bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Cellular DNA Damage Responses in Cancer: An In Vitro-Calibrated Agent-Based Model Simulating Monolayer and Spheroid Treatment Responses to ATR-Inhibiting Drugs
Authors: Hamis Sara , Yates James , Chaplain Mark A. J. , Powathil Gibin G.
Published: August 2021

We combine a systems pharmacology approach with an agent-based modelling approach to simulate LoVo cells subjected to AZD6738, an ATR (ataxia–telangiectasia-mutated and rad3-related kinase) inhibiting anti-cancer drug that can hinder tumour proliferation by targeting cellular DNA damage responses. The agent-based model used in this study is governed by a set of empirically observable rules. By adjusting only the rules when moving between monolayer and multi-cellular tumour spheroid simulations, whilst keeping the fundamental mathematical model and parameters intact, the agent-based model is first parameterised by monolayer in vitro data and is thereafter used to simulate treatment responses in in vitro tumour spheroids subjected to dynamic drug delivery. Spheroid simulations are subsequently compared to in vivo data from xenografts in mice. The spheroid simulations are able to capture the dynamics of in vivo tumour growth and regression for approximately 8 days post-tumour injection. Translating quantitative information between in vitro and in vivo research remains a scientifically and financially challenging step in preclinical drug development processes. However, well-developed in silico tools can be used to facilitate this in vitro to in vivo translation, and in this article, we exemplify how data-driven, agent-based models can be used to bridge the gap between in vitro and in vivo research. We further highlight how agent-based models, that are currently underutilised in pharmaceutical contexts, can be used in preclinical drug development.
Wirtschaftsstatistik im Wandel – Wichtige gesetzliche Neuerungen in der 19. Legislaturperiode
Authors: Bork Christhart , Pannhorst Matthias , Weißenberger Martin
Published: August 2021

Die 19. Legislaturperiode neigt sich dem Ende, was Anlass dazu gibt, einen Rückblick auf die gesetzlichen Neuerungen in dieser Zeit im Bereich der Wirtschaftsstatistik vorzunehmen. Gerade die Corona-Krise hat einmal mehr gezeigt, wie wichtig moderne, zeitnah verfügbare und differenzierte Wirtschaftsstatistiken für die Wirtschaftspolitik sind. Dieser oft (zu) wenig beachtete Politikzweig entwickelt sich seit Jahren äußerst dynamisch. Getrieben von mehreren Großprojekten, die umfassende Reformen bestehender Statistikgesetzgebung anstießen, und stets geprägt von der sich rapide vollziehenden Digitalisierung der amtlichen Statistik waren die gesetzlichen Vorhaben in der Statistikgesetzgebung der 19. Legislaturperiode außergewöhnlich umfangreich und vielschichtig. In diesem Artikel wollen wir die einzelnen Vorhaben in den Blick nehmen und Kontext, Genese sowie besondere Herausforderungen kurz beschreiben.
Childhood traumatization and dissociative experiences among maladaptive and normal daydreamers in a Hungarian sample
Authors: Sándor Alexandra , Bugán Antal , Nagy Attila , Nagy Nikolett , Tóth-Merza Katalin , Molnár Judit
Published: August 2021

The aim of the study was to identify some potential etiological segments of maladaptive daydreaming, especially the relationships between maladaptive daydreaming, childhood traumatization, and dissociative propensity. The questionnaire package included the Hungarian version of the Maladaptive Daydreaming Scale, the Traumatic Antecedents Questionnaire, as well as the Dissociation Questionnaire. 717 participants were recruited online, 106 of whom were problematic daydreamers. The results revealed that certain types of childhood trauma occurred significantly more frequently in the group of maladaptive daydreamers. Furthermore, maladaptive daydreamers possessed a significantly higher level of dissociative propensity compared to normal daydreamers. The estimated SEM models showed that dissociative experiences - more precisely Identity confusion and fragmentation and Lack of control – mediated the relationship between certain childhood traumatic experiences and maladaptive daydreaming. The results suggest that we should consider childhood traumatization and increased dissociative propensity as potentially significant factors in the etiology of maladaptive daydreaming.
Dirichlet series expansions of p-adic L-functions
Authors: Knospe Heiko , Washington Lawrence C.
Published: August 2021

We study p-adic L-functions $$L_p(s,\chi )$$

L
p

(
s
,
χ
)

for Dirichlet characters $$\chi $$
χ
. We show that $$L_p(s,\chi )$$

L
p

(
s
,
χ
)

has a Dirichlet series expansion for each regularization parameter c that is prime to p and the conductor of $$\chi $$
χ
. The expansion is proved by transforming a known formula for p-adic L-functions and by controlling the limiting behavior. A finite number of Euler factors can be factored off in a natural manner from the p-adic Dirichlet series. We also provide an alternative proof of the expansion using p-adic measures and give an explicit formula for the values of the regularized Bernoulli distribution. The result is particularly simple for $$c=2$$

c
=
2

, where we obtain a Dirichlet series expansion that is similar to the complex case.
A New Ensemble-Based Intrusion Detection System for Internet of Things
Authors: Abbas Adeel , Khan Muazzam A. , Latif Shahid , Ajaz Maria , Shah Awais Aziz , Ahmad Jawad
Published: August 2021

