bluuebunny/crossref_metadata_2025 huggingface dataset:
Growth of vortical disturbances entrained in the entrance region of a circular pipe
Authors: Ricco Pierre , Alvarenga Claudia
Published: December 2021

The development and growth of unsteady three-dimensional vortical disturbances entrained in the entry region of a circular pipe is investigated by asymptotic and numerical methods for Reynolds numbers between

$1000$

and

$10\,000$

, based on the pipe radius and the bulk velocity. Near the pipe mouth, composite asymptotic solutions describe the dynamics of the oncoming disturbances, revealing how these disturbances are altered by the viscous layer attached to the pipe wall. The perturbation velocity profiles near the pipe mouth are employed as rigorous initial conditions for the boundary-region equations, which describe the flow in the limit of low frequency and large Reynolds number. The disturbance flow is initially primarily present within the base-flow boundary layer in the form of streamwise-elongated vortical structures, i.e. the streamwise velocity component displays an intense algebraic growth, while the cross-flow velocity components decay. Farther downstream the disturbance flow occupies the whole pipe, although the base flow is mostly inviscid in the core. The transient growth and subsequent viscous decay are confined in the entrance region, i.e. where the base flow has not reached the fully developed Poiseuille profile. Increasing the Reynolds number and decreasing the frequency causes more intense perturbations, whereas small azimuthal wavelengths and radial characteristic length scales intensify the viscous dissipation of the disturbance. The azimuthal wavelength that causes the maximum growth is found. The velocity profiles are compared successfully with available experimental data and the theoretical results are helpful to interpret the only direct numerical dataset of a disturbed pipe-entry flow.
Tempered fractional LES modeling
Authors: Samiee Mehdi , Akhavan-Safaei Ali , Zayernouri Mohsen
Published: December 2021

The presence of non-local interactions and intermittent signals in the homogeneous isotropic turbulence grant multi-point statistical functions a key role in formulating a new generation of large-eddy simulation (LES) models of higher fidelity. We establish a tempered fractional-order modelling framework for developing non-local LES subgrid-scale models, starting from the kinetic transport. We employ a tempered Lévy-stable distribution to represent the source of turbulent effects at the kinetic level, and we rigorously show that the corresponding turbulence closure term emerges as the tempered fractional Laplacian,

$(\varDelta +\lambda )^{\alpha } (\cdot )$

, for

$\alpha \in (0,1)$

,

$\alpha \neq \frac {1}{2}$

and

$\lambda >0$

in the filtered Navier–Stokes equations. Moreover, we prove the frame invariant properties of the proposed model, complying with the subgrid-scale stresses. To characterize the optimum values of model parameters and infer the enhanced efficiency of the tempered fractional subgrid-scale model, we develop a robust algorithm, involving two-point structure functions and conventional correlation coefficients. In an a priori statistical study, we evaluate the capabilities of the developed model in fulfilling the closed essential requirements, obtained for a weaker sense of the ideal LES model (Meneveau, Phys. Fluids, vol. 6, issue 2, 1994, pp. 815–833). Finally, the model undergoes the a posteriori analysis to ensure the numerical stability and pragmatic efficiency of the model.
Interaction of cavitation bubbles with the interface of two immiscible fluids on multiple time scales
Authors: Han Rui , Zhang A-Man , Tan Sichao , Li Shuai
Published: December 2021

We experimentally, numerically and theoretically investigate the nonlinear interaction between a cavitation bubble and the interface of two immiscible fluids (oil and water) on multiple time scales. The underwater electric discharge method is utilized to generate a cavitation bubble near or at the interface. Both the bubble dynamics on a short time scale and the interface evolution on a much longer time scale are recorded via high-speed photography. Two mechanisms are found to contribute to the fluid mixing in our system. First, when a bubble is initiated in the oil phase or at the interface, an inertia-dominated high-speed liquid jet generated from the collapsing bubble penetrates the water–oil interface, and consequently transports fine oil droplets into the water. The critical standoff parameter for jet penetration is found to be highly dependent on the density ratio of the two fluids. Furthermore, the pinch-off of an interface jet produced long after the bubble dynamics stage is reckoned as the second mechanism, carrying water droplets into the oil bulk. The dependence of the bubble jetting behaviours and interface jet dynamics on the governing parameters is systematically studied via experiments and boundary integral simulations. Particularly, we quantitatively demonstrate the respective roles of surface tension and viscosity in interface jet dynamics. As for a bubble initiated at the interface, an extended Rayleigh–Plesset model is proposed that well predicts the asymmetric dynamics of the bubble, which accounts for a faster contraction of the bubble top and a downward liquid jet.
Linear instability of lid- and pressure-driven flows in channels textured with longitudinal superhydrophobic grooves
Authors: Tomlinson Samuel D. , Papageorgiou Demetrios T.
Published: December 2021

