bluuebunny/crossref_metadata_2025 huggingface dataset:
Living under siege: resilience, hopelessness, and psychological distress among Palestinian students in the Gaza Strip
Authors: Veronese Guido , Pepe Alessandro , Diab Marwan , Abu Jamey Yasser , Kagee Ashraf
Published: October 2021

Background

Moving from an approach oriented to adaptation and functioning, the current paper explored the network of cumulative associations between the effects of the siege and resilience on mental health.

Methods

We sought to explore the impact of the siege on psychological distress (anxiety, depression, and stress) and the moderating effect of resilience and hopelessness in a sample of 550 Palestinian university students. We hypothesized that the siege effect would impact psychological distress so that the more people were affected by the siege, the more mental symptoms of common mental disorders they would report. We also expected that the siege would negatively impact both resilience and participants' hopelessness.

Results

Findings showed that higher scores on the scale measuring effect of the siege were associated with hopelessness. Furthermore, living under siege compromised participants’ resilience. The more the siege affected individuals, the lower resilience were protecting participants mental health and the more hopelessness was exposing them to anxiety, stress, and depression.

Conclusion

Our findings draw attention to how the ongoing violation of human rights influences people's mental health in Gaza. Implications for clinicians and policymakers are discussed.
THE BATTLE OF GAUGAMELA AND THE QUESTION OF VISIBILITY ON THE BATTLEFIELD
Authors: Marciak Michał , Szypuła Bartłomiej , Sobiech Marcin , Pirowski Tomasz
Published: October 2021

The aim of this paper is to contribute to the long-standing topographical enigma of the identification of Gaugamela. In this study, a GIS method known as viewshed analysis is employed to solve a certain historical problem.1 According to ancient sources, on the eve of the battle the approaching Macedonian army and the Persian troops that were waiting on the battlefield could not see each other because of intervening hills at a distance of c. 12 km. However, the two armies gained a full view of their respective positions once the Macedonians reached the hills c. six km away from the Persian positions. Our analysis shows that the identification of the battlefield near Tell Gomel, in the Kurdistan Region of Iraq, is consistent with the visibility requirements of the ancient sources, while the previous identifications of the battlefield in the vicinity of Karamleis and Qaraqosh (Stein 1942; Sushko 1936; Zouboulakis 2015, 2016) feature poor results in terms of expected visibility.
Self-similar fault slip in response to fluid injection
Authors: Viesca Robert C.
Published: October 2021

There is scientific and industrial interest in understanding how geologic faults respond to transient sources of fluid. Natural and artificial sources can elevate pore fluid pressure on the fault frictional interface, which may induce slip. We consider a simple boundary value problem to provide an elementary model of the physical process and to provide a benchmark for numerical solution procedures. We examine the slip of a fault that is an interface of two elastic half-spaces. Injection is modelled as a line source at constant pressure and fluid pressure is assumed to diffuse along the interface. The resulting problem is an integro-differential equation governing fault slip, which has a single dimensionless parameter. The expansion of slip is self-similar and the rupture front propagates at a factor$\lambda$of the diffusive length scale$\sqrt {\alpha t}$. We identify two asymptotic regimes corresponding to$\lambda$being small or large and perform a perturbation expansion in each limit. For large$\lambda$, in the regime of a so-called critically stressed fault, a boundary layer emerges on the diffusive length scale, which lags far behind the rupture front. We demonstrate higher-order matched asymptotics for the integro-differential equation, and in doing so, we derive a multipole expansion to capture successive orders of influence on the outer problem for fault slip for a driving force that is small relative to the crack dimensions. Asymptotic expansions are compared with accurate numerical solutions to the full problem, which are tabulated to high precision.
Purely elastic linear instabilities in parallel shear flows with free-slip boundary conditions
Authors: Lellep Martin , Linkmann Moritz , Eckhardt Bruno , Morozov Alexander
Published: October 2021

We perform a linear stability analysis of viscoelastic plane Couette and plane Poiseuille flows with free-slip boundary conditions. The fluid is described by the Oldroyd-B constitutive model, and the flows are driven by a suitable body force. We find that both types of flow become linearly unstable, and we characterise the spatial structure of the unstable modes. By performing a boundary condition homotopy from the free-slip to no-slip boundaries, we demonstrate that the unstable modes are directly related to the least stable modes of the no-slip problem, destabilised under the free-slip situation. We discuss how our observations can be used to study recently discovered purely elastic turbulence in parallel shear flows.
Heat transfer in the seabed boundary layer
Authors: Michele S. , Stuhlmeier R. , Borthwick A.G.L.
Published: October 2021

We present a theoretical model of the temperature distribution in the boundary layer region close to the seabed. Using a perturbation expansion, multiple scales and similarity variables, we show how free-surface waves enhance heat transfer between seawater and a seabed with a solid, horizontal, smooth surface. Maximum heat exchange occurs at a fixed frequency depending on ocean depth, and does not increase monotonically with the length and phase speed of propagating free-surface waves. Close agreement is found between predictions by the analytical model and a finite-difference scheme. It is found that free-surface waves can substantially affect the spatial evolution of temperature in the seabed boundary layer. This suggests a need to extend existing models that neglect the effects of a wave field, especially in view of practical applications in engineering and oceanography.
New solutions for periodic interfacial gravity waves
Authors: Guan X. , Vanden-Broeck J.-M. , Wang Z.
Published: October 2021