The domain of Internet of Things (IoT) has witnessed immense adaptability over the last few years by drastically transforming human lives to automate their ordinary daily tasks. This is achieved by interconnecting heterogeneous physical devices with different functionalities. Consequently, the rate of cyber threats has also been raised with the expansion of IoT networks which puts data integrity and stability on stake. In order to secure data from misuse and unusual attempts, several intrusion detection systems (IDSs) have been proposed to detect the malicious activities on the basis of predefined attack patterns. The rapid increase in such kind of attacks requires improvements in the existing IDS. Machine learning has become the key solution to improve intrusion detection systems. In this study, an ensemble-based intrusion detection model has been proposed. In the proposed model, logistic regression, naive Bayes, and decision tree have been deployed with voting classifier after analyzing model’s performance with some prominent existing state-of-the-art techniques. Moreover, the effectiveness of the proposed model has been analyzed using CICIDS2017 dataset. The results illustrate significant improvement in terms of accuracy as compared to existing models in terms of both binary and multi-class classification scenarios.
Dual-phase-lag one-dimensional thermo-porous-elasticity with microtemperatures
Authors: Liu Z. , Quintanilla R.
Published: August 2021

This paper is devoted to studying the linear system of partial differential equations modelling a one-dimensional thermo-porous-elastic problem with microtemperatures in the context of the dual-phase-lag heat conduction. Existence, uniqueness, and exponential decay of solutions are proved. Polynomial stability is also obtained in the case that the relaxation parameters satisfy a certain equality. Our arguments are based on the theory of semigroups of linear operators.
Identification of Adrenomedullin-Induced S-Nitrosylated Proteins in JEG-3 Placental Cells
Authors: Li Yingting , Zhong Liuying , Lee Cheuk-Lun , Chiu Philip C.N. , Chen Min
Published: August 2021

Extravillous cytotrophoblast (EVCT) is responsible for trophoblast invasion, which is important during placentation. Dysregulation of the process leads to pregnancy complications. S-nitrosylation of proteins is associated with cell invasion in many cell types. Adrenomedullin (ADM), a polypeptide expressed abundantly in the first-trimester placentas, induces EVCT invasion by upregulation of protein S-nitrosylation. This study aimed to identify the S-nitrosylated proteins induced by ADM in the JEG-3 placental cells. By using affinity chromatography followed by mass spectrometric analysis, tubulin, enolase, eukaryotic translation initiation factor 4A1, actin, annexin II (ANX II), and glyceraldehyde 3-phosphate dehydrogenaseprotein-1 were found to be S-nitrosylated by ADM. In vitro treatment with ADM or S-Nitrosoglutathione (GSNO) significantly increased the ANX II surface expression, but not its total expression in the JEG-3 cells. Translocation of ANX II to cell surface has been reported to act as a cell surface receptor to plasmin, plasminogen, and tissue plasminogen activator (tPA), thereby stimulating cell invasion and migration. However, in this study, ADM-induced surface expression of ANX II in the JEG-3 cells was not associated with changes in the secretory and membrane-bound tPA activities. Future studies are required to understand the roles of surface expression of S-nitrosylated ANX II on trophoblast functions. To conclude, this study provided evidences that ADM regulated the nitric oxide signaling pathway and modulated trophoblast invasion.
Sexual Satisfaction and Associated Biopsychosocial Factors in Stroke Patients Admitted to Specialized Cognitive Rehabilitation
Authors: Vikan Jannike K. , Snekkevik Hildegun , Nilsson Marie I. , Stanghelle Johan K. , Geirdal Amy Østertun , Fugl-Meyer Kerstin S.
Published: August 2021

Introduction

The consequences of stroke on sexual life in stroke patients in need of specialized cognitive rehabilitation have been limited explored. A biopsychosocial perspective in post-stroke sexuality studies is warranted to capture the complex picture of stroke consequences and sexual life after stroke and sexual satisfaction is an important outcome measure when exploring such multifactorial associations.

Aim

To explore sexual satisfaction and associated biopsychosocial factors in stroke patients admitted to specialized cognitive rehabilitation.

Methods

A cross-sectional study was performed including 91 consecutive stroke patients admitted to specialized cognitive rehabilitation. Data were collected from medical records and by face-to-face interviews using a structured interview guide and questionnaires. Descriptive and inferential statistics were applied.

Main outcome measures

A wide range of biopsychosocial variables including medical and sociodemographic characteristics, social support, sexual complaints, aspects of sexual life, psychological distress and life satisfaction were analyzed in relation to the main outcome “Satisfaction with sexual life.”

Results

Only 33 % were satisfied with sexual life. Prevalence of sexual complaints was high, more frequent in women (84%) than in men (64%). Three-quarters were less sexually active than before stroke. Multivariable analyses showed that anxiety, sleep problems, manifested sexual complaint, decrease in sexual activity and fear of partner rejection were significantly associated with low odds of sexual satisfaction, while affectionate support and partnership satisfaction were significant for sexual satisfaction. When combined in a biopsychosocial multivariable model only fear of partner rejection (OR 0.07; 95 % CI: 0.01–0.42) and decrease in sexual activity (OR 0.11; 95 % CI: 0.02–0.58) showed significant contribution to sexual satisfaction.

