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This paper presents a numerical study on the flow around two tandem circular cylinders beneath a free surface at a Reynolds number of $180$. The free-surface effects on the wake dynamics and hydrodynamic forces are investigated through a parametric study, covering a parameter space of gap ratios from $0.20$ to $2.00$, spacing ratios from $1.50$ to $4.00$ and Froude numbers from $0.2$ to $0.8$. A jet-like flow accompanied by a shear layer of positive vorticity separating from the free surface is formed in the wake at small gap ratios, which significantly alters the wake pattern through its dynamic behaviours. At shallow submergence depths, the three-dimensional wake transitions from mode B to mode A as the distance between the cylinders increases. As submergence depth increases, the wavy deformation of the primary vortex cores disappears in the wake, and the flow transitions to a two-dimensional state. Higher Froude numbers can extend the effect of the free surface to deeper submergence depths. The critical spacing ratio tends to be larger at higher Froude numbers. Furthermore, the free-surface deformation is examined. The free-surface profile typically comprises a hydraulic jump immediately ahead of the upstream cylinder, trapped waves in the vicinity of the two tandem cylinders and well-defined travelling waves on the downstream side. The frequencies of the waves cluster around the vortex shedding frequency, indicating a close association between the generation of waves and the vortex shedding process.
Timing of food intake is an emerging aspect of nutrition; however, there is a lack of research accurately assessing food timing in the context of the circadian system. The study aimed to investigate the relation between food timing relative to clock time and endogenous circadian timing with adiposity and further explore sex differences in these associations among 151 young adults aged 18–25 years. Participants wore wrist actigraphy and documented sleep and food schedules in real time for 7 consecutive days. Circadian timing was determined by dim-light melatonin onset (DLMO). The duration between last eating occasion and DLMO (last EO-DLMO) was used to calculate the circadian timing of food intake. Adiposity was assessed using bioelectrical impedance analysis. Of the 151 participants, 133 were included in the statistical analysis finally. The results demonstrated that associations of adiposity with food timing relative to circadian timing rather than clock time among young adults living in real-world settings. Sex-stratified analyses revealed that associations between last EO-DLMO and adiposity were significant in females but not males. For females, each hour increase in last EO-DLMO was associated with higher BMI by 0·51 kg/m2 (P = 0·01), higher percent body fat by 1·05 % (P = 0·007), higher fat mass by 0·99 kg (P = 0·01) and higher visceral fat area by 4·75 cm2 (P = 0·02), whereas non-significant associations were present among males. The findings highlight the importance of considering the timing of food intake relative to endogenous circadian timing instead of only as clock time.
EXOSC10 is an exosome-associated ribonuclease that degrades and processes a wide range of transcripts in the nucleus. The initial segment (IS) of the epididymis is crucial for sperm transport and maturation in mice by affecting the absorption and secretion that is required for male fertility. However, the role of EXOSC10 ribonuclease-mediated RNA metabolism within the IS in the regulation of gene expression and sperm maturation remains unknown. Herein, we established an Exosc10 conditional knockout (Exosc10 cKO) mouse model by crossing Exosc10F/F mice with Lcn9-Cre mice which expressed recombinase in the principal cells of IS as early as post-natal day 17. Morphological and histological analyses revealed that Exosc10 cKO males had normal spermatogenesis and development of IS. Moreover, the sperm concentration, morphology, motility, and frequency of acrosome reactions in the cauda epididymides of Exosc10 cKO mice were comparable with those of control mice. Thus, Exosc10 cKO males had normal fertility. Collectively, our genetic mouse model and findings demonstrate that loss of EXOSC10 in the IS of epididymis is dispensable for sperm maturation and male fertility.