Two-dimensional periodic interfacial gravity waves travelling between two homogeneous fluids of finite depth are considered. A boundary-integral-equation method coupled with Fourier expansions of the unknown functions is used to obtain highly accurate solutions. Our numerical results show excellent agreement with those already obtained by Maklakov & Sharipov using a different scheme (J. Fluid Mech., vol. 856, 2018, pp. 673–708). We explore the global bifurcation mechanism of periodic interfacial waves and find three types of limiting wave profiles. The new families of solutions appear either as isolated branches or as secondary branches bifurcating from the primary branch of solutions.
Adjusting to precarity: how and why the Roslin Institute forged a leading role for itself in international networks of pig genomics research
Authors: Lowe James W. E.
Published: October 2021

From the 1980s onwards, the Roslin Institute and its predecessor organizations faced budget cuts, organizational upheaval and considerable insecurity. Over the next few decades, it was transformed by the introduction of molecular biology and transgenic research, but remained a hub of animal geneticists conducting research aimed at the livestock-breeding industry. This paper explores how these animal geneticists embraced genomics in response to the many-faceted precarity that the Roslin Institute faced, establishing it as a global centre for pig genomics research through forging and leading the Pig Gene Mapping Project (PiGMaP); developing and hosting resources, such as a database for genetic linkage data; and producing associated statistical and software tools to analyse the data. The Roslin Institute leveraged these resources to play a key role in further international collaborations as a hedge against precarity. This adoption of genomics was strategically useful, as it took advantage of policy shifts at the national and European levels towards funding research with biotechnological potential. As genomics constitutes a set of infrastructures and resources with manifold uses, the development of capabilities in this domain also helped Roslin to diversify as a response to precarity.
Effects of distance from semi-natural habitat on fall armyworm (Spodoptera frugiperda, J. E. Smith) and its potential natural enemies in Ghana
Authors: Jordon Matthew W. , Hackett Talya D. , Aboagye-Antwi Fred , Eziah Vincent Y. , Lewis Owen T.
Published: October 2021

Insect crop pests are a major threat to food security in sub-Saharan Africa. Configuration of semi-natural habitat within agricultural landscapes has the potential to enhance biological pest control, helping to maintain yields whilst minimising the negative effects of pesticide use. Fall armyworm (Spodoptera frugiperda, J. E. Smith) is an increasingly important pest of maize in sub-Saharan Africa, with reports of yield loss between 12 and 45%. We investigated the patterns of fall armyworm leaf damage in maize crops in Ghana, and used pitfall traps and dummy caterpillars to assess the spatial distribution of potential fall armyworm predators. Crop damage from fall armyworm at our study sites increased significantly with distance from the field edge, by up to 4% per m. We found evidence that Araneae activity, richness and diversity correspondingly decreased with distance from semi-natural habitat, although Hymenoptera richness and diversity increased. Our preliminary findings suggest that modifying field configuration to increase the proximity of maize to semi-natural habitat may reduce fall armyworm damage and increase natural enemy activity within crops. Further research is required to determine the level of fall armyworm suppression achievable through natural enemies, and how effectively this could safeguard yields.
Rapports à autrui et personnalité de base dans les premiers travaux de Mikel Dufrenne
Authors: Chamois Camille
Published: October 2021

Cet article souligne l'originalité et la pertinence des premiers travaux de Mikel Dufrenne (notamment publiés entre 1946 et 1953) pour les sciences humaines contemporaines. Sous l'influence de Georges Gurvitch, Dufrenne s'est en effet intéressé de près à l'anthropologie culturelle américaine et notamment au concept de « personnalité de base » d'Abram Kardiner, auquel il tente de donner une consistance philosophique à partir, d'une part, de la tradition transcendantale kantienne et, d'autre part, de la théorie du Mitsein heideggérienne. Nous montrons que ce projet se heurte à la question proprement psychologique de l'historicité des catégories de l'expérience.
Efficiency of fertilization with coated urea in the cultivation of cactus pear under rainfed conditions in Brazilian savannah
Authors: Magalhães R. M. F. , Edvan R. L. , Ratke R. F. , de. Oliveira M. E. , de. M. Carvalho C. B. , Araújo J. S. , da. C. Araújo D. L. , do. Nascimento R. R.
Published: October 2021

Cactus pear is an important species for animal feeding in the regions of dry climate. There is no information on the fertilization with coated urea in the cultivation of cactus pear under rainfed conditions in the savannah region. The aim of the current study was to evaluate the forage potential of Nopalea cochenillifera variety Doce in yellow latosol under rainfed conditions in the Brazilian savannah, comparing the fertilization with urea and coated urea in different levels. A randomized block design was adopted, in a 2 × 4 × 2 factorial scheme, with the factors corresponding to two sources of nitrogen (urea and urea coated with polymers, N+), four levels of nitrogen (0, 60, 120 and 240 kg/ha/year) and two harvests (year I and year II). The plants were evaluated after 1 year of growth, in each year of evaluation, regarding the characteristics of growth, production, chemical and mineral composition and nutritional value. The level of 240 kg/ha provided higher emission of cladodes per plant (17.33 and 18.17), respectively, for N+ and urea. The highest nitrogen use efficiency was found in the level of 60 kg N/ha (142 kg/ha/year). NFC values were 3.5 g/kg dry matter (DM) higher when the cactus pear was fertilized with urea in year I and 5.4 g/kg DM in year II. The use of conventional urea promoted better results of agronomic and nutritional characteristics of the cactus pear, under rainfed regime, when compared to the use of urea coated with polymers.
The Political Economy of China's Dramatically Improved Coal Safety Record
Authors: Wright Tim
Published: October 2021