Conclusion

The variety of predictors for sexual satisfaction indicates that therapeutic actions need to be individualized and points towards a broad assessment and interventional approach to meet the sexual rehabilitation needs of stroke patients with cognitive impairments in need of specialized rehabilitation.
Effectiveness of prophylactic ondansetron in preventing spinal anesthesia induced hypotension and bradycardia in pregnant mother undergoing elective cesarean delivery: A double blinded randomized control trial, 2021
Authors: Mohamed Salih , Befkadu Aynalem , Mohammed Ayub , Neme Derartu , Ahmed Siraj , Yimer Yusuf , Girma Timsel
Published: August 2021

ABSTRACT

Background:

Spinal anesthesia is the most common techniques of regional anesthesia for cesarean section. However, hypotension is the most common complication associated with nausea and vomiting, altered mental status and risk of aspiration. Bradycardia is also a common feature of profound circulatory collapse under neuraxial anesthesia. After verification that, serotonin can induce BJR reflex and can causes bradycardia or hypotension, researchers started to evaluate the effect of ondansetron to decrease BJR reflex in human being.

Objectives:

To assess the effect of prophylactic ondansetron for prevention of spinal induced hypotension and bradycardia in parturients undergoing cesarean delivery from June 1, 2020 to January 30, 2021.

Method:

ology: A double blinded randomized control trial conducted in Dilla university referral hospital by recruiting 70 patients with systematic random sampling technique. Patients were randomized into ondansetron group (n = 35) and control group (n = 35). Mann Whitney U test was used for continuous non-normally distributed data and independent sample t-test for normally distributed data. Mixed ANOVA was used to analysis the interaction of the within and between factors. Categorical variable between the groups were analyzed using fisher exact and chi square test. p -value<0.05 is considered statically significant.

Result:

There were no significant differences in the incidence of hypotension between ondansetron (20(57) and saline group (21(60%)). There were no significant difference in incidence of bradycardia among the two groups p > 0.05. Perioperative Phenylephrine consumption was 36.43 ± 45.91 mcg and 32.14 ± 46.79 mcg in ondansetron and saline group respectively with P = 0.700. The incidence of shivering was lower in ondansetron group (11%) than saline group (45%) with (p = 0.04) and the perioperative rescue shivering requirement was higher in saline group (p = 0.00).

Conclusion:

and Recommendations: Prophylaxis administration of intravenous Ondansetron at a dose of 10 mg before spinal anesthesia was not effective in reducing the incidence of hypotension and bradycardia in pregnant women undergoing cesarean section.

Highlights
Spanish speakers’ English schwar production: Does orthography play a role?
Authors: Shea Christine
Published: August 2021

This study examines how input mode – whether written or auditory – interacts with orthography in the production of North American English (NAE) schwar (/ɝ/, found in fur, heard, bird) by native Spanish speakers. Greater orthographic interference was predicted for written input, given the obligatory activation of orthographic representations in the execution of the task. Participants were L1 Mexican Spanish/L2 English speakers (L2, n = 15) and NAE (n = 15, rhotic dialect speakers). The target items were 10 schwar words and 10 words matched in graphemes to the onset and nucleus of the schwar words (e.g., bird was matched with big), for a total of 20 items. The degree of overlap between schwar productions across group and input mode (L2 only) was analyzed, followed by a generalized additive mixed model analysis of F3, one of the acoustic cues to rhotacization. Results showed that L2 schwar productions were different from the NAE productions in both the overlap and F3 measures, and the written input mode showed greater L1 orthographic interference than the auditory input mode, supporting the hypothesis that L1 orthography–phonology correspondences affect L2 productions of English schwar words.
Petrophysical Property Modifications by Alteration in a Volcanic Sequence at IODP Site U1513, Naturaliste Plateau
Authors: Lee Eun Young , Tejada Maria Luisa G. , Song Insun , Chun Seung Soo , Gier Susanne , Riquier Laurent , White Lloyd T. , Schnetger Bernhard , Brumsack Hans‐Jürgen , Jones Matthew M. , Martinez Mathieu
Published: August 2021

Petrophysical properties of volcanic rocks are controlled by lithology and subsequent modification by alteration processes. Investigating the linkages, using a range of different techniques, are important to establish how petrophysical properties can inform about the alteration state of volcanic rocks. Here, we compile petrophysical data and correlate these with geochemical and mineralogical analyses acquired from a volcanic sequence on the Naturaliste Plateau, offshore southwest Australia (International Ocean Discovery Program Site U1513). The sequence consists of alternating basalt lava flows and volcaniclastic deposits, intruded by multiple dolerite dikes. Variable alteration intensities from fresh‐slight to strong are quantified using Chemical Index of Alteration. Intervals of slightly altered dikes exhibit low porosity and high values of bulk density, P‐wave velocity, and thermal conductivity. The increase of alteration intensity corresponds to decreases in bulk density to ∼2 g/cm3, P‐wave velocity to ∼2,000 m/s, thermal conductivity to ∼1.2 W/(m·K) and an increase in porosity up to 50%. Natural Gamma Ray and magnetic susceptibility vary downhole with rock composition and at lithologic boundaries. The distinct variations exhibit a good correlation with primary lithologic characteristics and secondary mineralogical and textural changes attributed to alteration processes. We provide synthesis models of petrophysical variation with alteration intensity. Although differences in primary lithology and alteration type introduce limitations and uncertainties, there is a reasonable applicability of our results to rapidly characterize the alteration intensity and volcanic stratigraphy in volcanic sequences and to calibrate wireline log‐based determinations. This will help others to develop strategies for exploration, drilling, and geophysical research of volcanic rocks.
Sediment Routing and Anthropogenic Impact in the Huanghe River Catchment, China: An Investigation Using Nd Isotopes of River Sediments
Authors: Guo Yulong , Li Chao , Wang Chenyu , Xu Juan , Jin Chenyang , Yang Shouye
Published: August 2021