The spatio-temporal scales, as well as a comprehensive self-sustained mechanism of the reattachment unsteadiness in shock wave/boundary layer interaction, are investigated in this study. Direct numerical simulations reveal that the reattachment unsteadiness of a Mach 7.7 laminar inflow causes over $26\,\%$ variation in wall friction and up to $20\,\%$ fluctuation in heat flux at the reattachment of the separation bubble. A statistical approach, based on the local reattachment upstream movement, is proposed to identify the spanwise and temporal scales of reattachment unsteadiness. It is found that two different types, i.e. self-induced and random processes, dominate different regions of reattachment. A self-sustained mechanism is proposed to comprehend the reattachment unsteadiness in the self-induced region. The intrinsic instability of the separation bubble transports vorticity downstream, resulting in an inhomogeneous reattachment line, which gives rise to baroclinic production of quasi-streamwise vortices. The pairing of these vortices initiates high-speed streaks and shifts the reattachment line upstream. Ultimately, viscosity dissipates the vortices, triggering instability and a new cycle of reattachment unsteadiness. The temporal scale and maximum vorticity are estimated with the self-sustained mechanism via order-of-magnitude analysis of the enstrophy. The advection speed of friction, derived from the assumption of coherent structures advecting with a Blasius-type boundary layer, aligns with the numerical findings.
Suppressing mode degradation is the key issue for high-power laser delivery; however, diagnosing mode degradation in its entirety, ranging from the contents and origins to locations, has always been a major obstacle. Here, a versatile approach for tracing the origins of mode coupling is demonstrated through addressing the differential intermodal dispersions of fiber modes. Full recognition for modal contents and the origins of mode degradation are experimentally completed in a two-mode fiber laser delivery system, which assists a significant improvement of beam quality M2 from 1.35 to 1.15 at the highest power of over 300 W. This method yields a quantitative characterization for manipulating the individual mode of dual-mode coupling origins or their combinations. This work points toward a promising strategy for the online tracing of mode coupling in cascade fiber links, thus enabling further pursuit of seeking extreme beam quality in high-power fiber laser systems.
Phase I clinical trials aim to find the highest dose of a novel drug that may be administrated safely without having serious adverse effects. Model-based designs have recently become popular in dose-finding procedures. Our objective is to provide an overview of phase I clinical trials in oncology.
Methods:
A retrospective analysis of phase I clinical trials in oncology was performed by using the PubMed database between January 1, 2020, and December 31, 2022. We extracted all papers with the inclusion of trials in oncology and kept only those in which dose escalation or/ and dose expansion were conducted. We also compared the study parameters, design parameters, and patient parameters between industry-sponsored studies and academia-sponsored research.
Result:
Among the 1450 papers retrieved, 256 trials described phase I clinical trials in oncology. Overall, 71.1% of trials were done with a single study cohort, 56.64% of trials collected a group of at least 20 study volunteers, 55.1% were sponsored by industry, and 99.2% of trials had less than 10 patients who experienced DLTs.
The traditional 3 + 3 (73.85%) was still the most prevailing method for the dose-escalation approach. More than 50% of the trials did not reach MTDs. Industry-sponsored study enrolled more patients in dose-escalation trials with benefits of continental cooperation. Compared to previous findings, the usage of model-based design increased to about 10%, and the percentage of traditional 3 + 3 design decreased to 74%.
Conclusions:
Phase I traditional 3 + 3 designs perform well, but there is still room for development in novel model-based dose-escalation designs in clinical practice.
This paper retrospectively analysed the prevalence of macrolide-resistant Mycoplasma pneumoniae (MRMP) in some parts of China. Between January 2013 and December 2019, we collected 4,145 respiratory samples, including pharyngeal swabs and alveolar lavage fluid. The highest PCR-positive rate of M. pneumoniae was 74.5% in Beijing, the highest resistance rate was 100% in Shanghai, and Gansu was the lowest with 20%. The highest PCR-positive rate of M. pneumoniae was 74.5% in 2013, and the highest MRMP was 97.4% in 2019; the PCR-positive rate of M. pneumoniae for adults in Beijing was 17.9% and the MRMP was 10.48%. Among the children diagnosed with community-acquired pneumonia (CAP), the PCR-positive and macrolide-resistant rates of M. pneumoniae were both higher in the severe ones. A2063G in domain V of 23S rRNA was the major macrolide-resistant mutation, accounting for more than 90%. The MIC values of all MRMP to erythromycin and azithromycin were ≥ 64 μg/ml, and the MICs of tetracycline and levofloxacin were ≤ 0.5 μg/ml and ≤ 1 μg/ml, respectively. The macrolide resistance varied in different regions and years. Among inpatients, the macrolide-resistant rate was higher in severe pneumonia. A2063G was the common mutation, and we found no resistance to tetracycline and levofloxacin.