It is known that an increased flow rate can be achieved in channel flows when smooth walls are replaced by superhydrophobic surfaces. This reduces friction and increases the flux for a given driving force. Applications include thermal management in microelectronics, where a competition between convective and conductive resistance must be accounted for in order to evaluate any advantages of these surfaces. Of particular interest is the hydrodynamic stability of the underlying basic flows, something that has been largely overlooked in the literature, but is of key relevance to applications that typically base design on steady states or apparent-slip models that approximate them. We consider the global stability problem in the case where the longitudinal grooves are periodic in the spanwise direction. The flow is driven along the grooves by either the motion of a smooth upper lid or a constant pressure gradient. In the case of smooth walls, the former problem (plane Couette flow) is linearly stable at all Reynolds numbers whereas the latter (plane Poiseuille flow) becomes unstable above a relatively large Reynolds number. When grooves are present our work shows that additional instabilities arise in both cases, with critical Reynolds numbers small enough to be achievable in applications. Generally, for lid-driven flows one unstable mode is found that becomes neutral as the Reynolds number increases, indicating that the flows are inviscidly stable. For pressure-driven flows, two modes can coexist and exchange stability depending on the channel height and slip fraction. The first mode remains unstable as the Reynolds number increases and corresponds to an unstable mode of the two-dimensional Rayleigh equation, while the second mode becomes neutrally stable at infinite Reynolds numbers. Comparisons of critical Reynolds numbers with the experimental observations for pressure-driven flows of Daniello et al. (Phys. Fluids, vol. 21, issue 8, 2009, p. 085103) are encouraging.
Lochkovian (Lower Devonian) conodonts from the Alengchu section, western Yunnan, China
Authors: Lu Jian-Feng , Ma Xue-Ping , Qie Wen-Kun , Liang Kun , Chen Bo
Published: December 2021

The Lochkovian (Lower Devonian) conodont biostratigraphy in China is poorly known, and conodont-based subdivision schemes for the Lochkovian in peri-Gondwana (the Spanish Central Pyrenees, the Prague Synform, Sardinia, and the Carnic Alps) have not been tested in China. Therefore, we studied conodonts from the lower part (Bed 9 to Bed 13) of the Shanjiang Formation at the Alengchu section of Lijiang, western Yunnan to test the application of established subdivision schemes. The conodont fauna is assignable to 12 taxa belonging to eight genera (Ancyrodelloides, Flajsella, Lanea, Wurmiella, Zieglerodina, Caudicriodus, Pelekysgnathus, and Pseudooneotodus), and enables recognition of two chronostratigraphical intervals from the lower part of the Shanjiang Formation. The interval ranging from the uppermost part of Bed 9 to the upper part of Bed 10 belongs to the lower Lochkovian; whereas an interval covering the uppermost part of Bed 11 to the upper part of Bed 13 is correlated with the upper half of the middle Lochkovian. The Silurian-Devonian boundary is probably located within Bed 9, in the basal part of the Shanjiang Formation. However, the scarcity of specimens precludes definitive identification of bases of the lower, middle, and upper Lochkovian as well as other conodont zones recognized in peri-Gondwana.
Implementing Partisan Symmetry: Problems and Paradoxes
Authors: DeFord Daryl , Dhamankar Natasha , Duchin Moon , Gupta Varun , McPike Mackenzie , Schoenbach Gabe , Sim Ki Wan
Published: December 2021

We consider the measures of partisan symmetry proposed for practical use in the political science literature, as clarified and developed in Katz, King, and Rosenblatt (2020, American Political Science Review 114, 164–178). Elementary mathematical manipulation shows the symmetry metrics to have surprising properties that call their meaningfulness into question. To accompany the general analysis, we study measures of partisan symmetry with respect to recent voting patterns in Utah, Texas, and North Carolina, flagging problems in each case. Taken together, these observations should raise major concerns about the available techniques for quantitative scores of partisan symmetry—including the mean–median score, the partisan bias score, and the more general “partisan symmetry standard”—with the decennial redistricting underway.
Simple dynamics in non-monotone Kolmogorov systems
Authors: Niu Lei , Ruiz-Herrera Alfonso
Published: December 2021

In this paper we analyse the global dynamical behaviour of some classical models in the plane. Informally speaking we prove that the folkloric criteria based on the relative positions of the nullclines for Lotka–Volterra systems are also valid in a wide class of discrete systems. The method of proof consists of dividing the plane into suitable positively invariant regions and applying the theory of translation arcs in a subtle manner. Our approach allows us to extend several results of the theory of monotone systems to nonmonotone systems. Applications in models with weak Allee effect, population models for pioneer-climax species, and predator–prey systems are given.
AN APPLICATION OF SCHUR’S ALGORITHM TO VARIABILITY REGIONS OF CERTAIN ANALYTIC FUNCTIONS II
Authors: ALI MD FIROZ , ALLU VASUDEVARAO , YANAGIHARA HIROSHI
Published: December 2021

We extend our study of variability regions, Ali et al. [‘An application of Schur algorithm to variability regions of certain analytic functions–I’, Comput. Methods Funct. Theory, to appear] from convex domains to starlike domains. Let
$\mathcal {CV}(\Omega )$
be the class of analytic functions f in
${\mathbb D}$
with
$f(0)=f'(0)-1=0$
satisfying
$1+zf''(z)/f'(z) \in {\Omega }$
. As an application of the main result, we determine the variability region of
$\log f'(z_0)$
when f ranges over
$\mathcal {CV}(\Omega )$
. By choosing a particular
$\Omega $
, we obtain the precise variability regions of
$\log f'(z_0)$
for some well-known subclasses of analytic and univalent functions.
The development of linguistic stimuli for the Swedish Situated Phoneme test
Authors: Witte Erik , Ekeroot Jonas , Köbler Susanne
Published: December 2021