The Huanghe once had a sediment flux of >1,000 Mt/yr, but this has decreased by ∼90% as its river sediment routing systems have undergone dramatic changes influenced by human activities such as dam construction. However, the way in which the sediment geochemistry of the river has responded to the altered sediment routing processes is not well known. This study investigates the sediment source‐to‐sink routing regime of the Huanghe River using Nd isotope fingerprinting. Four major source terranes, namely the Songpan‐Ganzi (SG) Block, Ordos Desert (OD), Chinese Loess Plateau (CLP) and North China Craton (NCC) are recognized according to their distinct Nd isotopes. The gradual downstream decrease in εNd values in sediments of the upper Huanghe indicates a decreasing contribution of material from the SG Block and a corresponding increase contribution of local underlying basement rocks, which is inferred to be related to sediment capture by a cascade of hydroelectric dams. A gradual increase in εNd from Yinchuan to Tongguan suggests an increasing contribution from the CLP under intense erosion. Relatively low εNd in the downstream sediments suggest a contribution from proximal NCC basement, consistent with the shift from deposition to erosion in the lower channel in recent years. The marked heterogeneity in Nd isotopes in the Huanghe sediments corresponds well to sediment source‐to‐sink processes in response to increasing human impacts. In a setting of global rivers facing strong anthropogenic impacts, the ways in which altered sediment routing systems affect river sediment geochemistry deserve more research attention.
On the Impact of Rainfall Spatial Variability, Geomorphology, and Climatology on Flash Floods
Authors: Saharia Manabendra , Kirstetter Pierre‐Emmanuel , Vergara Humberto , Gourley Jonathan J. , Emmanuel Isabelle , Andrieu Hervé
Published: August 2021

The effects of spatial variability of rainfall, geomorphology, and climatology of precipitation and temperature on the hydrologic response remain poorly understood. This study characterizes the catchment response in terms of a variable called flashiness, that describes the severity of the flood response as the rate of rise of the unit discharge. It overcomes limitations of prior works based on limited case studies or simulations by gathering information on basins of widely varying characteristics and by using a high‐resolution rainfall and flooding event data set spanning 10 years over the Continental United States. The objective is to develop a robust understanding of how rainfall spatial variability influences flash flood severity and to assess its contribution relative to basin physiography and climatology. This study explores the first‐order dependencies as well as the variability in these relationships and investigates the complex interactions using a multi‐dimensional statistical modeling approach. The results confirm that the spatial organization of rainfall influences the basin response on par with geomorphology and climatology. Basin physiography dampens the effect of lower rainfall intensities, while higher rainfall overwhelms other factors and primarily contributes to flashiness. Dispersion of precipitation with respect to the flow path decreases flood severity. An improved understanding of sub‐basin scale rainfall spatial variability aids in developing a robust flash flood severity index to identify and mitigate flash flooding situations as well as identifying basins which could most benefit from distributed hydrologic modeling.
Inferring Polluted Asian Absorbing Aerosol Properties Using Decadal Scale AERONET Measurements and a MIE Model
Authors: Wang Shuo , Wang Xinying , Cohen Jason Blake , Qin Kai
Published: August 2021

Absorbing aerosols uniquely impact radiation, aerosol transport, and meteorology. This paper quantifies black carbon core and sulphate shell size and mass using decadal measurements of multi‐spectral aerosol optical depth, single scattering albedo, and angstrom exponent from Aerosol Robotic Network stations located throughout East, Southeast, and South Asia, in connection with a MIE model. All sites are uniquely characterized into four types: urban, biomass burning, long‐range transport, and clean. Unique size and mass probability distributions of both the core and shell are calculated within each classification. Well known urban, biomass burning, and clean sites are all properly identified. Furthermore, two unique sites previously thought to not have multiple characteristics are identified, with urban and biomass burning significant in Beijing and long‐range transport significant in the otherwise clean South China Sea at Taiping Island. It is hoped that these results will allow for advances in attribution and radiative forcing studies.
Impact of Tropical Cyclones on Geostrophic Velocity of the Western Boundary Current
Authors: Park Jae‐Hyoung , Pak Gyundo , Kim Eun Jin , Kang Sok Kuh
Published: August 2021

Tropical cyclones (TC), which are among the most destructive natural phenomena on Earth, have significant impacts on the western boundary current (WBC). We quantify the direct impact of TCs on the surface geostrophic velocity of the Kuroshio, the WBC in the western North Pacific, by analyzing satellite‐derived geostrophic current data and using results from theoretical and numerical models. The study reveals that TCs decrease the surface geostrophic velocity by 14 cm s−1 which is 16% of the mean velocity of the Kuroshio (85 cm s−1), with the reduced velocity maintained for a month. The decrease in velocity of the Kuroshio is mainly (87%) due to the effect of TC‐driven upwelling (“Cooling effect”), the effect of ocean heat uptake after the TC (“Warming effect”) being minor (13%); these are basically enabled by the strong thermal gradient around the Kuroshio.
Electrified Postsunrise Ionospheric Perturbations at Millstone Hill
Authors: Zhang Shun‐Rong , Erickson Philip J. , Gasque L. C. , Aa Ercha , Rideout William , Vierinen Juha , Goncharenko Larisa P. , Coster Anthea J.
Published: August 2021

