bluuebunny/crossref_metadata_2025 huggingface dataset:
CURSE TABLETS AGAINST THIEVES IN ROMAN BRITAIN: THE SOCIAL AND LEGAL INFLUENCES ON A MAGICAL-RELIGIOUS TECHNOLOGY
Authors: Natalías Celia Sánchez
Published: March 2022

This article deals with curse tablets against thieves, also known as ‘prayers for justice’. In the first part, I offer a short introduction to the topic and the scholarly debate surrounding the definition of this type of inscription, concluding that a more emic approach can help us understand the complex nature of a technology that, far from being monolithic, evolved over time and space. In the second part, I compare the literary and epigraphic evidence (in Greek and Latin), pointing out the similarities and differences between our different sources of information. Finally, I turn to the handful of Latin curse tablets from Roman Britain in which the stolen object's value is divided between the principal and the invoked gods. In my view, this type of transaction should be analysed as a new take on the more traditional votum, in which legal concepts such as obligatio or ownership also play an important role. By establishing an almost contractual agreement with a deity, practitioners obtained not only divine assistance but also tangible evidence of the god's participation.
Greek History
Authors: Vlassopoulos Kostas
Published: March 2022

Free labour constitutes the largest black hole in ancient Greek economic and social history. The New Institutional Economics approaches that are currently so influential in Greek economic history focus on growth and transaction costs, but have largely ignored labour; it is not accidental that Bresson's monumental synthesis of ancient Greek economies has no chapter devoted to the issue. This is what makes the volume edited by Edmund Stewart, Edward Harris, and David Lewis on skilled labour and professionalism in ancient societies such an important contribution. The thirteen chapters explore three major issues. The first concerns the processes through which the division of labour and specialization created distinctions between unskilled and skilled labour. The second theme focuses on the major advantages that treasured skills offered to those individuals and groups that possessed them, and the ways in which individuals and states recruited and bargained with skilled labourers. The third is the extent to which it is possible to use the concept of professionalization to describe the process by which some ancient occupations came to constitute professions. The volume examines various case studies: while in some instances it is possible to describe such forms of skilled labour as professions (doctors, sculptors, musicians, actors), in other areas (athletes, soldiers) such a label is highly misleading. Particularly valuable in this respect is the exploration of the impact of various factors and processes on the extent of professionalization of different occupations.
Judges and Academics, and the Endless Road to Unattainable Perfection
Authors: Burrows Lord
Published: March 2022

This article is a lightly revised version of the Lionel Cohen Lecture 2021 given by the author in October 2021. It looks at the relationship between legal academics and judges. The title of the article derives from one of the judgments of the great Lord Goff. The article has three main parts. First, it explores the increased influence of legal academics on judges in England and Wales towards the end of the twentieth century. Secondly, it examines how academic work can assist judges and makes a plea for recognition of the importance of ‘practical legal scholarship’. Finally, drawing on the author's own recent experience, the article examines how being a judge of the United Kingdom Supreme Court differs from being an academic.
Entomopathogenic nematodes associated with organic honeybush (Cyclopia spp.) cultivation in South Africa
Authors: Daramola Fisayo Y. , Lewu Francis B. , Malan Antoinette P.
Published: March 2022

Entomopathogenic nematodes (EPNs) of the genera Steinernema and Heterorhabditis have demonstrated great potential as useful bio-control agents in the management of certain important soil-inhabiting insect pests of agricultural crops. In a survey of nematodes associated with organic honeybush cultivation, soil samples were obtained from nine organic honeybush plots, which are located in the Bredasdorp area of the Western Cape province of South Africa. The EPNs were isolated from soil by baiting with larvae of Galleria mellonella (greater wax moth) and identified by the amplification of the internal transcribed spacer region using the primer set TW81 and AB28. EPNs were abundant in the honeybush orchards, accounting for about 50% of the sampled fields and five EPN species were identified including Heterorhabditis bacteriophora, Heterorhabditis safricana, Steinernema khoisanae,. Steinernema nguyeni, Oscheius sp. and an unknown EPN, therefore suggesting a substantial diversity of EPNs in the sampled fields. A 100% mortality of infected G. mellonella larvae was recorded within 48 h of exposure to the nematodes. However, although these EPNs have been previously reported in South Africa, it is the first time they are found in such diversity on a conservative tillage management system in organic honeybush cultivation.
Κολληθέντɛς in Acts 17.34 and the Establishment of the Athenian Church
Authors: Evans David A.
Published: March 2022