China's coal safety has improved dramatically since 2003. This article will present the official data and conclude that it is almost impossible that the figures conceal a situation where there has not been remarkable improvement. Structural factors including China's level of economic development, changes in the labour market and the economic health of the industry have played an important role, but state commitment and policies have been central at least to the speed and magnitude of the improvement.
Morphological and electrophysiological specializations of photoreceptors in the love spot of hover fly Volucella pellucens
Authors: Ignatova Irina I. , Miinalainen Ilkka , Frolov Roman V.
Published: October 2021

Studies of functional variability in the compound eyes of flies reveal superior temporal resolution of photoreceptors from the frontal areas that mediate binocular vision, and in males mate recognition and pursuit. However, the mechanisms underlying differences in performance are not known. Here, we investigated properties of hover fly Volucella pellucens photoreceptors from two regions of the retina, the frontal-dorsal “love spot” and the lateral one. Morphologically, the microvilli of the frontal-dorsal photoreceptors were relatively few in number per rhabdomere cross-section, short and narrow. In electrophysiological experiments involving stimulation with prolonged white-noise and natural time intensity series, frontal-dorsal photoreceptors demonstrated comparatively high corner frequencies and information rates. Investigation of possible mechanisms responsible for their superior performance revealed significant differences in the properties of quantum bumps, and, unexpectedly, relatively high absolute sensitivity of the frontal-dorsal photoreceptors. Analysis of light adaptation indicated that photoreceptors from two regions adapt similarly but because frontal-dorsal photoreceptors were depolarized much stronger by the same stimuli than the lateral photoreceptors, they reached a deeper state of adaptation associated with higher corner frequencies of light response. Recordings from the photoreceptor axons were characterized by spike-like events that can significantly expand the frequency response range. Seamless integration of spikes into the graded voltage responses was enabled by light adaptation mechanisms that accelerate kinetics and decrease duration of depolarizing light response transients.
Comparative Cellular Localization of Sugar Residues in Bull (Bos taurus) and Donkey (Equus asinus) Testes Using Lectin Histochemistry
Authors: Gewaily Mahmoud S , Kassab Mohamed , Aboelnour Asmaa , Almadaly Essam A , Noreldin Ahmed E
Published: October 2021

Lectins are glycoproteins of a non-immune origin often used as histochemical reagents to study the distribution of glycoconjugates in different types of tissues. In this study, we performed a comparative cellular localization of sugar residues in bull and donkey testes using immunofluorescent lectin histochemistry. We inspected the cellular localization of the glycoconjugates within the testes using 11 biotin-labeled lectins (LCA, ConA, PNA, WGA, DBA, SBA, ECA, BPL, PTL-II, UEA-1, and PHA-E4) classified under six groups. Although the basic testicular structure in both species was similar, the cellular components showed different lectin localization patterns. The statistical analysis revealed no significant association between the intensity of labeling and different variables, including group and type of lectin and type of cell examined, at p < 0.05. However, a stronger response tended to occur in the donkey than in the bull testes (odds ratio: 1.3). These findings may be associated with the different cellular compositions of the glycoproteins and modification changes during spermatogenesis. Moreover, glycoconjugate profiling through lectin histochemistry can characterize some cell-type selective markers that will be helpful in studying bull and donkey spermatogenesis.
Turning Over the Keys: Public Prisons, Private Equity, and the Normalization of Markets Behind Bars
Authors: Swanson Jacob , Fainsod Katzenstein Mary
Published: October 2021

In recent decades, public prisons and jails have increasingly outsourced operational functions by “turning over the keys” to private business and, more recently and specifically, to private equity. By the early 2000s, private equity-owned corporations had entered the core sectors of prison and jail operations, creating “markets behind bars” in telecommunications, commissary sales, health provision, and a range of other services. Two decades later, they have become a quasi-oligopolistic market force across the carceral economy. Reacting to these developments, scholars and activists have explored how private firms generate profits by extracting resources from families of the incarcerated. Less explored is the fact that it is often and particularly private equity firms that partner with public carceral institutions in these extractive practices. In this reflection, we propose a three-part schematic for understanding how such partnerships, with their attendant predation on the poor and people of color, have become normalized. We focus, first, on the mechanism of bureaucracy through which mutual profit-making by public and private entities becomes regularized; second, we explore the legal mechanisms—the apparently small but potent and politically unexamined legal maneuvers—that enable the redirection of family resources beyond the support of a loved one to the operational needs of jails and prisons; finally, we trace the role of gender as a social mechanism through which private equity and its prison/jail partners rely simultaneously on women’s traditional role as caretaker and non-traditional role as primary breadwinner. We show that all three mechanisms are crucial to the economic functioning of the carceral state.
Late Holocene Climate Changes in the Altai Region Based on a First High‐Resolution Biomarker Isotope Record From Lake Khar Nuur
Authors: Bliedtner Marcel , Struck Julian , Strobel Paul , Salazar Gary , Szidat Sönke , Bazarradnaa Enkhtuya , Lloren Ronald , Dubois Nathalie , Zech Roland
Published: October 2021