We provide evidence that midlatitude postsunrise traveling ionospheric disturbances (TIDs) are comprised of electrified waves with an eastward propagation component. The post‐sunrise gravity wave (GW) wind‐induced dynamo action effectively generated periodic meridional polarization electric fields (PEFs), facilitating TID zonal propagation in a similar fashion as GW‐driven neutral perturbations. A combination of near‐simultaneous eastward and upward observations using the Millstone Hill incoherent scatter radar along with 2‐dimensional total electron content maps allowed resolution of TID vertical and horizontal propagation as well as zonal ion drifts (meridional PEFs). In multiple observations, oscillated in the early morning during periods when TIDs exhibited downward phase progression, 30–60 min period, 140 m/s eastward speed, and 70 km vertical wavelength. Inside these TIDs, multiple flow vortexes occurred in a vertical‐zonal plane spanning the ionospheric topside and bottomside. Subsequently, PEFs weakened after a few hours as TID horizontal wavefronts rotated clockwise.
Interaction Between Stratospheric Kelvin Waves and Gravity Waves in the Easterly QBO Phase
Authors: Kim Young‐Ha , Achatz Ulrich
Published: August 2021

A general circulation model is used to study the interaction between parameterized gravity waves (GWs) and large‐scale Kelvin waves in the tropical stratosphere. The simulation shows that Kelvin waves with substantial amplitudes (∼10 m s−1) can significantly affect the distribution of GW drag by modulating the local shear. Furthermore, this effect is localized to regions above strong convective organizations that generate large‐amplitude GWs, so that at a given altitude it occurs selectively in a certain phase of Kelvin waves. Accordingly, this effect also contributes to the zonal‐mean GW drag, which is large in the middle stratosphere during the phase transition of the quasi‐biennial oscillation (QBO). Furthermore, we detect an enhancement of Kelvin‐wave momentum flux due to GW drag modulated by Kelvin waves. The result implies an importance of GW dynamics coupled to Kelvin waves in the QBO progression.
Characterizing the Relationship Between Non‐Darcy Effect and Hydraulic Aperture in Rough Single Fractures
Authors: Xing Kun , Qian Jiazhong , Ma Haichun , Luo Qiankun , Ma Lei
Published: August 2021

Hydraulic aperture (eh) which is independent of inertial effect has been widely used as an important parameter to study the geometric properties of single fractures in previous studies. However, the inertial effect dependence of hydraulic aperture was gradually revealed in recent studies. Therefore, hydraulic aperture could provide a new method to characterize the non‐Darcy effect. In this study, 2D numerical simulations based on Navier‐Stokes equation were carried out to explore the feasibility of characterizing non‐Darcy effect based on hydraulic aperture. The results showed that the onset of flow regimes transition from Darcy to non‐Darcy could be well characterized by the hydraulic aperture. Before the non‐Darcy flow appeared, the initial hydraulic aperture (eh0) maintained constant regardless of the inertial effect (quantified by non‐Darcy effect factor E), once the non‐Darcy effect emerged, the hydraulic aperture decreased with the increase of inertial effect. The increased volume of low‐velocity zone in the rough single fractures was considered as the mechanism of non‐Darcy effect. And the existence of critical relative roughness (Rc) was found and it would affect the critical non‐Darcy effect factor (Ed) or critical Reynolds number (Rec) by affecting the development of low velocity region and preferential flow paths. From the overall trend, the hydraulic aperture decreased with the increase of E, and it fluctuated due to the development of recirculation zones (RZs). Moreover, the predictive model of non‐Darcy effect factor (E) based on hydraulic aperture was obtained and the validity of the model was preliminarily verified.
Lysosomes in acute myeloid leukemia: potential therapeutic targets?
Authors: Rafiq Sreoshee , McKenna Sharon L. , Muller Sylviane , Tschan Mario P. , Humbert Magali
Published: August 2021

Lysosomes, since their discovery, have been primarily known for degrading cellular macromolecules. However, in recent studies, they have begun to emerge as crucial regulators of cell homeostasis. They are at the crossroads of catabolic and anabolic pathways and are intricately involved in cellular trafficking, nutrient signaling, energy metabolism, and immune regulation. Their involvement in such essential cellular functions has renewed clinical interest in targeting the lysosome as a novel way to treat disease, particularly cancer. Acute myeloid leukemia (AML) is an aggressive blood cancer with a low survival probability, particularly in older patients. The genomic landscape of AML has been extensively characterized but few targeted therapies (with the exception of differentiation therapy) can achieve a long-term cure. Therefore, there is an unmet need for less intensive and more tolerable therapeutic interventions. In this review, we will give an overview on the myriad of functions performed by lysosomes and their importance in malignant disease. Furthermore, we will discuss their relevance in hematopoietic cells and different ways to potentially target them in AML.
Grey and white matter microstructure is associated with polygenic risk for schizophrenia
Authors: Stauffer Eva-Maria , Bethlehem Richard A. I. , Warrier Varun , Murray Graham K. , Romero-Garcia Rafael , Seidlitz Jakob , Bullmore Edward T.
Published: August 2021