The speech perception ability of people with hearing loss can be efficiently measured using phonemic-level scoring. We aimed to develop linguistic stimuli suitable for a closed-set phonemic discrimination test in the Swedish language called the Situated Phoneme (SiP) test. The SiP test stimuli that we developed consisted of real monosyllabic words with minimal phonemic contrast, realised by phonetically similar phones. The lexical and sublexical factors of word frequency, phonological neighbourhood density, phonotactic probability, and orthographic transparency were similar between all contrasting words. Each test word was recorded five times by two different speakers, including one male and one female. The accuracy of the test-word recordings was evaluated by 28 normal-hearing subjects in a listening experiment with a silent background using a closed-set design. With a few exceptions, all test words could be correctly discriminated. We discuss the results in terms of content- and construct-validity implications for the Swedish SiP test.
Impact of the COVID-19 pandemic on human salmonellosis in the Netherlands
Authors: Mughini-Gras Lapo , Chanamé Pinedo Linda , Pijnacker Roan , van den Beld Maaike , Wit Ben , Veldman Kees , Bosh Thijs , Franz Eelco
Published: December 2021

The public health measures implemented to control coronavirus disease 2019 (COVID-19) may influence also other infectious diseases. Using national laboratory surveillance data, we assessed the impact of the COVID-19 pandemic on human salmonellosis in the Netherlands until March 2021. Salmonellosis incidence decreased significantly after March 2020: in the second, third and fourth quarters of 2020, and in the first quarter of 2021, the incidence decreased by 55%, 57%, 47% and 37%, respectively, compared to the same quarters of 2016–2019. The decrease was strongest among travel-related cases (94%, 84%, 79% and 93% in the aforementioned quarters, respectively). Other significant changes were: increased proportion of cases among older adults and increased proportion of invasive infections, decreased proportion of trimethoprim resistance and increased proportion of serovar Typhimurium monophasic variant vs. Enteritidis. This led to decreased contributions of laying hens and increased contributions of pigs and cattle as sources of human infections. The observed changes probably reflect a combination of reduced exposure to Salmonella due to restrictions on international travels and gatherings, closure of dine-in restaurants, catering and hospitality sectors at large and changes in healthcare-seeking and diagnostic behaviours.
Dilated cardiomyopathy associated with a mutation in the dispatched RND transporter family member 1 gene
Authors: Torpoco Rivera Diana M. , Hafzalah Mina , Pomerantz Daniel J. , Garcia Richard U.
Published: December 2021

Dilated cardiomyopathy is the most common presentation of cardiomyopathy in children with 20–35% of patients having an identified genetic component. There are more than 30 genes implicated in the pathogenesis of dilated cardiomyopathy. We present the first report of a female infant with dilated cardiomyopathy with a genetic variant in the dispatched RND transporter family member 1 gene.
A gray zone in the literature: indications, options, and outcomes for surgical repair of pulmonary artery aneurysms
Authors: Arslanoglu Ergin , Kara Kenan Abdurrahman , Yigit Fatih , Arkan Cüneyt , Ozcan Esra , Arısut Seda , Uslu Ufuk , Cine Nihat , Tuncer Eylem , Ceyran Hakan
Published: December 2021

Pulmonary artery aneurysms are rare. They are characterised by an aneurysmatic dilatation of the pulmonary vascular bed, including the main pulmonary artery or the accompanying pulmonary artery branches. Increases in pulmonary flow and pulmonary artery pressure increase the risk of rupture: when these conditions are detected, surgical intervention is necessary.

This study is a retrospective analysis of 33 patients treated in our paediatric cardiac surgery clinic from 2012 to 2020. Aneurysms and pseudoaneurysms in patients who were patched for right ventricular outflow tract reconstruction and corrected with a conduit were excluded from the study. Seventeen (51.5%) of the patients included in the study were female and 16 (48.5%) were male. The patients were aged between 23 and 61 years (mean 30.66 ± 12.72 years). Graft interpositions were performed in 10 patients (30.3%) and pulmonary artery plications were performed in 23 patients (69.7%) to repair aneurysms. There was no significant difference in mortality between the two groups (p > 0.05).

Pulmonary artery aneurysm interventions are safe, life-saving treatments that prevent fatal complications such as ruptures, but at present there is no clear guidance regarding surgical timing or treatment strategies. Pulmonary artery interventions should be performed in symptomatic patients with dilations ≥5 cm or asymptomatic patients with dilations ≥8 cm; pulmonary artery pressure, right ventricular systolic pressure, and pulmonary artery aneurysm diameter must be considered when planning surgeries, their timing, and making decisions regarding indications. Experienced surgical teams can achieve satisfactory results using one of the following surgical techniques: reduction pulmonary arterioplasty, plication, or graft replacement.
On critical hope and the anthropos of non-anthropocentric discourses. Some thoughts on archaeology in the Anthropocene
Authors: Hacıgüzeller Piraye
Published: December 2021

In this essay I scrutinize the non-anthropocentric discourses used by the social sciences and humanities narratives and critiques of the Anthropocene. Although not always predominant within the academic Anthropocene debate, such discursive strands remain politically and ethically inspiring and influential in that debate and for the public discourse concerning the epoch. I stress that these discourses inherit the hope for human progress that characterizes critical theory of the Frankfurt school, i.e. ‘critical hope’, a type of hope that renders the non-anthropocentric discourses self-contradictory. Even when they manage to escape the hold of critical hope, these discourses, I argue, suffer from ethical and political failings due to their inherent lack of focus on human–human relations and largely ahistorical nature. I conclude the essay by advocating an Anthropocene archaeology that remains critical of and learns from the ethical and political shortcomings of non-anthropocentric perspectives and making a related call for a slow archaeology of the Anthropocene.
Political–Economic Determinants of External Import Protection under a Preferential Trade Agreement
Authors: Tovar Patricia
Published: December 2021

