Three types of flows, namely synchronous, quasi-periodic and desynchronized flows (along with 14 flow regimes) are mapped out in the (G, KC, Re)-parameter space. The observed flow characteristics around four cylinders in a diamond arrangement show a few unique features that are absent in the flow around four cylinders in a square arrangement reported by Tong et al. (J. Fluid Mech., vol. 769, 2015, pp. 298–336). These include (i) the dominance of flow around the cluster-scale structure at $G=0.5$ and 1, (ii) a substantial reduction of regime D flows in the regime maps, (iii) new quasi-periodic (phase trapping) $\text{D}^{\prime }$ (at $G=0.5$ and 1) and period-doubling $\text{A}^{\prime }$ flows (at $G=1$) and most noteworthily (iv) abnormal behaviours at ($G\leqslant 2$) (referred to as holes hereafter) such as the appearance of spatio-temporal synchronized flows in an area surrounded by a single type of synchronized flow in the regime map ($G=0.5$). The mode competition between the cluster-scale and cylinder-scale flows is identified as the key flow mechanism responsible for those unique flow features, with the support of evidence derived from quantitative analysis. Phase dynamics is introduced for the first time in bluff-body flows, to the best knowledge of the authors, to quantitatively interpret the flow response (e.g. quasi-periodic flow features) around the cluster. It is instrumental in revealing the nature of regime $\text{D}^{\prime }$ flows where the cluster-scale flow features are largely synchronized with the forcing of incoming oscillatory flow (phase trapping) but are modulated by localized flow features.
This paper presents a numerical investigation of oscillatory flow around a circular cylinder that is placed in proximity to a plane boundary that is parallel to the cylinder axis. The onset and development of the Honji instability are studied over a range of Stokes numbers ($\unicode[STIX]{x1D6FD}$) and gap-to-diameter ratios ($e/D$) at a fixed Keulegan–Carpenter number ($KC=2$). Four flow regimes are identified in the ($e/D,\unicode[STIX]{x1D6FD}$)-plane: (I) featureless two-dimensional flow, (II) stable Honji vortex, (III) unstable Honji vortex and (IV) chaotic flow. As $e/D$ increases from $-0.5$ (embedment) to $1$, the critical Stokes number $\unicode[STIX]{x1D6FD}_{cr}$ for the onset of the Honji instability follows two side-by-side convex functions, peaking at the connection point of $e/D=0.125$ and reaching troughs at $e/D=0$ and 0.375. The Honji instability is always initiated on the gap side of the cylinder surface for $0.375\leqslant e/D\leqslant 2$ and occurs only on the top side for $-0.5\leqslant e/D<0.125$. The location for the initiation of the Honji instability switches from the gap side to the top side of the cylinder surface for $0.125<e/D<0.375$. No Honji instability is observed at $e/D=0.125$, where the flow three-dimensionality is developed through a different flow mechanism. Consistently, the three-dimensional kinetic energy of the flow, which represents a measure of the strength of flow three-dimensionality, varies with $e/D$ in a trend opposite to that of $\unicode[STIX]{x1D6FD}_{cr}$. Three physical mechanisms are identified as being responsible for the observed variation trend of $\unicode[STIX]{x1D6FD}_{cr}$ with $e/D$ and for various flow phenomena, which are the blockage effect induced by the geometry setting, the existence of the Stokes layer on the plane boundary and the favourable pressure gradient in the flow direction over the gap between the cylinder and the plane surface.
This paper focuses on the characteristics of the regime C flow (Tatsuno & Bearman, J. Fluid Mech., vol. 211, 1990, pp. 157–182) around an oscillating circular cylinder in still water. The regime C flow is characterised by the formation of large-scale vortex cores arranged as opposed von Kármán vortex streets, resulting from a regular switching of vortex shedding directions with respect to the axis of oscillation. Both Floquet analysis and direct numerical simulations (DNS) are performed to investigate the two- (2-D) and three-dimensional (3-D) instabilities. The present study reveals that the low-wavenumber 3-D instability can emerge slightly before the 2-D instability in regime C. In total, five spanwise vortex modes were identified: (i) standing-wave pattern, S-mode; (ii) travelling-wave pattern, T-mode; (iii) mixed ST-mode; (iv) X-type vortex pattern, X-mode; and (v) U-type vortex pattern, U-mode. The modal analysis conducted in this study demonstrates that the vortex patterns and the corresponding spatial and temporal modulations of the dynamic loads of the S-, T- and mixed ST-modes are mainly induced by the 3-D instability of a single wavenumber. The characteristics of the X-mode are due to the superposition of the 3-D instabilities of multiple wavenumbers. The U-mode is dominated by a 2-D instability and its interaction with 3-D instabilities. The domain size dependence study demonstrates that the regime C flow is very sensitive to the spanwise length of the computational domain. The subcritical nature of the regime C flow is responsible for the discrepancy in the marginal stability curves obtained by independent Floquet stability analysis, DNS and physical experiments.