It is commonly stated that while the author of Acts records some conversions that resulted from Paul's Athenian ministry, it is unlikely that a church was established in the city. This article argues, through an analysis of the use of the κολλάω word family in Luke-Acts, the Septuagint, early Christian writings and other relevant texts, that Luke uses the participle κολληθέντɛς as a way of signifying that a Christian community was indeed gathered together in Athens at this time. Leaving other social groups to join Paul and the other new believers, the new group is fused together by their shared faith, forming a new faith community in this ancient city.
Geometrically constrained path planning for robotic grasping with Differential Evolution and Fast Marching Square
Authors: Muñoz Javier , López Blanca , Quevedo Fernando , Barber Ramón , Garrido Santiago , Moreno Luis
Published: March 2022

This paper presents a new approach for geometrically constrained path planning applied to the field of robotic grasping. The method proposed in this paper is based on the Fast Marching Square (FM
$\, ^2$
) and a path calculation approach based on an optimization evolutionary filter named Differential Evolution (DE). The geometric restrictions caused by the link lengths of the kinematic chain composed by the robot arm and hand are introduced in the path calculation phase. This phase uses both the funnel potential of the surroundings created with FM
$\, ^2$
and the kinematic constraints of the robot as cost functions to be minimized by the evolutionary filter. The use of an optimization filter allows for a near-optimal solution that satisfies the kinematic restrictions, while preserving the characteristics of a path computed with FM
$\, ^2$
. The proposed method is tested in a simulation using a robot composed by a mobile base with two arms.
Integrating burrowing crayfish and waterfowl conservation management on moist-soil wetlands
Authors: Bloomer Caitlin C , Taylor Christopher A , Distefano Robert J
Published: March 2022

The North American Waterfowl Management Plan highlights the importance of enhancing waterfowl habitat for productivity and resilience. Many forms of land management are conducted in wetlands to support the diverse communities of waterfowl and other species. Primary burrowing crayfish are also abundant and important in these environments, but little research is available assessing the effects of waterfowl land management on primary burrowers. We examined the response of the digger crayfish,Creaserinus fodiens, to the common vegetation management practices of mowing and disking at waterfowl conservation areas in south-eastern Missouri. Our results demonstrated that at a fine scale, crayfish density was affected by only canopy cover. We also highlighted distributional effects of landscape-level environmental variables and suggested that habitat generalists were tolerant of vegetation management, responding more to vegetation composition and broader landscape effects. We discuss wetlands conservation practices and suggest that burrowing crayfish management would integrate well with some current management strategies for waterfowl.
Impact of the ARCH Project on National Capacity Development on Disaster Health Management among the ASEAN Member States and Japan
Authors: Kita Taro , Limpaporn Sansana , Silapunt Phumin , Koido Yuichi , Toyokuni Yoshiki , Ikeda Shuichi
Published: March 2022

Objective:

This report tries to capture the impact of the Project for Strengthening the ASEAN Regional Capacity on Disaster Health Management (ARCH Project) in each ASEAN Member State (AMS) and Japan as a result of the ARCH Project implementation since July 2016.

Methods:

Impact on AMS: The analysis of the impact on AMS was based on a comparison of the impact of the project on management and coordination of Emergency Medical Teams (EMTs), and application of the project outcome in actual emergency operations compared to the previous status in each AMS.

Impact on Japan: The history of the development of disaster medicine in Japan was reviewed, with an aim to analyze the impact of supporting AMS through the ARCH Project on Japan, and the possibility of bi-directional cooperation in the future.