The stalling of WTO multilateralism and the proliferation of preferential trade agreements in recent decades have drawn substantial attention to the impacts of preferential liberalization. A critical question is how they affect the trade barriers imposed against outsiders. I examine the relationship between preferential trade liberalization and protection against non-member countries by testing the predictions of a political–economy model based on the previous literature. Focusing on a specific model allows me to uncover the mechanisms via which preferential liberalization affects external import protection, whereas most of the existing literature has focused on establishing the sign of the effect only. Furthermore, I focus on not only tariffs, as most studies do, but also on the temporary trade barriers of antidumping and safeguards. I test the predictions for Latin America and obtain results that provide solid evidence supporting two mechanisms from the theory, which lead to lower protection against non-members of a preferential trade agreement. First, a lower preferential import protection level means that the increase in preferential imports from increasing the external tariff creates a smaller increase in tariff revenue. Second, as preferential import protection is cut, there is a decrease in the markup and sales of domestic firms, and thus raising the external import protection generates less profit. Moreover, this second effect is present when the political motivation of the government is sufficiently strong.
Can we determine burdensome transitions in the last year of life based on time of occurrence and frequency? An explanatory mixed-methods study
Authors: Schippel Nicolas , Dust Gloria , von Reeken Christian , Voltz Raymond , Strupp Julia , Rietz Christian
Published: December 2021

Objective

Burdensome transitions are typically defined as having a transition in the last three days or multiple hospitalizations in the last three months of life, which is seldom verified with qualitative accounts from persons concerned. This study analyses types and frequencies of transitions in the last year of life and indicators of burdensome transitions from the perspective of bereaved relatives.

Method

Cross-sectional explanatory mixed-methods study with 351 surveyed and 41 interviewed bereaved relatives in a German urban area. Frequencies, t-tests, and Spearman correlations were computed for quantitative data. Qualitative data were analyzed using content analysis with provisional and descriptive coding/subcoding.

Results

Transitions rise sharply during the last year of life. 8.2% of patients experience a transition in the last three days and 7.8% three or more hospitalizations in the last three months of life. An empathetic way of telling patients about the prospect of death is associated with fewer transitions in the last month of life (r = 0.185, p = 0.046). Professionals being aware of the preferred place of death corresponds to fewer hospitalizations in the last three months of life (1.28 vs. 0.97, p = 0.021). Qualitative data do not confirm that burden in transitions is linked to having transitions in the last three days or multiple hospitalizations in the last three months of life. Burden is associated with (1) late and non-empathetic communication about the prospect of death, (2) not coordinating care across settings, and (3) not considering patients’ preferences.

Significance of results

Time of occurrence and frequency appear to be imperfect proxies for burdensome transitions. The subjective burden seems to be associated rather with insufficient information, preparation, and management of transitions.
De novo assembly, annotation and molecular marker identification from the leaf transcriptome of Ocimum gratissimum L.
Authors: Tanuja  , Parasar Nibir Ranjan , Kumar Ravichandiran , Natarajan Purushothaman , Parani Madasamy
Published: December 2021

Ocimum gratissimum L. is a well-known medicinal plant with several therapeutic properties, but molecular studies on this species are lacking. Therefore, we have sequenced the whole transcriptome from the leaves of O. gratissimum and assembled 121,651 transcripts. The transcriptome of O. gratissimum was closely related to Sesamum indicum and Erythranthe guttata in congruence with the molecular phylogenetic relationships among these species. Further, 62,194 transcripts were annotated and classified according to the GO terms concerning the biological process, cellular component and metabolic function. In the KEGG pathway analysis, 34,876 transcripts were mapped to 149 pathways and 1410 of them were involved in the biosynthesis of secondary metabolites. In the phenylpropanoid pathway, 101 transcripts were associated with the biosynthesis of eugenol, the principal constituent of the essential oil of O. gratissimum. In the caffeine metabolism pathway, none of the transcripts was related to caffeine biosynthesis, supportive of the caffeine-free nature of Ocimum. Transcripts coding for the metallothionein were abundant in the leaves, supporting the observation that O. gratissimum is an accumulator of heavy metals. We also identified the 930 transcripts coding for 59 transcription factors families with myeloblastosis transcription factors being the most predominant. About 6500 simple sequence repeats were identified, which will be useful in DNA marker-based applications. This is the first report of the leaf transcriptome of O. gratissimum, which will serve as an essential resource for further molecular studies in this important medicinal species.
Small- and Wide-Angle X-Ray Scattering (SAXS/WAXS) with Temperature-Controlled Stages Makes Phase Identification Faster than Ever
Authors: Wu Han , Stacey Duncan
Published: December 2021

X-ray diffraction (XRD) is a fingerprint technique for the analysis of atomic and molecular structures of crystalline materials, from polymers and plastics, through to structural composites and biomaterials. These all have crystallographic phases in the nanostructure, which greatly influence the macro properties of the material—from insulin and hemoglobin to semiconductors and solar cells. Here, we look at how XRD analysis using a small- and wide-angle X-ray scattering (SAXS/WAXS) system under full vacuum brings the possibility of crystallographic sample characterization, with temperature and environmental control, direct to the laboratory, and how this improves the workflow for phase identification.
The lack of statistical power of subgroup analyses in meta-analyses: a cautionary note
Authors: Cuijpers Pim , Griffin Jason W. , Furukawa Toshi A.
Published: December 2021