Genes involved in melanin production directly impact insect pigmentation and can affect diverse physiology and behaviours. The role these genes have on sex behaviour, however, is unclear. In the present study, the crucial melanin pigment gene black was functionally characterised in an urban pest, the German cockroach, Blattella germanica. RNAi knockdown of B. germanica black (Bgblack) had no effect on survival, but did result in black pigmentation of the thoraxes, abdomens, heads, wings, legs, antennae, and cerci due to cuticular accumulation of melanin. Sex-specific variation in the pigmentation pattern was apparent, with females exhibiting darker coloration on the abdomen and thorax than males. Bgblack knockdown also resulted in wing deformation and negatively impacted the contact sex pheromone-based courtship behaviour of males. This study provides evidence for black function in multiple aspects of B. germanica biology and opens new avenues of exploration for novel pest control strategies.
As an environmental factor, temperature impacts the distribution of species and influences interspecific competition. The molecular chaperones encoded by small heat shock proteins (sHsps) are essential for rapid, appropriate responses to environmental stress. This study focuses on Hsp20.8, which encodes a temperature-responsive sHsp in Liriomyza trifolii, an insect pest that infests both agricultural and ornamental crops. Hsp20.8 expression was highest at 39℃ in L. trifolii pupae and adults, and expression levels were greater in pupae than in adults. Recombinant Hsp20.8 was expressed in Escherichia coli and conferred a higher survival rate than the empty vector to bacterial cells exposed to heat stress. RNA interference experiments were conducted using L. trifolii adults and prepupae and the knockdown of Hsp20.8 expression increased mortality in L. trifolii during heat stress. The results expand our understanding of sHsp function in Liriomyza spp. and the ongoing adaptation of this pest to climate change. In addition, this study is also important for predicting the distribution of invasive species and proposing new prevention and control strategies based on temperature adaptation.
Screen time in infancy is linked to changes in social-emotional development but the pathway underlying this association remains unknown. We aim to provide mechanistic insights into this association using brain network topology and to examine the potential role of parent–child reading in mitigating the effects of screen time.
Methods
We examined the association of screen time on brain network topology using linear regression analysis and tested if the network topology mediated the association between screen time and later socio-emotional competence. Lastly, we tested if parent–child reading time was a moderator of the link between screen time and brain network topology.
Results
Infant screen time was significantly associated with the emotion processing-cognitive control network integration (p = 0.005). This network integration also significantly mediated the association between screen time and both measures of socio-emotional competence (BRIEF-2 Emotion Regulation Index, p = 0.04; SEARS total score, p = 0.04). Parent–child reading time significantly moderated the association between screen time and emotion processing-cognitive control network integration (β = −0.640, p = 0.005).
Conclusion
Our study identified emotion processing-cognitive control network integration as a plausible biological pathway linking screen time in infancy and later socio-emotional competence. We also provided novel evidence for the role of parent–child reading in moderating the association between screen time and topological brain restructuring in early childhood.
Direct numerical simulations are performed to study temporal variations of the wall shear stresses and flow dynamics in the turbulent pulsatile pipe flow. The mechanisms, responsible for the paradoxical phenomenon for which the amplitude of the oscillating wall shear stress in the turbulent flow is smaller than that in the laminar flow for the same pulsation conditions, are investigated. It is shown that the delayed response of turbulence in the buffer layer generates a large magnitude of the radial gradient of the Reynolds shear stress near the wall, which counteracts the effect of the oscillating pressure gradient on the change of the streamwise velocity and hence reduces the amplitude of the wall shear stress. Such a delayed response consists of two processes: the delayed development of near-wall streaks and the subsequent energy redistribution from the streamwise velocity fluctuation to the other two co-existing components. This is a dynamical manifestation of the viscoelasticity of turbulent eddies. As the frequency is reduced, the variation of the friction Reynolds number results in a phase-wise variation of the time scale and intensity of the turbulence response, causing the hysteresis of the wall shear stress. Such a phase asymmetry is amplified by the increase of the pulsation amplitude. An examination of the energy spectra reveals that the near-wall streaks are stretched in the streamwise direction during the acceleration phase, and then break up into small-scale structures in the deceleration phase, accompanied by the enhanced dissipation that transforms the turbulent kinetic energy into heat.