Results:

Impact on AMS: Since the initiation of the ARCH Project, AMS has made significant progress in WHO EMT accreditation, strengthening EMTCC capacity for receiving international assistance, as well as the development of legislation or strategic plans related to DHM, and application of the Project products such as standard operating procedures or regional tools in actual disasters/emergencies.

Impact on Japan: Disaster medicine in Japan originated from the Cambodian refugees’ relief mission in 1979. Since then, the management system has been strengthened including the foundation of the Japan Disaster Relief (JDR) Team, a structure with a legal foundation. The experience gained through international operations has contributed to the development of Japan’s domestic disaster response system. Japan learned the operational effectiveness of the post-disaster health surveillance system through the disaster response operation in 2013 Typhoon Yolanda Disaster in Philippines and introduced a modified system in Japan for domestic disaster response, which was later refined and proposed for an international standard.

Conclusion:

ARCH Project is highly appreciated by AMS as the opportunity to share knowledge and experience among countries and thereby contributing to achieving the “One ASEAN, One Response” concept, as well as the driving force for each AMS to develop its capacity in DHM. While the ARCH Project started to support AMS to strengthen its regional capacity in disaster health management, it is important to build a bi-directional relationship between ASEAN and Japan in terms of mutual learning and support to tackle future disasters.
Impact of the COVID‐19 Economic Downturn on Tropospheric Ozone Trends: An Uncertainty Weighted Data Synthesis for Quantifying Regional Anomalies Above Western North America and Europe
Authors: Chang Kai‐Lan , Cooper Owen R. , Gaudel Audrey , Allaart Marc , Ancellet Gerard , Clark Hannah , Godin‐Beekmann Sophie , Leblanc Thierry , Van Malderen Roeland , Nédélec Philippe , Petropavlovskikh Irina , Steinbrecht Wolfgang , Stübi René , Tarasick David W. , Torres Carlos
Published: March 2022

This study quantifies the association between the COVID‐19 economic downturn and 2020 tropospheric ozone anomalies above Europe and western North America, and their impact on long‐term trends. Anomaly detection for an atmospheric time series is usually carried out by identifying potentially aberrant data points relative to climatological values. However, detecting ozone anomalies from sparsely sampled ozonesonde profiles (once per week at most sites) is challenging due to ozone's high temporal variability. We first demonstrate the challenges for summarizing regional trends based on independent time series from multiple nearby ozone profiling stations. We then propose a novel regional‐scale anomaly detection framework based on generalized additive mixed models, which accounts for the sampling frequency and inherent data uncertainty associated with each vertical profile data set, measured by ozonesondes, lidar or commercial aircraft. This method produces a long‐term monthly time series with high vertical resolution that reports ozone anomalies from the surface to the middle‐stratosphere under a unified framework, which can be used to quantify the regional‐scale ozone anomalies during the COVID‐19 economic downturn. By incorporating extensive commercial aircraft data and frequently sampled ozonesonde profiles above Europe, we show that the complex interannual variability of ozone can be adequately captured by our modeling approach. The results show that free tropospheric ozone negative anomalies in 2020 are the most profound since the benchmark year of 1994 for both Europe and western North America, and positive trends over 1994–2019 are diminished in both regions by the 2020 anomalies.
Magmatism at Passive Margins: Effects of Depth‐Dependent Wide Rifting and Lithospheric Counterflow
Authors: Lu Gang , Huismans Ritske S.
Published: March 2022