One of the most used methods to examine sources of heterogeneity in meta-analyses is the so-called ‘subgroup analysis’. In a subgroup analysis, the included studies are divided into two or more subgroups, and it is tested whether the pooled effect sizes found in these subgroups differ significantly from each other. Subgroup analyses can be considered as a core component of most published meta-analyses. One important problem of subgroup analyses is the lack of statistical power to find significant differences between subgroups. In this paper, we explore the power problems of subgroup analyses in more detail, using ‘metapower’, a recently developed statistical package in R to examine power in meta-analyses, including subgroup analyses. We show that subgroup analyses require many more included studies in a meta-analysis than are needed for the main analyses. We work out an example of an ‘average’ meta-analysis, in which a subgroup analysis requires 3–4 times the number of studies that are needed for the main analysis to have sufficient power. This number of studies increases exponentially with decreasing effect sizes and when the studies are not evenly divided over the subgroups. Higher heterogeneity also requires increasing numbers of studies. We conclude that subgroup analyses remain an important method to examine potential sources of heterogeneity in meta-analyses, but that meta-analysts should keep in mind that power is very low for most subgroup analyses. As in any statistical evaluation, researchers should not rely on a test and p-value to interpret results, but should compare the confidence intervals and interpret results carefully.
Characterizing Methane Emission Hotspots From Thawing Permafrost
Authors: Elder C. D. , Thompson D. R. , Thorpe A. K. , Chandanpurkar H. A. , Hanke P. J. , Hasson N. , James S. R. , Minsley B. J. , Pastick N. J. , Olefeldt D. , Walter Anthony K. M. , Miller C. E.
Published: December 2021

Methane (CH4) emissions from climate‐sensitive ecosystems within the northern permafrost region represent a potentially large but highly uncertain source, with current estimates spanning a factor of seven (11–75 Tg CH4 yr−1). Accelerating permafrost thaw threatens significant increases in pan‐Arctic CH4 emissions, amplifying the permafrost carbon feedback. We used airborne imaging spectroscopy with meter‐scale spatial resolution and broad coverage to identify a previously undiscovered CH4 emission hotspot adjacent to a thermokarst lake in interior Alaska. Hotspot emissions were confined to <1% of the 10 ha lake study area. Ground‐based chamber measurements confirmed average daily fluxes from the hotspot of 1,170 mg CH4 m−2 d−1, with extreme daily maxima up to 24,200 mg CH4 m−2 d−1. Ground‐based geophysical measurements revealed thawed permafrost directly beneath the CH4 hotspot, extending to a depth of ∼15 m, indicating that the intense CH4 emissions likely originated from recently thawed permafrost. Hotspot emissions accounted for ∼40% of total diffusive CH4 emissions from the lake study site. Combining study site findings with hotspot statistics from our 70,000 km2 airborne survey across Alaska and northwestern Canada, we estimate that pan‐Arctic terrestrial thermokarst hotspots currently emit 1.1 (0.1–5.2) Tg CH4 yr−1, or roughly 4% of the annual pan‐Arctic wetland budget from just 0.01% of the northern permafrost land area. Our results suggest that significant proportions of pan‐Arctic CH4 emissions originate from disproportionately small areas of previously undetermined thermokarst emissions hotspots, and that pan‐Arctic CH4 emissions may increase non‐linearly as thermokarst processes increase under a warming climate.
Regulation of common neurological disorders by gut microbial metabolites
Authors: Park Jeongho , Kim Chang H.
Published: December 2021

The gut is connected to the CNS by immunological mediators, lymphocytes, neurotransmitters, microbes and microbial metabolites. A mounting body of evidence indicates that the microbiome exerts significant effects on immune cells and CNS cells. These effects frequently result in the suppression or exacerbation of inflammatory responses, the latter of which can lead to severe tissue damage, altered synapse formation and disrupted maintenance of the CNS. Herein, we review recent progress in research on the microbial regulation of CNS diseases with a focus on major gut microbial metabolites, such as short-chain fatty acids, tryptophan metabolites, and secondary bile acids. Pathological changes in the CNS are associated with dysbiosis and altered levels of microbial metabolites, which can further exacerbate various neurological disorders. The cellular and molecular mechanisms by which these gut microbial metabolites regulate inflammatory diseases in the CNS are discussed. We highlight the similarities and differences in the impact on four major CNS diseases, i.e., multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and autism spectrum disorder, to identify common cellular and molecular networks governing the regulation of cellular constituents and pathogenesis in the CNS by microbial metabolites.
GTF2E2 is a novel biomarker for recurrence after surgery and promotes progression of esophageal squamous cell carcinoma via miR-139-5p/GTF2E2/FUS axis
Authors: Zhang Yujie , Zhang Yuxin , Ai Bo , Gong Juejun , Li Yichen , Yu Shiying , Cai Xiuyu , Zhang Li
Published: December 2021