Oscillatory flow around a circular cylinder close to a plane boundary is numerically investigated at low-to-intermediate Keulegan–Carpenter ($KC$) and Stokes numbers ($\unicode[STIX]{x1D6FD}$) for different gap-to-diameter ratios ($e/D$). A set of unique flow regimes is observed and classified based on the established nomenclature in the ($KC,\unicode[STIX]{x1D6FD}$)-space. It is found that the flow is not only influenced by $e/D$ but also by the ratio of the thickness of the Stokes boundary layer ($\unicode[STIX]{x1D6FF}$) to the gap size (e). At relatively large $\unicode[STIX]{x1D6FF}/e$ values, vortex shedding through the gap is suppressed and vortices are only shed from the top of the cylinder. At intermediate values of $\unicode[STIX]{x1D6FF}/e$, flow through the gap is enhanced, resulting in horizontal gap vortex shedding. As $\unicode[STIX]{x1D6FF}/e$ is further reduced below a critical value, the influence of $\unicode[STIX]{x1D6FF}/e$ becomes negligible and the flow is largely dependent on $e/D$. A hysteresis phenomenon is observed for the transitions in the flow regime. The physical mechanisms responsible for the hysteresis and the variation of marginal stability curves with $e/D$ are explored at $KC=6$ through specifically designed numerical simulations. The Stokes boundary layer over the plane boundary is found to be responsible for the relatively large hysteresis range over $0.25<e/D<1.0$. Three mechanisms have been identified to the change of the marginal stability curve over $e/D$, which are the blockage effect due to the geometry setting, the favourable pressure gradient over the gap and the location of the leading eigenmode relative to the cylinder.
A numerical analysis of flow around a circular cylinder oscillating in-line with a steady flow is carried out over a range of driving frequencies $(f_{d})$ at relatively low amplitudes $(A)$ and a constant Reynolds number of 175 (based on the free-stream velocity). The vortex shedding is investigated, especially when the shedding frequency $(f_{s})$ synchronises with the driving frequency. A series of modes of synchronisation are presented, which are referred to as the $p/q$ modes, where $p$ and $q$ are natural numbers. When a $p/q$ mode occurs, $f_{s}$ is detuned to $(p/q)f_{d}$, representing the shedding of $p$ pairs of vortices over $q$ cycles of cylinder oscillation. The $p/q$ modes are further characterised by the periodicity of the transverse force over every $q$ cycles of oscillation and a spatial–temporal symmetry possessed by the global wake. The synchronisation modes $(p/q)$ with relatively small natural numbers are less sensitive to the change of external control parameters than those with large natural numbers, while the latter is featured with a narrow space of occurrence. Although the mode of synchronisation can be almost any rational ratio (as shown for $p$ and $q$ smaller than 10), the probability of occurrence of synchronisation modes with $q$ being an even number is much higher than $q$ being an odd number, which is believed to be influenced by the natural even distribution of vortices in the wake of a stationary cylinder.
A thin-film field-effect transistor (TFT) is a three-terminal device comprising source, drain, and gate electrodes, a dielectric layer, a semiconductor layer, and a substrate. The TFT is a fundamental building component in a variety of electronic devices. Developing an intrinsically stretchable TFT entails availability and usage of a functional material with elastomeric deformability in response to an externally applied stress. This represents a major materials challenge. In this article, we survey strategies to synthesize these elastomeric functional materials, and how these materials are assembled to fabricate intrinsically stretchable TFT devices. Developing solution-based printing technology to assemble intrinsically stretchable TFTs is considered a prospective strategy for wearable electronics for industrial adaptation in the near future.
Two-dimensional direct numerical simulation and Floquet stability analysis have been performed at moderate Keulegan–Carpenter number ($KC$) and low Reynolds number ($Re$) for a square cross-section cylinder with its face normal to the oscillatory flow. Based on the numerical simulations a map of flow regimes is formed and compared to the map of flow around an oscillating circular cylinder by Tatsuno & Bearman (J. Fluid Mech., vol. 211, 1990, pp. 157–182). Two new flow regimes have been observed, namely A$^{\prime }$ and F$^{\prime }$. The regime A$^{\prime }$ found at low $KC$ is characterised by the transverse convection of fluid particles perpendicular to the motion; and the regime F$^{\prime }$ found at high $KC$ shows a quasi-periodic feature with a well-defined secondary period, which is larger than the oscillation period. The Floquet analysis demonstrates that when the two-dimensional flow breaks the reflection symmetry about the axis of oscillation, the quasi-periodic instability and the synchronous instability with the imposed oscillation occur alternately for the square cylinder along the curve of marginal stability. This alternate pattern in instabilities leads to four distinct flow regimes. When compared to the vortex shedding in otherwise unidirectional flow, the two quasi-periodic flow regimes are observed when the oscillation frequency is close to the Strouhal frequency (or to half of it). Both the flow regimes and marginal stability curve shift in the $(Re,KC)$-space compared to the oscillatory flow around a circular cylinder and this shift appears to be consistent with the change in vortex formation time associated with the lower Strouhal frequency of the square cylinder.
crAssphage is a newly discovered gut bacteriophage. However, its pathogenicity and molecular epidemiology in humans are as yet unclear. In this study, we investigated the association between crAssphage and diarrhoea, as well as the molecular epidemiology of crAssphage in Chinese patients from our hospital. Our results indicated that there were no significant differences in the crAssphage-positive ratio and viral loads in faecal supernatants between adults with diarrhoea and healthy adults. Of infants and children with diarrhoea, 2·8% were found to be crAssphage-positive, including two infants aged <1 month. Markedly, of all confirmed crAssphage-positive strains, 100% had the ORF00039 deletion and 77·8% had low identity of ORF00018 compared to crAssphage (GenBank accession no. NC_024711, designated genotype 1). Thus, crAssphage was not associated with diarrhoea and most strains of crAssphage in Chinese patients (designated genotype 2) were characterized by the ORF00039 deletion and low identity of ORF00018.