Rifted passive margins exhibit a large variety in the timing, distribution, and amount of magmatism. The factors controlling magmatism during rifted margin formation, remain, however, incompletely understood, partly owing to the complex rifting styles. In this study, we use 2‐Dimensional numerical models to investigate the effects of depth‐dependent wide rifting and lithospheric counterflow on magmatism during rifted margin formation. Results show that a strong crust promotes narrow margins with a sharp transition to normal thickness oceanic crust whereas a weak crust promotes depth‐dependent wide rifting, with preferential removal of mantle lithosphere, leading to formation of wide margins with over‐thickened (>18 km) igneous crust in the distal margin. Counterflow of depleted lithospheric mantle, in contrast, may delay syn‐rift magmatism, and result in exhumed a‐magmatic continental mantle at narrow margins. The combination of wide rifting and lithospheric counterflow results in magma‐poor wide margins, with in some cases a transition to excess magmatic activity at breakup. Our models provide an explanation for the contrasting magmatic productivity at narrow and wide rifted margins, such as observed in the Lofoten‐Vesterålen, Newfoundland, Kwanza Basin, and Orange Basin margins.
Thermal Equations of State of Corundum and Rh2O3 (II)‐Type Al2O3 up to 153 GPa and 3400 K
Authors: Shi Weigang , Wei Wei , Sun Ningyu , Mao Zhu , Prakapenka Vitali B.
Published: March 2022

In this study, we present new experimental constraints on the thermal equations of state of corundum and Rh2O3(II)‐type Al2O3 up to 153 GPa and 3400 K using synchrotron X‐ray diffraction in laser‐heated diamond anvil cells. Corundum was observed to transform into a mixture of corundum and Rh2O3(II)‐type Al2O3 at 106 GPa and 2300 K, accompanied by a strong kinetic barrier. The Rh2O3(II)‐type Al2O3 further transforms into the CaIrO3‐phase at 156 GPa and 3700 K. The transition from corundum to Rh2O3(II)‐type Al2O3 along a normal mantle geotherm could lead to a 1.9(5)% increase in density (ρ) but a 0.6(3)% decrease in bulk sound velocity (VΦ). Al2O3 is one of the major components of the anorthositic crust once this old crust was subducted to the deep mantle. Using the obtained thermoelastic parameters, we further modeled ρ and VΦ profiles of primordial anorthositic crust and found that the subducted fate of the primordial anorthositic crust depended strongly on its temperature. Our modeling reveals that primordial anorthositic crust along a normal mantle geotherm could descend to the transition zone but be trapped at the topmost lower mantle with a greater VΦ. Sinking of the anorthositic crust to the lower mantle can only occur along a 500–1000 K colder slab geotherm.
Spatial and Interannual Patterns of Epipelagic Summer Mesozooplankton Community Structures in the Western Arctic Ocean in 2016–2020
Authors: Kim Jee‐Hoon , La Hyoung Sul , Cho Kyoung‐Ho , Jung Jinyoung , Kang Sung‐Ho , Lee Kanghyun , Yang Eun Jin
Published: March 2022

Mesozooplankton play a crucial role as primary or secondary consumers in Arctic ecosystems and are sensitive indicators of environmental changes. This research is the first comprehensive Arctic zooplankton study covering the area ranging from the southern Chukchi Sea (SCS) and the northern Chukchi Sea (NCS) to the East Siberian Sea (ESS). Mesozooplankton samples were collected at 151 stations in the western Arctic Ocean each August from 2016 to 2020. The mesozooplankton abundance of the study area ranged from 9 to 6,172 ind. m−3, and the predominant group was copepods at 7–3,866 ind. m−3, of which Pseudocalanus spp. and Calanus glacialis were the most abundant copepods. In the SCS, small copepods and meroplankton, such as Pseudocalanus spp., Cirripedia larvae, Echinodermata larvae, and Centropages abdominalis were the predominant taxa. Especially in 2019, C. abdominalis dominated over meroplankton when water temperatures were high (maximum 12.5°C; sea surface temperature, SST). In the NCS and ESS, C. glacialis, Pseudocalanus spp., Metridia longa, Oithona similis, Parasagitta elegans, and Calanus hyperboreus were abundant. The distributions and structures of mesozooplankton communities indicated variability over large spatial scales in the western Arctic waters because of variations in multiple factors, such as water temperature, salinity, and sea ice; however, geographical effects cannot be ignored even during alterations in the physical properties. Our results suggest that these variable patterns of mesozooplankton communities fluctuate horizontally from south to north as warming progresses on a regional bathymetric basis, and can be used to infer the fate of mesozooplankton communities in the study area.
Long‐Lead Predictability of Western North Pacific Subtropical High
Authors: Pan Mengxin , Lu Mengqian
Published: March 2022