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal gastrointestinal malignancies with high mortality. Recurrence develops within only a few years after curative resection and perioperative adjuvant therapy in 30–50% of these patients. Therefore, it is essential to identify postoperative recurrence biomarkers to facilitate selecting the following surveillance and therapeutic strategies. The general transcription factor IIE subunit beta (GTF2E2) is crucial for physiological and pathological functions, but its roles in the aggression and recurrence of ESCC remain ambiguous. In this study, we found that GTF2E2 was highly expressed in ESCC samples, and elevated GTF2E2 expression predicted early recurrence after surgery for ESCC patients. High expression of GTF2E2 associated with more aggressive clinic features and poor prognosis. GTF2E2 promoted the proliferation and mobility of ESCC cells in vitro and in vivo. We further revealed that miR-139-5p repressed GTF2E2 expression by downregulating its mRNA through binding with Argonaute 2 (Ago2). Rescue assays suggested that miR-139-5p affected GTF2E2-mediated ESCC progression. Moreover, GTF2E2 positively interacted with FUS promoter and regulated FUS expression, and the phenotype changes caused by GTF2E2 manipulation were recovered by rescuing FUS expression in ESCC cells. Additionally, we demonstrated that GTF2E2 promotes ESCC cells progression via activation of the AKT/ERK/mTOR pathway. In conclusion, GTF2E2 may serve as a novel biomarker for recurrence after surgery and a potential therapeutic target for ESCC patients, and it promotes ESCC progression via miR-139-5p/GTF2E2/FUS axis.
Secreted frizzled related-protein 2 (Sfrp2) deficiency decreases adult skeletal stem cell function in mice
Authors: de Castro Luis Fernandez , Sworder Brian J. , Mui Byron , Futrega Kathryn , Berendsen Agnes , Phillips Matthew D. , Burbach Nathan J. , Cherman Natasha , Kuznetsov Sergei , Gabet Yankel , Holmbeck Kenn , Robey Pamela G.
Published: December 2021

In a previous transcriptomic study of human bone marrow stromal cells (BMSCs, also known as bone marrow-derived “mesenchymal stem cells”), SFRP2 was highly over-represented in a subset of multipotent BMSCs (skeletal stem cells, SSCs), which recreate a bone/marrow organ in an in vivo ectopic bone formation assay. SFRPs modulate WNT signaling, which is essential to maintain skeletal homeostasis, but the specific role of SFRP2 in BMSCs/SSCs is unclear. Here, we evaluated Sfrp2 deficiency on BMSC/SSC function in models of skeletal organogenesis and regeneration. The skeleton of Sfrp2-deficient (KO) mice is overtly normal; but their BMSCs/SSCs exhibit reduced colony-forming efficiency, reflecting low SSC self-renewal/abundancy. Sfrp2 KO BMSCs/SSCs formed less trabecular bone than those from WT littermates in the ectopic bone formation assay. Moreover, regeneration of a cortical drilled hole defect was dramatically impaired in Sfrp2 KO mice. Sfrp2-deficient BMSCs/SSCs exhibited poor in vitro osteogenic differentiation as measured by Runx2 and Osterix expression and calcium accumulation. Interestingly, activation of the Wnt co-receptor, Lrp6, and expression of Wnt target genes, Axin2, C-myc and Cyclin D1, were reduced in Sfrp2-deficient BMSCs/SSCs. Addition of recombinant Sfrp2 restored most of these activities, suggesting that Sfrp2 acts as a Wnt agonist. We demonstrate that Sfrp2 plays a role in self-renewal of SSCs and in the recruitment and differentiation of adult SSCs during bone healing. SFRP2 is also a useful marker of BMSC/SSC multipotency, and a factor to potentially improve the quality of ex vivo expanded BMSC/SSC products.
PIAS1 alleviates diabetic peripheral neuropathy through SUMOlation of PPAR-γ and miR-124-induced downregulation of EZH2/STAT3
Authors: Hou Zixin , Chen Ji , Yang Huan , Hu Xiaoling , Yang Fengrui
Published: December 2021

Diabetic peripheral neuropathy (DPN) is a frequently occurring chronic complication of diabetes. In this study, we aim to explore the regulatory mechanism of protein inhibitor of activated STAT1 (PIAS1) in DPN in terms of autophagy and apoptosis of Schwann cells. The SUMOlation of PPAR-γ by PIAS1 was examined, and ChIP was performed to verify the binding of PPAR-γ to miR-124 promoter region. Dual-luciferase gene reporter assay was used to validate the binding affinity between miR-124 and EZH2/STAT3. Following loss‐ and gain‐of-function experiments, in vitro assays in high glucose-treated Schwann cells (SC4) and in vivo assays in db/db and ob/ob mice were performed to detect the effects of PIAS1 on autophagy and apoptosis of Schwann cells as well as symptoms of DPN by regulating the PPAR-γ-miR-124-EZH2/STAT3. The expression of PIAS1, PPAR-γ, and miR-124 was downregulated in the sciatic nerve tissue of diabetic mice. PIAS1 enhanced the expression of PPAR-γ through direct binding and SUMOlation of PPAR-γ. PPAR-γ enhanced the expression of miR-124 by enhancing the promoter activity of miR-124. Furthermore, miR-124 targeted and inversely modulated EZH2 and STAT3, promoting the autophagy of Schwann cells and inhibiting their apoptosis. In vivo experiments further substantiated that PIAS1 could promote the autophagy and inhibit the apoptosis of Schwann cells through the PPAR-γ-miR-124-EZH2/STAT3 axis. In conclusion, PIAS1 promoted SUMOlation of PPAR-γ to stabilize PPAR-γ expression, which upregulated miR-124 to inactivate EZH2/STAT3, thereby inhibiting apoptosis and promoting autophagy of Schwann cells to suppress the development of DPN.
The cytosolic iron–sulfur cluster assembly (CIA) pathway is required for replication stress tolerance of cancer cells to Chk1 and ATR inhibitors
Authors: Redwood Abena B. , Zhang Xiaomei , Seth Sahil B. , Ge Zhongqi , Bindeman Wendy E. , Zhou Xinhui , Sinha Vidya C. , Heffernan Timothy P. , Piwnica-Worms Helen
Published: December 2021