The Late Holocene marks a substantial cultural and economic transition in the eastern Eurasian Steppe and Altai Region with the dispersal of nomadic pastoralism. So far, paleoclimate conditions during this time remain unclear and controversial. Here, we present a high‐resolution 4.2 ka paleoclimate record from Lake Khar Nuur in the Mongolian Altai that is based on lake sediment proxies and biomarker compound‐specific δ2H analyses. Our results document increased aridity before ∼3.7 cal. ka BP, followed by two pronounced phases of warm and wet conditions from ∼3.5–2.8 to ∼2.3–1.5 cal. ka BP, and a strong increase in aridity since ∼1.5 cal. ka BP. Phases of warmer and wetter conditions coincide with a negative North Atlantic Oscillation, which has been responsible for advecting moisture into the region by more southerly‐displaced Westerlies and possibly favored the expansion of mobile nomadic pastoralism in the region.
Surface Salinity Under Transitioning Ice Cover in the Canada Basin: Climate Model Biases Linked to Vertical Distribution of Fresh Water
Authors: Rosenblum E. , Fajber R. , Stroeve J. C. , Gille S. T. , Tremblay L. B. , Carmack E. C.
Published: October 2021

The Canada Basin has exhibited a significant trend toward a fresher surface layer and thus a more stratified upper‐ocean over the past three decades. State‐of‐the‐art ice‐ocean models, by contrast, tend to simulate a surface layer that is saltier and less stratified than observed. Here, we examine decadal changes to seasonal processes that may contribute to this wide‐reaching model bias using climate model simulations from the Community Earth System Model and below‐ice observations from the Arctic Ice Dynamics Joint Experiment in 1975 and Ice Tethered Profilers in 2006–2012. In contrast to the observations, the models simulate salinity profiles that show relatively little variation between 1975 and 2012. We demonstrate that this bias can be mainly attributed to unrealistically deep vertical mixing in the model, creating a surface layer that is saltier than observed. The results provide insight for climate model improvement with broad implications for Arctic sea ice and ecosystem dynamics.
Fault Trace Corrugation and Segmentation as a Measure of Fault Structural Maturity
Authors: Manighetti I. , Mercier A. , De Barros L.
Published: October 2021

As faults grow over time and become more “mature,” some of their geometrical and mechanical properties evolve, and these changes modify earthquake behavior. It is thus of prime importance to know the degree of structural maturity of a fault that is likely to produce large earthquakes. Although this concept is extensively used, there is no common definition or metric to measure the structural maturity of a fault. We analyzed the heterogeneity of the surface traces of 13 large seismogenic faults whose maturity is known qualitatively. We measured the corrugations and step‐over segmentation of the traces from ∼100 m to the fault length scale. Corrugations and some properties of the segmentation are found to vary with fault structural maturity. We provide scaling relationships that quantify the structural maturity of a fault based on its surface trace. These results should help in parameterizing source faults in earthquake models.
Do Atlantic‐European Weather Regimes Physically Exist?
Authors: Hochman Assaf , Messori Gabriele , Quinting Julian F. , Pinto Joaquim G. , Grams Christian M.
Published: October 2021

The subseasonal variability of the extratropical large‐scale atmospheric flow is characterized by recurrent or quasi‐stationary circulation anomalies, termed weather regimes. Despite the usefulness of these regimes in numerous meteorological and socioeconomic applications, there is an ongoing debate as to whether they represent physical modes of the atmosphere, or are merely useful statistical categorizations. Here, we answer this question for wintertime Atlantic‐European regimes. We argue that dynamical systems theory applied to a refined regime definition provides strong evidence in support of most weather regimes being physically meaningful. This finding underpins the broad relevance of weather regimes, for understanding the response of the atmosphere to external forcing, supporting subseasonal weather forecasting, and down scaling of climate projections.
Estimating Effective Normal Stress During Slow Slip Events From Slip Velocities and Shear Stress Variations
Authors: Kobayashi Takuma , Sato Toshinori
Published: October 2021

Theoretical analyses using a rate‐ and state‐dependent friction law have shown quasistatic and stable slip behaviors following velocity weakening. We estimated spatiotemporal slip distributions for six slow slip events (SSEs) off the Boso Peninsula, Japan, from Global Navigation Satellite System data and plotted their shear stress variations vs. slip velocity, here called “trajectories.” Most trajectories are similar to theoretical stable trajectories, implying that the Boso SSEs represent a quasistatic and stable process, and that the gradient of the trajectories during slip acceleration is equal to the product of the friction coefficients of the slipping plates (a–b) and the effective normal stress (). Taking (a–b) = −0.003, we estimate that the effective normal stresses during the SSEs were 10–50 MPa at 12.5–20.5 km depth. These values are much smaller than the lithostatic pressures at those depths, implying high pore pressures on the slow slip interface.
Assessing Multi‐Stream Radiative Transfer Schemes for the Calculation of Aerosol Radiative Forcing in the Martian Atmosphere
Authors: Chen‐Chen H. , Pérez‐Hoyos S. , Sánchez‐Lavega A.
Published: October 2021