Recent discovery of approximately 270 common genetic variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. We hypothesized that normal variation in PRS would be associated with magnetic resonance imaging (MRI) phenotypes of brain morphometry and tissue composition. We used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macrostructural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts. Linear mixed-effect models were used to investigate associations between PRS and brain structure at global and regional scales, controlled for multiple comparisons. Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures, and 14 white matter tracts. Other microstructural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate, and prefrontal cortical areas, insula, and hippocampus. Post-hoc bidirectional Mendelian randomization analyses provided preliminary evidence in support of a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia. Risk-related reduction in NDI is plausibly indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks. Cortical, subcortical, and white matter microstructure may be linked to the genetic mechanisms of schizophrenia.
The Smac mimetic BV6 cooperates with STING to induce necroptosis in apoptosis-resistant pancreatic carcinoma cells
Authors: Hannes Sabine , Karlowitz Rebekka , van Wijk Sjoerd J. L.
Published: August 2021

Pancreatic cancer (PC) still remains a major cause of cancer-related death worldwide and alternative treatments are urgently required. A common problem of PC is the development of resistance against apoptosis that limits therapeutic success. Here we demonstrate that the prototypical Smac mimetic BV6 cooperates with the stimulator of interferon (IFN) genes (STING) ligand 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) to trigger necroptosis in apoptosis-deficient PC cells. Pharmacological inhibition of key components of necroptosis signaling, such as receptor-interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL), significantly rescues PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death, suggesting the induction of necroptosis. Consistently, 2′3′-cGAMP/BV6 co-treatment promotes phosphorylation of MLKL. Furthermore, we show that 2′3′-cGAMP stimulates the production of type I IFNs, which cooperate with BV6 to trigger necroptosis in apoptosis-deficient settings. STING silencing via siRNA or CRISPR/Cas9-mediated gene knockout protects PC cells from 2′3′-cGAMP/BV6/zVAD.fmk-mediated cell death. Interestingly, we demonstrate that nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNFα), and IFN-regulatory factor 1 (IRF1) signaling are involved in triggering 2′3′-cGAMP/BV6/zVAD.fmk-induced necroptosis. In conclusion, we show that activated STING and BV6 act together to exert antitumor effects on PC cells with important implications for the design of new PC treatment concepts.
Exosomal transfer of tumor-associated macrophage-derived hsa_circ_0001610 reduces radiosensitivity in endometrial cancer
Authors: Gu Xiaobin , Shi Yonggang , Dong Meilian , Jiang Li , Yang Jing , Liu Zheyan
Published: August 2021

The occurrence of radioresistance is a clinical obstacle to endometrial cancer (EC) treatment and induces tumor relapse. In this study, we found that tumor-associated macrophages (TAMs) enriched in EC specimens were determined to present an M2-like phenotype. In vitro, the coculture of M2-polarized macrophages significantly downregulated the radiosensitivity of EC cells by releasing exosomes. Hsa_circ_0001610 was found to be abundant in exosomes derived from M2-polarized macrophages (EXOs), and hsa_circ_0001610 knockdown eliminated the reduction effect of EXOs on the radiosensitivity of EC cells. The following mechanism research revealed that hsa_circ_0001610 functioned as the competing endogenous RNA of miR-139-5p, thereby upregulating cyclin B1 expression, which is a vital pusher of radioresistance in several types of cancer by regulating the cell cycle. Hsa_circ_0001610 overexpression reduced the radiosensitivity of EC cells, which was then reversed by miR-139-5p overexpression. In vivo, the promotion effect of EXOs on xenograft tumor growth in nude mice treated with irradiation was further reinforced after hsa_circ_0001610 overexpression. In conclusion, TAM-derived exosomes transferred hsa_circ_0001610 to EC cells, and the overexpressed hsa_circ_0001610 in EC cells released cyclin B1 expression through adsorbing miR-139-5p, thereby weakening the radiosensitivity of EC cells.
Microbial production of megadalton titin yields fibers with advantageous mechanical properties
Authors: Bowen Christopher H. , Sargent Cameron J. , Wang Ao , Zhu Yaguang , Chang Xinyuan , Li Jingyao , Mu Xinyue , Galazka Jonathan M. , Jun Young-Shin , Keten Sinan , Zhang Fuzhong
Published: August 2021

Manmade high-performance polymers are typically non-biodegradable and derived from petroleum feedstock through energy intensive processes involving toxic solvents and byproducts. While engineered microbes have been used for renewable production of many small molecules, direct microbial synthesis of high-performance polymeric materials remains a major challenge. Here we engineer microbial production of megadalton muscle titin polymers yielding high-performance fibers that not only recapture highly desirable properties of natural titin (i.e., high damping capacity and mechanical recovery) but also exhibit high strength, toughness, and damping energy — outperforming many synthetic and natural polymers. Structural analyses and molecular modeling suggest these properties derive from unique inter-chain crystallization of folded immunoglobulin-like domains that resists inter-chain slippage while permitting intra-chain unfolding. These fibers have potential applications in areas from biomedicine to textiles, and the developed approach, coupled with the structure-function insights, promises to accelerate further innovation in microbial production of high-performance materials.
Lowering the thermal noise barrier in functional brain mapping with magnetic resonance imaging
Authors: Vizioli Luca , Moeller Steen , Dowdle Logan , Akçakaya Mehmet , De Martino Federico , Yacoub Essa , Uğurbil Kamil
Published: August 2021