The relationship between ATR/Chk1 activity and replication stress, coupled with the development of potent and tolerable inhibitors of this pathway, has led to the clinical exploration of ATR and Chk1 inhibitors (ATRi/Chk1i) as anticancer therapies for single-agent or combinatorial application. The clinical efficacy of these therapies relies on the ability to ascertain which patient populations are most likely to benefit, so there is intense interest in identifying predictive biomarkers of response. To comprehensively evaluate the components that modulate cancer cell sensitivity to replication stress induced by Chk1i, we performed a synthetic-lethal drop-out screen in a cell line derived from a patient with triple-negative breast cancer (TNBC), using a pooled barcoded shRNA library targeting ~350 genes involved in DNA replication, DNA damage repair, and cycle progression. In addition, we sought to compare the relative requirement of these genes when DNA fidelity is challenged by clinically relevant anticancer breast cancer drugs, including cisplatin and PARP1/2 inhibitors, that have different mechanisms of action. This global comparison is critical for understanding not only which agents should be used together for combinatorial therapies in breast cancer patients, but also the genetic context in which these therapies will be most effective, and when a single-agent therapy will be sufficient to provide maximum therapeutic benefit to the patient. We identified unique potentiators of response to ATRi/Chk1i and describe a new role for components of the cytosolic iron–sulfur assembly (CIA) pathway, MMS19 and CIA2B-FAM96B, in replication stress tolerance of TNBC.
Connected-UNets: a deep learning architecture for breast mass segmentation
Authors: Baccouche Asma , Garcia-Zapirain Begonya , Castillo Olea Cristian , Elmaghraby Adel S.
Published: December 2021

Breast cancer analysis implies that radiologists inspect mammograms to detect suspicious breast lesions and identify mass tumors. Artificial intelligence techniques offer automatic systems for breast mass segmentation to assist radiologists in their diagnosis. With the rapid development of deep learning and its application to medical imaging challenges, UNet and its variations is one of the state-of-the-art models for medical image segmentation that showed promising performance on mammography. In this paper, we propose an architecture, called Connected-UNets, which connects two UNets using additional modified skip connections. We integrate Atrous Spatial Pyramid Pooling (ASPP) in the two standard UNets to emphasize the contextual information within the encoder–decoder network architecture. We also apply the proposed architecture on the Attention UNet (AUNet) and the Residual UNet (ResUNet). We evaluated the proposed architectures on two publically available datasets, the Curated Breast Imaging Subset of Digital Database for Screening Mammography (CBIS-DDSM) and INbreast, and additionally on a private dataset. Experiments were also conducted using additional synthetic data using the cycle-consistent Generative Adversarial Network (CycleGAN) model between two unpaired datasets to augment and enhance the images. Qualitative and quantitative results show that the proposed architecture can achieve better automatic mass segmentation with a high Dice score of 89.52%, 95.28%, and 95.88% and Intersection over Union (IoU) score of 80.02%, 91.03%, and 92.27%, respectively, on CBIS-DDSM, INbreast, and the private dataset.
Unique features of a recombinant haemagglutinin influenza vaccine that influence vaccine performance
Authors: Arunachalam Arun B. , Post Penny , Rudin Deborah
Published: December 2021

The influenza vaccine field has been constantly evolving to improve the speed, scalability, and flexibility of manufacturing, and to improve the breadth and longevity of the protective immune response across age groups, giving rise to an array of next generation vaccines in development. Among these, the recombinant influenza vaccine tetravalent (RIV4), using a baculovirus expression vector system to express recombinant haemagglutinin (rHA) in insect cells, is the only one to have reached the market and has been studied extensively. We describe how the unique structural features of rHA in RIV4 improve protective immune responses compared to conventional influenza vaccines made from propagated influenza virus. In addition to the sequence integrity, characteristic of recombinant proteins, unique post-translational processing of the rHA in insect cells instills favourable tertiary and quaternary structural features. The absence of protease-driven cleavage and addition of simple N-linked glycans help to preserve and expose certain conserved epitopes on HA molecules, which are likely responsible for the high levels of broadly cross-reactive and protective antibodies with rare specificities observed with RIV4. Furthermore, the presence of uniform compact HA oligomers and absence of egg proteins, viral RNA or process impurities, typically found in conventional vaccines, are expected to eliminate potential adverse reactions to these components in susceptible individuals with the use of RIV4. These distinct structural features and purity of the recombinant HA vaccine thus provide a number of benefits in vaccine performance which can be extended to other viral targets, such as for COVID-19.
Human blastoids model blastocyst development and implantation
Authors: Kagawa Harunobu , Javali Alok , Khoei Heidar Heidari , Sommer Theresa Maria , Sestini Giovanni , Novatchkova Maria , Scholte op Reimer Yvonne , Castel Gaël , Bruneau Alexandre , Maenhoudt Nina , Lammers Jenna , Loubersac Sophie , Freour Thomas , Vankelecom Hugo , David Laurent , Rivron Nicolas
Published: December 2021