The atmosphere of Mars presents a strong response to aerosol radiative forcing compared to that of the Earth, thus atmospheric models should have accurate radiative transfer algorithms for the simulation of temperatures and circulation. In this work, we evaluate the radiative effects of dust aerosol calculated by different radiative transfer schemes and the influence of dust properties in these calculations. Two‐stream solutions were compared with multistream discrete ordinate methods. Fluxes and heating rates were evaluated for a variety of atmospheric conditions, including dust storms. The results show that in low‐to‐medium dust opacity scenarios, the highly efficient two‐stream methods provide accurate estimations, with heating rate errors of less than 2 K/sol. These errors increase with opacity, when differences of 20 K/sol are reached, which may be relevant in the simulations of temperature fields and atmospheric circulation under regional and global dust storm conditions. In such cases, the use of four‐stream or higher order methods may be required, although accuracy improvements for eight‐ or higher‐stream schemes were negligible. The influence of dust particle properties in aerosol radiative forcing estimations is mainly due to the particle size, where variations of 20% of the effective radius resulted in differences of 5 K/sol; the shape of the particles showed a minor impact, with differences of <2 K/sol. The results of this study contribute to quantification of the uncertainties in current Mars climate models and may help modellers to select the appropriate approach depending on the scenario.
Combined Drug Targeting of p53-dependent and -independent Pathways Depletes Myelofibrosis Hematopoietic Stem/Progenitor Cells
Authors: Lu Min , Xia Lijuan , Elmansy Nada , Clementelli Cara , Tremblay Douglas , Hoffman Ronald
Published: October 2021

Current therapy for myelofibrosis (MF) results in a limited prolongation of patient survival. In order to improve treatment outcomes, we developed a strategy to effectively deplete MF hematopoietic stem/progenitor cells (HSPCs). In the present study, an imipridone, ONC201, was combined with RG7112, an antagonist of MDM2, a p53 negative regulator, to activate downstream events of the p53 and TNF-related apoptosis-inducing ligand (TRAIL)/death receptor (DR) pathways. As compared to treatment with the individual drugs, the combination of ONC201 and RG7112 promoted greater degrees of apoptosis of MF CD34+ cells through activation of both p53-dependent and -independent pathways. Importantly, treatment with ONC201-RG7112 not only decreased the number of JAK2V617F+ and calreticulin mutated colonies assayed from MF CD34+ cells, but allowed for the persistence or appearance of JAK2 wild type colonies. Treatment with ONC201 combined with RG7112 could be a potentially effective strategy for treating MF patients.
Cross-species anxiety tests in psychiatry: pitfalls and promises
Authors: Bach Dominik R.
Published: October 2021

Behavioural anxiety tests in non-human animals are used for anxiolytic drug discovery, and to investigate the neurobiology of threat avoidance. Over the past decade, several of them were translated to humans with three clinically relevant goals: to assess potential efficacy of candidate treatments in healthy humans; to develop diagnostic tests or biomarkers; and to elucidate the pathophysiology of anxiety disorders. In this review, we scrutinise these promises and compare seven anxiety tests that are validated across species: five approach-avoidance conflict tests, unpredictable shock anticipation, and the social intrusion test in children. Regarding the first goal, three tests appear suitable for anxiolytic drug screening in humans. However, they have not become part of the drug development pipeline and achieving this may require independent confirmation of predictive validity and cost-effectiveness. Secondly, two tests have shown potential to measure clinically relevant individual differences, but their psychometric properties, predictive value, and clinical applicability need to be clarified. Finally, cross-species research has not yet revealed new evidence that the physiology of healthy human behaviour in anxiety tests relates to the physiology of anxiety symptoms in patients. To summarise, cross-species anxiety tests could be rendered useful for drug screening and for development of diagnostic instruments. Using these tests for aetiology research in healthy humans or animals needs to be queried and may turn out to be unrealistic.
Obesity-linked circular RNA circTshz2-2 regulates the neuronal cell cycle and spatial memory in the brain
Authors: Yoon Gwangho , Lim Yeong-Hwan , Jo Danbi , Ryu Juhee , Song Juhyun , Kim Young-Kook
Published: October 2021

Metabolic syndromes, including obesity, cause neuropathophysiological changes in the brain, resulting in cognitive deficits. Only a few studies explored the contribution of non-coding genes in these pathophysiologies. Recently, we identified obesity-linked circular RNAs (circRNA) by analyzing the brain cortices of high-fat-fed obese mice. In this study, we scrutinized a conserved and neuron-specific circRNA, circTshz2-2, which affects neuronal cell cycle and spatial memory in the brain. Transcriptomic and cellular analysis indicated that circTshz2-2 dysregulation altered the expression of cell division-related genes and induced cell cycle arrest at the G2/M phase of the neuron. We found that circTshz2-2 bound to the YY1 transcriptional complex and suppressed Bdnf transcription. Suppression of circTshz2-2 increased BDNF expression and reduced G2/M checkpoint proteins such as Cyclin B2 and CDK1 through BDNF/TrkB signaling pathway, resulting in cell cycle arrest and neurite elongation. Inversely, overexpression of circTshz2-2 decreased BDNF expression, induced cell cycle proteins, and shortened the neurite length, indicating that circTshz2-2 regulates neuronal cell cycle and structure. Finally, we showed that circTshz2-2 affects spatial memory in wild-type and obese mice. Our data have revealed potential regulatory roles of obesity-related circTshz2-2 on the neuronal cell cycle and memory function providing a novel link between metabolic syndromes and cognitive deficits.
Antibody-dependent cellular cytotoxicity response to SARS-CoV-2 in COVID-19 patients
Authors: Yu Yuanling , Wang Meiyu , Zhang Xiaoai , Li Shufen , Lu Qingbin , Zeng Haolong , Hou Hongyan , Li Hao , Zhang Mengyi , Jiang Fei , Wu Jiajing , Ding Ruxia , Zhou Zehua , Liu Min , Si Weixue , Zhu Tao , Li Hangwen , Ma Jie , Gu Yuanyuan , She Guangbiao , Li Xiaokun , Zhang Yulan , Peng Ke , Huang Weijin , Liu Wei , Wang Youchun
Published: October 2021