Functional magnetic resonance imaging (fMRI) has become an indispensable tool for investigating the human brain. However, the inherently poor signal-to-noise-ratio (SNR) of the fMRI measurement represents a major barrier to expanding its spatiotemporal scale as well as its utility and ultimate impact. Here we introduce a denoising technique that selectively suppresses the thermal noise contribution to the fMRI experiment. Using 7-Tesla, high-resolution human brain data, we demonstrate improvements in key metrics of functional mapping (temporal-SNR, the detection and reproducibility of stimulus-induced signal changes, and accuracy of functional maps) while leaving the amplitude of the stimulus-induced signal changes, spatial precision, and functional point-spread-function unaltered. We demonstrate that the method enables the acquisition of ultrahigh resolution (0.5 mm isotropic) functional maps but is also equally beneficial for a large variety of fMRI applications, including supra-millimeter resolution 3- and 7-Tesla data obtained over different cortical regions with different stimulation/task paradigms and acquisition strategies.
A nutrient-responsive hormonal circuit mediates an inter-tissue program regulating metabolic homeostasis in adult Drosophila
Authors: Koyama Takashi , Terhzaz Selim , Naseem Muhammad T. , Nagy Stanislav , Rewitz Kim , Dow Julian A. T. , Davies Shireen A. , Halberg Kenneth V.
Published: August 2021

Animals maintain metabolic homeostasis by modulating the activity of specialized organs that adjust internal metabolism to external conditions. However, the hormonal signals coordinating these functions are incompletely characterized. Here we show that six neurosecretory cells in the Drosophila central nervous system respond to circulating nutrient levels by releasing Capa hormones, homologs of mammalian neuromedin U, which activate the Capa receptor (CapaR) in peripheral tissues to control energy homeostasis. Loss of Capa/CapaR signaling causes intestinal hypomotility and impaired nutrient absorption, which gradually deplete internal nutrient stores and reduce organismal lifespan. Conversely, increased Capa/CapaR activity increases fluid and waste excretion. Furthermore, Capa/CapaR inhibits the release of glucagon-like adipokinetic hormone from the corpora cardiaca, which restricts energy mobilization from adipose tissue to avoid harmful hyperglycemia. Our results suggest that the Capa/CapaR circuit occupies a central node in a homeostatic program that facilitates the digestion and absorption of nutrients and regulates systemic energy balance.
Asymmetric biomimetic transamination of α-keto amides to peptides
Authors: Cai Weiqi , Qiao Xuelong , Zhang Hao , Li Bo , Guo Jianhua , Zhang Liangliang , Chen Wen-Wen , Zhao Baoguo
Published: August 2021

Peptides are important compounds with broad applications in many areas. Asymmetric transamination of α-keto amides can provide an efficient strategy to synthesize peptides, however, the process has not been well developed yet and still remains a great challenge in both enzymatic and catalytic chemistry. For biological transamination, the high activity is attributed to manifold structural and electronic factors of transaminases. Based on the concept of multiple imitation of transaminases, here we report N-quaternized axially chiral pyridoxamines1for enantioselective transamination of α-keto amides, to produce various peptides in good yields with excellent enantio- and diastereoselectivities. The reaction is especially attractive for the synthesis of peptides made of unnatural amino acids since it doesn’t need great efforts to make chiral unnatural amino acids before amide bond formation.
The bowfin genome illuminates the developmental evolution of ray-finned fishes
Authors: Thompson Andrew W. , Hawkins M. Brent , Parey Elise , Wcisel Dustin J. , Ota Tatsuya , Kawasaki Kazuhiko , Funk Emily , Losilla Mauricio , Fitch Olivia E. , Pan Qiaowei , Feron Romain , Louis Alexandra , Montfort Jérôme , Milhes Marine , Racicot Brett L. , Childs Kevin L. , Fontenot Quenton , Ferrara Allyse , David Solomon R. , McCune Amy R. , Dornburg Alex , Yoder Jeffrey A. , Guiguen Yann , Roest Crollius Hugues , Berthelot Camille , Harris Matthew P. , Braasch Ingo
Published: August 2021

The bowfin (Amia calva) is a ray-finned fish that possesses a unique suite of ancestral and derived phenotypes, which are key to understanding vertebrate evolution. The phylogenetic position of bowfin as a representative of neopterygian fishes, its archetypical body plan and its unduplicated and slowly evolving genome make bowfin a central species for the genomic exploration of ray-finned fishes. Here we present a chromosome-level genome assembly for bowfin that enables gene-order analyses, settling long-debated neopterygian phylogenetic relationships. We examine chromatin accessibility and gene expression through bowfin development to investigate the evolution of immune, scale, respiratory and fin skeletal systems and identify hundreds of gene-regulatory loci conserved across vertebrates. These resources connect developmental evolution among bony fishes, further highlighting the bowfin’s importance for illuminating vertebrate biology and diversity in the genomic era.
Herbaceous perennial ornamental plants can support complex pollinator communities
Authors: Erickson E. , Patch H. M. , Grozinger C. M.
Published: August 2021