One week after fertilization, human embryos implant into the uterus. This event requires the embryo to form a blastocyst consisting of a sphere encircling a cavity lodging the embryo proper. Stem cells can form a blastocyst model that we called a blastoid1. Here we show that naive human pluripotent stem cells cultured in PXGL medium2and triply inhibited for the Hippo, TGF-β and ERK pathways efficiently (with more than 70% efficiency) form blastoids generating blastocyst-stage analogues of the three founding lineages (more than 97% trophectoderm, epiblast and primitive endoderm) according to the sequence and timing of blastocyst development. Blastoids spontaneously form the first axis, and we observe that the epiblast induces the local maturation of the polar trophectoderm, thereby endowing blastoids with the capacity to directionally attach to hormonally stimulated endometrial cells, as during implantation. Thus, we propose that such a human blastoid is a faithful, scalable and ethical model for investigating human implantation and development3,4.
A combination of circulating microRNA-375-3p and chemokines CCL11, CXCL12, and G-CSF differentiate Crohn’s disease and intestinal tuberculosis
Authors: Roy Susree , Ghosh Suchandrima , Banerjee Mallica , Laha Sayantan , Bhattacharjee Dipanjan , Sarkar Rajib , Ray Sujay , Banerjee Arko , Ghosh Ranajoy , Halder Aniket , Ghosh Alakendu , Chatterjee Raghunath , Datta Simanti , Dhali Gopal Krishna , Banerjee Soma
Published: December 2021

Differentiation of Crohn’s disease (CD) from intestinal tuberculosis (ITB) is a big challenge to gastroenterologists because of their indistinguishable features and insensitive diagnostic tools. A non-invasive biomarker is urgently required to distinguish ITB/CD patients particularly in India, a TB endemic region, where CD frequency is increasing rapidly due to urbanization. Among the three differentially expressed miRNAs obtained from small RNA transcriptomic profiling of ileocaecal/terminal ileal tissue of ITB/CD patients (n = 3), only two down-regulated miRNAs, miR-31-5p, and miR-215-5p showed comparable data in qRT-PCR. Out of which, only miR-215-5p was detectable in the patient’s plasma, but there was no significant difference in expression between ITB/CD. On the other hand, miR-375-3p, the pulmonary TB specific marker was found in higher amount in the plasma of ITB patients than CD while reverse expression was observed in the ileocaecal/terminal ileal tissues of the same patients. Next, using Bioplex pro-human cytokine 48-plex screening panel, only three chemokines, Eotaxin-1/CCL11, SDF-1α/CXCL12, and G-CSF have noted significantly different levels in the serum of ITB/CD patients. ROC analysis has revealed that compared to a single molecule, a combination of miR-375-3p + Eotaxin-1/CCL11 + SDF-1α /CXCL12 + G-CSF showed a better AUC of 0.83, 95% CI (0.69–0.96) with 100% specificity and positive predictive value while sensitivity, negative predictive value, and accuracy were 56%, 69%, and 78% respectively in distinguishing ITB from CD. This study suggests that a combination of plasma markers shows better potential in differentiating ITB from CD than a single marker and this panel of markers may be used for clinical management of ITB/CD patients.
The optics of the human eye at 8.6 µm resolution
Authors: Bonaque-González Sergio , Trujillo-Sevilla Juan M. , Velasco-Ocaña Miriam , Casanova-González Óscar , Sicilia-Cabrera Miguel , Roqué-Velasco Alex , Ceruso Sabato , Oliva-García Ricardo , Martín-Hernández Javier , Gomez-Cardenes Oscar , Marichal-Hernández José G. , Gatinel Damien , Holladay Jack T. , Rodríguez-Ramos José M.
Published: December 2021

Ocular optics is normally estimated based on up to 2,600 measurement points within the pupil of the eye, which implies a lateral resolution of approximately 175 µm for a 9 mm pupil diameter. This is because information below this resolution is not thought to be relevant or even possible to obtain with current measurement systems. In this work, we characterize the in vivo ocular optics of the human eye with a lateral resolution of 8.6 µm, which implies roughly 1 million measurement points for a pupil diameter of 9 mm. The results suggest that the normal human eye presents a series of hitherto unknown optical patterns with amplitudes between 200 and 300 nm and is made up of a series of in-phase peaks and valleys. If the results are analysed at only high lateral frequencies, the human eye is also found to contain a whole range of new information. This discovery could have a great impact on the way we understand some fundamental mechanisms of human vision and could be of outstanding utility in certain fields of ophthalmology.
Young honeybees show learned preferences after experiencing adulterated pollen
Authors: Lajad Rocío , Moreno Emilia , Arenas Andrés
Published: December 2021

Pollen selection affects honeybee colony development and productivity. Considering that pollen is consumed by young in-hive bees, and not by foragers, we hypothesized that young bees learn pollen cues and adjust their preferences to the most suitable pollens. To assess whether young bees show preferences based on learning for highly or poorly suitable pollens, we measured consumption preferences for two pure monofloral pollens after the bees had experienced one of them adulterated with a deterrent (amygdalin or quinine) or a phagostimulant (linoleic acid). Preferences were obtained from nurse-aged bees confined in cages and from nurse bees in open colonies. Furthermore, we tested the bees’ orientation in a Y-maze using a neutral odour (Linalool or Nonanal) that had been previously associated with an amygdalin-adulterated pollen. Consumption preferences of bees, both in cages and in colonies, were reduced for pollens that had been adulterated with deterrents and increased for pollens that had been supplemented with linoleic acid. In the Y-maze, individuals consistently avoided the odours that they had previously experienced paired with the deterrent-adulterated pollen. Results show that nurse-aged bees associate pollen-based or pollen-related cues with either a distasteful/malaise experience or a tasty/nutritious event, leading to memories that bias their pollen-mediated response.