Antibody-dependent cellular cytotoxicity (ADCC) responses to viral infection are a form of antibody regulated immune responses mediated through the Fc fragment. Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered ADCC responses contributes to COVID-19 disease development is currently not well understood. To understand the potential correlation between ADCC responses and COVID-19 disease development, we analyzed the ADCC activity and neutralizing antibody response in 255 individuals ranging from asymptomatic to fatal infections over 1 year post disease. ADCC was elicited by 10 days post-infection, peaked by 11–20 days, and remained detectable until 400 days post-infection. In general, patients with severe disease had higher ADCC activities. Notably, patients who had severe disease and recovered had higher ADCC activities than patients who had severe disease and deceased. Importantly, ADCC activities were mediated by a diversity of epitopes in SARS-COV-2-infected mice and induced to comparable levels against SARS-CoV-2 variants of concern (VOCs) (B.1.1.7, B.1.351, and P.1) as that against the D614G mutant in human patients and vaccinated mice. Our study indicates anti-SARS-CoV-2 ADCC as a major trait of COVID-19 patients with various conditions, which can be applied to estimate the extra-neutralization level against COVID-19, especially lethal COVID-19.
Changes in circulating exosome molecular profiles following surgery/(chemo)radiotherapy: early detection of response in head and neck cancer patients
Authors: Theodoraki M.-N. , Laban S. , Jackson E. K. , Lotfi R. , Schuler P. J. , Brunner C. , Hoffmann T. K. , Whiteside T. L. , Hofmann L.
Published: October 2021

Background

Head and neck cancers (HNSCC) are highly immunosuppressive. Plasma-derived exosomes of HNSCC patients carry immunomodulatory molecules, and their cargo correlates with clinical parameters. Here, we evaluated the exosomal molecular profile for early detection of treatment failure in locally advanced HNSCC patients treated with conventional therapy.

Methods

Plasma from 17 HNSCC patients was collected before, during, and after treatment by surgery with adjuvant (chemo)radiation and at recurrence. Exosomes were isolated by size-exclusion chromatography. Total exosomal protein (TEP) was used to estimate exosome load and on-bead flow cytometry to evaluate relative fluorescence intensity (RFI) of tumour-associated and immunoregulatory proteins on exosomes. Exosomal effects on the activity of and adenosine production by T cells was assessed by flow cytometry and mass spectrometry.

Results

TEP and the ratio of tumour-/immune-cell-derived exosomes varied during and after therapy with an overall decrease in the tumour-free follow-up but an increase at recurrence. RFI values of immunoregulatory proteins on exosomes, their ability for T cell inhibition and adenosine production changed during and after therapy. PD-L1 was the earliest discriminator for treatment failure and disease-free survival.

Conclusions

Monitoring of plasma exosomes during therapy represents a promising opportunity for early detection of treatment failure and risk stratification to delay/avoid recurrence.
Oncolytic adenoviruses synergistically enhance anti-PD-L1 and anti-CTLA-4 immunotherapy by modulating the tumour microenvironment in a 4T1 orthotopic mouse model
Authors: Zhang Huan , Xie Weimin , Zhang Yuning , Dong Xiwen , Liu Chao , Yi Jing , Zhang Shun , Wen Chunkai , Zheng Li , Wang Hua
Published: October 2021

Effective therapeutic strategies for triple-negative breast cancer (TNBC) are still lacking. Clinical data suggest that a large number of TNBC patients cannot benefit from single immune checkpoint inhibitor (ICI) treatment due to the immunosuppressive tumour microenvironment (TME). Therefore, combination immunotherapy is an alternative approach to overcome this limitation. In this article, we combined two kinds of oncolytic adenoviruses with ICIs to treat TNBC in an orthotopic mouse model. Histopathological analysis and immunohistochemistry as well as multiplex immunofluorescence were used to analyse the TME. The immunophenotype of the peripheral blood and spleen was detected by using flow cytometry. Oncolytic adenovirus-mediated immune activity in a coculture system of lytic supernatant and splenocytes supported the study of the mechanism of combination therapy in vitro. Our results showed that the combination of oncolytic adenoviruses with anti-programmed cell death-ligand 1 (anti-PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (anti-CTLA-4) (aPC) can significantly inhibit tumour growth and prolong survival in a TNBC model. The combination therapy synergistically enhanced the antitumour effect by recruiting CD8+T and T memory cells, reducing the number of regulatory T cells and tumour-associated macrophages, and promoting the polarization of macrophages from the M2 to the M1 phenotype to regulate the TME. The rAd.GM regimen performed better than the rAd.Null treatment. Furthermore, aPC efficiently blocked oncolytic virus-induced upregulation of PD-L1 and CTLA-4. These findings indicate that oncolytic adenoviruses can reprogramme the immunosuppressive TME, while ICIs can prevent immune escape after oncolytic virus therapy by reducing the expression of immune checkpoint molecules. Our results provide a mutually reinforcing strategy for clinical combination immunotherapy.
Genomic comparison between cerebrospinal fluid and primary tumor revealed the genetic events associated with brain metastasis in lung adenocarcinoma
Authors: Deng Zhiyong , Cui Liang , Li Pansong , Ren Nianjun , Zhong Zhe , Tang Zhi , Wang Lei , Gong Jianwu , Cheng Haofeng , Guan Yanfang , Yi Xin , Xia Xuefeng , Zhou Rongrong , He Zhengwen
Published: October 2021