Childhood maltreatment is an established risk factor for psychopathology. However, it remains unclear how childhood traumatic events relate to mental health problems and how the brain is involved. This study examined the serial mediation effect of brain morphological alterations and emotion-/reward-related functions on linking the relationship from maltreatment to depression. We recruited 156 healthy adolescents and young adults and an additional sample of 31 adolescents with major depressive disorder for assessment of childhood maltreatment, depressive symptoms, cognitive reappraisal and anticipatory/consummatory pleasure. Structural MRI data were acquired to identify maltreatment-related cortical and subcortical morphological differences. The mediation models suggested that emotional maltreatment of abuse and neglect, was respectively associated with increased gray matter volume in the ventral striatum and greater thickness in the middle cingulate cortex. These structural alterations were further related to reduced anticipatory pleasure and disrupted cognitive reappraisal, which contributed to more severe depressive symptoms among healthy individuals. The above mediating effects were not replicated in our clinical group partly due to the small sample size. Preventative interventions can target emotional and reward systems to foster resilience and reduce the likelihood of future psychiatric disorders among individuals with a history of maltreatment.
Landfill leachate is one of the most difficult effluents with which to deal from an environmental perspective because of its concentration and complex composition, including refractory and toxic components such as heavy metals or xenobiotic organic compounds. The objective of the present study was to use organically modified bentonite (OMB) to dispose of landfill leachate >10 y old. The OMB was synthesized using a new method, which removed four steps (filtering, washing, drying, and grinding) from the traditional process. After treatment using OMB, the chemical oxygen demand concentration (COD concentration, an index of the organic pollutants in the landfill leachate, was determined using the potassium dichromate method) of the landfill leachate sample decreased from 2400 to 245 mg/L in 5 h, i.e. the organic pollutants reduction efficiency was as high as 90%. Gas chromatography-mass spectrometry results indicated that most of the organic compounds were removed during the process. The modified and unmodified bentonite contained in the OMB deal with the hydrophobic and hydrophilic organic pollutants, respectively, resulting in significant degradation of the leachate. The study results have provided a new cost-effective method for treatment of landfill leachate.
The wide application of rare earth elements (REEs) in the development of a carbon–neutral society has urged resource exploration worldwide in recent years. Regolith-hosted REE deposits are a major source of global REE supply and are hosted mostly in clay minerals. Nonetheless, the ways in which changes in the physicochemical properties of clay minerals during weathering affect the concentrations of REEs in the regolith are not well known. In the current study, a world-class regolith-hosted REE deposit (Bankeng, South China) has been studied to illustrate further the effect of clay minerals on sorption and fractionation of REEs during weathering to form economic deposits. In the weathering profile, halloysite and illite are abundant in the saprolite due to weathering of feldspars and biotite from the bedrock. During weathering, halloysite and illite transform gradually to kaolinite and vermiculite. The large specific surface area, pore volume, and cation exchange capacity of the clay mineral assemblages are favorable to the sorption of REEs, probably because of the formation of vermiculite. The abundance of vermiculite could explain the enrichment of REEs in the upper part of the lower pedolith. For the saprolite-pedolith interface, halloysite is probably the main sorbent for the REEs, as indicated by the distinctive appearance of pore sizes of 2.4–2.8 nm characteristic of halloysite. The progressive transformation of halloysite to kaolinite reduces the pores and desorbs the REEs, causing REE depletion in the shallower soils. As a result, REEs were mobilized downward and re-sorbed in the lower pedolith-upper saprolite causing gradual enrichment and formation of these regolith-hosted deposits.