Human-designed landscapes can host diverse pollinator communities, and the availability of floral resources is central to supporting insect biodiversity in highly modified environments. However, some urban landscapes have relatively few pollinator-attractive plant species and management in urban environments rarely considers the function of these plants in generating and supporting a stable ecological community. Evaluations of 25 cultivars within five commercially popular herbaceous perennial ornamental plant genera (Agastache, Echinacea, Nepeta, Rudbeckia, and Salvia) revealed variation in the total and proportional abundance of visitors attracted. These varieties supported multiple pollinator functional groups, however bees were the primary visitors to in this system. Cultivars were assessed according to their function within a plant–pollinator network. Comparisons of artificial networks created with the six most attractive and six least attractive cultivars demonstrated that a planting scheme using the most attractive cultivars would attract nearly four times as many bee species, including several specialists and rare species. Plant diversity in the landscape was correlated with abundance and diversity of pollinator visitors, demonstrating that community context shapes a plant’s relative attractiveness to pollinators. We conclude that herbaceous perennial cultivars can support an abundance and diversity of pollinator visitors, however, planting schemes should take into consideration the effects of cultivar, landscape plant diversity, floral phenology, floral area, and contribution to a stable ecological community.
Homeostatic model of human thermoregulation with bi-stability
Authors: Hajnová Veronika , Zlámal Filip , Lenárt Peter , Bienertova-Vasku Julie
Published: August 2021

All homoiothermic organisms are capable of maintaining a stable body temperature using various negative feedback mechanisms. However, current models cannot satisfactorily describe the thermal adaptation of homoiothermic living systems in a physiologically meaningful way. Previously, we introduced stress entropic load, a novel variable designed to quantify adaptation costs, i.e. the stress of the organism, using a thermodynamic approach. In this study, we use stress entropic load as a starting point for the construction of a novel dynamical model of human thermoregulation. This model exhibits bi-stable mechanisms, a physiologically plausible features which has thus far not been demonstrated using a mathematical model. This finding allows us to predict critical points at which a living system, in this case a human body, may proceed towards two stabilities, only one of which is compatible with being alive. In the future, this may allow us to quantify not only the direction but rather the extent of therapeutic intervention in critical care patients.
Myocarditis occurrence with cancer immunotherapy across indications in clinical trial and post-marketing data
Authors: Makunts Tigran , Saunders Ila M. , Cohen Isaac V. , Li Mengxing , Moumedjian Talar , Issa Masara A. , Burkhart Keith , Lee Peter , Patel Sandip Pravin , Abagyan Ruben
Published: August 2021

Antibodies targeting the PD-1, PD-L1, and CTLA-4 immune checkpoint axis have been used in a variety of tumor types. They achieve anti-tumor activity through activating the patient’s own immune system to target immune response evading cancer cells. However, this unique mechanism of action may cause immune-related adverse events, irAEs. One of these irAEs is myocarditis which is associated with an alarming mortality rate. In this study we presented clinical cases of myocarditis from safety trial datasets submitted to the U.S. Food and Drug Administration, FDA. Additionally, we analyzed over fourteen million FDA Adverse Event Reporting System, FAERS, submissions. The statistical analysis of the FAERS data provided evidence of significantly increased reporting of myocarditis in patients administered immune checkpoint inhibitors alone, in combination with another immune checkpoint inhibitor, the kinase inhibitor axitinib, or chemotherapy, for all cancer types, when compared to patients administered chemotherapy. All combination therapies led to further increased reporting odds ratios of myocarditis. We further analyzed the occurrence of myocarditis by stratifying the reports into sub-cohorts based on specific cancer types and treatment/control groups in major cancer immunotherapy efficacy trials and confirmed the observed trend for each cohort.
Validating species distribution models to illuminate coastal fireflies in the South Pacific (Coleoptera: Lampyridae)
Authors: Sutherland Laura N. , Powell Gareth S. , Bybee Seth M.
Published: August 2021

The coastal areas of Vanuatu are under a multitude of threats stemming from commercialization, human development, and climate change. Atyphella Olliff is a genus of firefly that includes species endemic to these coastal areas and will need protection. The research that has already been conducted was affected by accessibility due to the remote nature of the islands which left numerous knowledge gaps caused by a lack of distributional data (e.g., Wallacean shortfall). Species distribution models (SDM) are a powerful tool that allow for the modeling of the broader distribution of a taxon, even with limited distributional data available. SDMs assist in filling the knowledge gap by predicting potential areas that could contain the species of interest, making targeted collecting and conservation efforts more feasible when time, resources, and accessibility are major limiting factors. Here a MaxEnt prediction was used to direct field collecting and we now provide an updated predictive distribution for this endemic firefly genus. The original model was validated with additional fieldwork, ultimately expanding the known range with additional locations first identified using MaxEnt. A bias analysis was also conducted, providing insight into the effect that developments such as roads and settlements have on collecting and therefore the SDM, ultimately allowing for a more critical assessment of the overall model. After demonstrating the accuracy of the original model, this new updated SDM can be used to identify specific areas that will need to be the target of future conservation efforts by local government officials.