Lung adenocarcinoma (LUAD) is most common pathological type of lung cancer. LUAD with brain metastases (BMs) usually have poor prognosis. To identify the potential genetic factors associated with BM, a genomic comparison for BM cerebrospinal fluid (CSF) and primary lung tumor samples obtained from 1082 early- and late-stage LUAD patients was performed. We found that single nucleotide variation (SNV) of EGFR was highly enriched in CSF (87% of samples). Compared with the other primary lung tissues, copy number gain of EGFR (27%), CDK4 (11%), PMS2 (11%), MET (10%), IL7R (8%), RICTOR (7%), FLT4 (5%), and FGFR4 (4%), and copy number loss of CDKN2A (28%) and CDKN2B (18%) were remarkably more frequent in CSF samples. CSF had significantly lower tumor mutation burden (TMB) level but more abundant copy number variant. It was also found that the relationships among co-occurrent and mutually exclusive genes were dynamically changing with LUAD development. Additionally, CSF (97% of samples) harbored more abundant targeted drugs related driver and fusion genes. The signature 15 associated with defective DNA mismatch repair (dMMR) was only identified in the CSF group. Cancer associated pathway analysis further revealed that ErbB (95%) and cell cycle (84%) were unique pathways in CSF samples. The tumor evolution analysis showed that CSF carried significantly fewer clusters, but subclonal proportion of EGFR was remarkably increased with tumor progression. Collectively, CSF sequencing showed unique genomic characteristics and the intense copy number instability associated with cell cycle disorder and dMMR might be the crucial genetic factors in BM of LUAD.
Pyrvinium pamoate regulates MGMT expression through suppressing the Wnt/β-catenin signaling pathway to enhance the glioblastoma sensitivity to temozolomide
Authors: Li Haisong , Liu Shuhan , Jin Rihua , Xu Haiyang , Li Yunqian , Chen Yong , Zhao Gang
Published: October 2021

Temozolomide (TMZ) is the mainstream chemotherapeutic drug for treating glioblastoma multiforme (GBM), but the intrinsic or acquired chemoresistance to TMZ has become the leading clinical concern, which is related to the repair of DNA alkylation sites by O6-methylguanine-DNA methyltransferase (MGMT). Pyrvinium pamoate (PP), the FDA-approved anthelminthic drug, has been reported to inhibit the Wnt/β-catenin pathway within numerous cancer types, and Wnt/β-catenin signaling pathway can modulate the expression of MGMT gene. However, whether PP affects the expression of MGMT and enhances TMZ sensitivity in GBM cells remains unclear. In the present study, we found that PP and TMZ had synergistic effect on inhibiting the viability of GBM cells, and PP induced inhibition of MGMT and enhanced the TMZ chemosensitivity of GBM cells through down-regulating Wnt/β-catenin pathway. Moreover, the overexpression of MGMT or β-catenin weakened the synergy between PP and TMZ. The mechanism of PP in inhibiting the Wnt pathway was indicated that PP resulted in the degradation of β-catenin via the AKT/GSK3β/β-catenin signaling axis. Moreover, Ser552 phosphorylation in β-catenin, which promotes its nuclear accumulation and transcriptional activity, is blocked by PP that also inhibits the Wnt pathway to some extent. The intracranial GBM mouse model also demonstrated that the synergy between PP and TMZ could be achieved through down-regulating β-catenin and MGMT, which prolonged the survival time of tumor-bearing mice. Taken together, our data suggest that PP may serve as the prospect medicine to improve the chemotherapeutic effect on GBM, especially for chemoresistant to TMZ induced by MGMT overexpression.
Identification of the suprachiasmatic nucleus venous portal system in the mammalian brain
Authors: Yao Yifan , Taub Alana B’nai , LeSauter Joseph , Silver Rae
Published: October 2021

There is only one known portal system in the mammalian brain - that of the pituitary gland, first identified in 1933 by Popa and Fielding. Here we describe a second portal pathway in the mouse linking the capillary vessels of the brain’s clock suprachiasmatic nucleus (SCN) to those of the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ. The localized blood vessels of portal pathways enable small amounts of important secretions to reach their specialized targets in high concentrations without dilution in the general circulatory system. These brain clock portal vessels point to an entirely new route and targets for secreted SCN signals, and potentially restructures our understanding of brain communication pathways.
Directed evolution of rRNA improves translation kinetics and recombinant protein yield
Authors: Liu Fan , Bratulić Siniša , Costello Alan , Miettinen Teemu P. , Badran Ahmed H.
Published: October 2021