Energy loss of protons with 90 and 100 keV energies penetrating through a hydrogen plasma target has been measured, where the electron density of the plasma is about 1016 cm−3 and the electron temperature is about 1-2 eV. It is found that the energy loss of protons in the plasma is obviously larger than that in cold gas and the experimental results based on the Bethe model calculations can be demonstrated by the variation of effective charge of protons in the hydrogen plasma. The effective charge remains 1 for 100 keV protons, while the value for 90 keV protons decreases to be about 0.92. Moreover, two empirical formulae are employed to extract the effective charge.
Fast neutron absorption spectroscopy is widely used in the study of nuclear structure and element analysis. However, due to the traditional neutron source pulse duration being of the order of nanoseconds, it is difficult to obtain a high-resolution absorption spectrum. Thus, we present a method of ultrahigh energy-resolution absorption spectroscopy via a high repetition rate, picosecond duration pulsed neutron source driven by a terawatt laser. The technology of single neutron count is used, which results in easily distinguishing the width of approximately 20 keV at 2 MeV and an asymmetric shape of the neutron absorption peak. The absorption spectroscopy based on a laser neutron source has one order of magnitude higher energy-resolution power than the state-of-the-art traditional neutron sources, which could be of benefit for precisely measuring nuclear structure data.
The third-order law links energy transfer rates in the inertial range of magneto- hydrodynamic (MHD) turbulence with third-order structure functions. Anisotropy, a typical property in the solar wind, challenges the applicability of the third-order law with the isotropic assumption. To shed light on the energy transfer process in the presence of anisotropy, we conducted direct numerical simulations of forced MHD turbulence with normal and hyper-viscosity under various strengths of the external magnetic field ($B_0$), and calculated three forms of third-order structure function with or without averaging of the azimuthal or polar angles with respect to $B_0$ direction. Correspondingly, three estimated energy transfer rates were obtained. The result shows that the peak of normalized third-order structure function occurs at larger scales closer to the $B_0$ direction, and the maximum of longitudinal transfer rates shifts away from the $B_0$ direction at larger $B_0$. Compared with normal viscous cases, hyper-viscous cases can attain better separated inertial range, thus facilitating the estimation of the energy cascade rates. We find that the widespread use of the isotropic form of the third-order law in estimating the energy transfer rates is questionable in some cases, especially when the anisotropy arising from the mean magnetic field is inevitable. In contrast, the direction-averaged third-order structure function properly accounts for the effect of anisotropy and predicts the energy transfer rates and inertial range accurately, even at very high $B_0$. With limited statistics, the third-order structure function shows a stronger dependence on averaging of azimuthal angles than the time, especially for high $B_0$ cases. These findings provide insights into the anisotropic effect on the estimation of energy transfer rates.
Interactions between oblique second mode and oblique waves at a high-speed boundary at Mach 4.5 are studied using linear stability theory, nonlinear parabolized stability equations (NPSE) and direct numerical simulation (DNS). Parametric analysis based on the NPSE suggests that the oblique second mode can amplify both the oblique first and second modes, with the former experiencing a higher amplification. Our analysis reveals that the mean-flow distortion and difference mode contribute to this enhancement, with the latter exerting a key influence through the parametric resonance process. Kinetic energy transfer analysis demonstrates that the oblique waves gain energy from the mean flow, rather than from the oblique second mode. Furthermore, we find that the mechanism underlying the interaction between a pair of second oblique waves and a single oblique wave is similar to that between an oblique second mode and an oblique wave, as the steady modes generated by the pair of oblique second modes have a limited impact on the oblique wave. Finally, DNS confirms the validity of two transition paths proposed in this study based on the NPSE results. The first path suggests that a pair of low-amplitude second oblique waves alone are insufficient to cause oblique breakdown, but the introduction of a pair of low-amplitude damping first oblique modes could lead to boundary layer breakdown. The second path involves the formation of a domino-like effect through the combination of different types of oblique waves with the appropriate parameters. These two nonlinear paths can lead to a fully developed turbulent boundary layer.