In bacteria, ribosome kinetics are considered rate-limiting for protein synthesis and cell growth. Enhanced ribosome kinetics may augment bacterial growth and biomanufacturing through improvements to overall protein yield, but whether this can be achieved by ribosome-specific modifications remains unknown. Here, we evolve 16S ribosomal RNAs (rRNAs) from Escherichia coli, Pseudomonas aeruginosa, and Vibrio cholerae towards enhanced protein synthesis rates. We find that rRNA sequence origin significantly impacted evolutionary trajectory and generated rRNA mutants with augmented protein synthesis rates in both natural and engineered contexts, including the incorporation of noncanonical amino acids. Moreover, discovered consensus mutations can be ported onto phylogenetically divergent rRNAs, imparting improved translational activities. Finally, we show that increased translation rates in vivo coincide with only moderately reduced translational fidelity, but do not enhance bacterial population growth. Together, these findings provide a versatile platform for development of unnatural ribosomal functions in vivo.
Exceptional uranium(VI)-nitride triple bond covalency from 15N nuclear magnetic resonance spectroscopy and quantum chemical analysis
Authors: Du Jingzhen , Seed John A. , Berryman Victoria E. J. , Kaltsoyannis Nikolas , Adams Ralph W. , Lee Daniel , Liddle Stephen T.
Published: October 2021

Determining the nature and extent of covalency of early actinide chemical bonding is a fundamentally important challenge. Recently, X-ray absorption, electron paramagnetic, and nuclear magnetic resonance spectroscopic studies have probed actinide-ligand covalency, largely confirming the paradigm of early actinide bonding varying from ionic to polarised-covalent, with this range sitting on the continuum between ionic lanthanide and more covalent d transition metal analogues. Here, we report measurement of the covalency of a terminal uranium(VI)-nitride by 15N nuclear magnetic resonance spectroscopy, and find an exceptional nitride chemical shift and chemical shift anisotropy. This redefines the 15N nuclear magnetic resonance spectroscopy parameter space, and experimentally confirms a prior computational prediction that the uranium(VI)-nitride triple bond is not only highly covalent, but, more so than d transition metal analogues. These results enable construction of general, predictive metal-ligand 15N chemical shift-bond order correlations, and reframe our understanding of actinide chemical bonding to guide future studies.
An intermittent detachment faulting system with a large sulfide deposit revealed by multi-scale magnetic surveys
Authors: Wu Tao , Tivey Maurice A. , Tao Chunhui , Zhang Jinhui , Zhou Fei , Liu Yunlong
Published: October 2021

Magmatic and tectonic processes can contribute to discontinuous crustal accretion and play an important role in hydrothermal circulation at ultraslow-spreading ridges, however, it is difficult to accurately describe the processes without an age framework to constrain crustal evolution. Here we report on a multi-scale magnetic survey that provides constraints on the fine-scale evolution of a detachment faulting system that hosts hydrothermal activity at 49.7°E on the Southwest Indian Ridge. Reconstruction of the multi-stage detachment faulting history shows a previous episode of detachment faulting took place 0.76~1.48 My BP, while the present fault has been active for the past ~0.33 My and is just in the prime of life. This fault sustains hydrothermal circulation that has the potential for developing a large sulfide deposit. High resolution multiscale magnetics allows us to constrain the relative balance between periods of detachment faulting and magmatism to better describe accretionary processes on an ultraslow spreading ridge.
Palladium-catalyzed regio- and enantioselective migratory allylic C(sp3)-H functionalization
Authors: Chen Ye-Wei , Liu Yang , Lu Han-Yu , Lin Guo-Qiang , He Zhi-Tao
Published: October 2021

Transition metal-catalyzed asymmetric allylic substitution with a suitably pre-stored leaving group in the substrate is widely used in organic synthesis. In contrast, the enantioselective allylic C(sp3)-H functionalization is more straightforward but far less explored. Here we report a catalytic protocol for the long-standing challenging enantioselective allylic C(sp3)-H functionalization. Through palladium hydride-catalyzed chain-walking and allylic substitution, allylic C-H functionalization of a wide range of acyclic nonconjugated dienes is achieved in high yields (up to 93% yield), high enantioselectivities (up to 98:2 er), and with 100% atom efficiency. Exploring the reactivity of substrates with varying pKa values uncovers a reasonable scope of nucleophiles and potential factors controlling the reaction. A set of efficient downstream transformations to enantiopure skeletons showcase the practical value of the methodology. Mechanistic experiments corroborate the PdH-catalyzed asymmetric migratory allylic substitution process.
ENSO impacts child undernutrition in the global tropics
Authors: Anttila-Hughes Jesse K. , Jina Amir S. , McCord Gordon C.
Published: October 2021

The El Niño Southern Oscillation (ENSO) is a principal component of global climate variability known to influence a host of social and economic outcomes, but its systematic effects on human health remain poorly understood. We estimate ENSO’s association with child nutrition at global scale by combining variation in ENSO intensity from 1986-2018 with children’s height and weight from 186 surveys conducted in 51 teleconnected countries, containing 48% of the world’s under-5 population. Warmer El Niño conditions predict worse child undernutrition in most of the developing world, but better outcomes in the small number of areas where precipitation is positively affected by warmer ENSO. ENSO’s contemporaneous effects on child weight loss are detectable years later as decreases in height. This relationship looks similar at both global and regional scale, and has not appreciably weakened over the last four decades. Results imply that almost 6 million additional children were underweight during the 2015 El Niño compared to a counterfactual of neutral ENSO conditions in 2015. This demonstrates a pathway through which human well-being remains subject to predictable climatic processes.