We present a new assembly of three steppingstones in thorough inquiry of the complex chain reaction from the diverse equatorial sea surface temperature (SST) pattern two‐season ahead to the East Asia summer weather condition, by regarding the western North Pacific subtropical high (WNPSH) as an anchor. We identified three predictors that are discordant with conventional climatic indices and achieve a good skill in the summer WNPSH prediction (temporal correlation coefficient of 0.78) with a two‐season long lead in the leave‐1‐year‐out cross‐validation during 1981–2020, despite the diversity of El Niño‐Southern Oscillation (ENSO) and Indian ocean dipole (IOD) patterns. Specifically, the first predictor captures the initiation and development of both IOD and El Niño via the SST warming over central equatorial Pacific in autumn; the second one serves as a better delegate of IOD by capturing the easterly acceleration over tropical Indian ocean; the third one illustrates the unprecedented informative role of upper‐level high pressure over the entire tropics in the WNPSH prediction with 5months lead time. They mediate the discordance between conventional climate indices and the diverse WNPSH response and caution people to revisit and rethink the complex atmosphere‐ocean coupled response from the diverse tropical SST patterns two seasons ahead to EA summer weather condition.
The ICON Earth System Model Version 1.0
Authors: Jungclaus J. H. , Lorenz S. J. , Schmidt H. , Brovkin V. , Brüggemann N. , Chegini F. , Crüger T. , De‐Vrese P. , Gayler V. , Giorgetta M. A. , Gutjahr O. , Haak H. , Hagemann S. , Hanke M. , Ilyina T. , Korn P. , Kröger J. , Linardakis L. , Mehlmann C. , Mikolajewicz U. , Müller W. A. , Nabel J. E. M. S. , Notz D. , Pohlmann H. , Putrasahan D. A. , Raddatz T. , Ramme L. , Redler R. , Reick C. H. , Riddick T. , Sam T. , Schneck R. , Schnur R. , Schupfner M. , von Storch J.‐S. , Wachsmann F. , Wieners K.‐H. , Ziemen F. , Stevens B. , Marotzke J. , Claussen M.
Published: March 2022

This work documents the ICON‐Earth System Model (ICON‐ESM V1.0), the first coupled model based on the ICON (ICOsahedral Non‐hydrostatic) framework with its unstructured, icosahedral grid concept. The ICON‐A atmosphere uses a nonhydrostatic dynamical core and the ocean model ICON‐O builds on the same ICON infrastructure, but applies the Boussinesq and hydrostatic approximation and includes a sea‐ice model. The ICON‐Land module provides a new framework for the modeling of land processes and the terrestrial carbon cycle. The oceanic carbon cycle and biogeochemistry are represented by the Hamburg Ocean Carbon Cycle module. We describe the tuning and spin‐up of a base‐line version at a resolution typical for models participating in the Coupled Model Intercomparison Project (CMIP). The performance of ICON‐ESM is assessed by means of a set of standard CMIP6 simulations. Achievements are well‐balanced top‐of‐atmosphere radiation, stable key climate quantities in the control simulation, and a good representation of the historical surface temperature evolution. The model has overall biases, which are comparable to those of other CMIP models, but ICON‐ESM performs less well than its predecessor, the Max Planck Institute Earth System Model. Problematic biases are diagnosed in ICON‐ESM in the vertical cloud distribution and the mean zonal wind field. In the ocean, sub‐surface temperature and salinity biases are of concern as is a too strong seasonal cycle of the sea‐ice cover in both hemispheres. ICON‐ESM V1.0 serves as a basis for further developments that will take advantage of ICON‐specific properties such as spatially varying resolution, and configurations at very high resolution.
Exploring Pathways to More Accurate Machine Learning Emulation of Atmospheric Radiative Transfer
Authors: Ukkonen Peter
Published: March 2022

Machine learning (ML) parameterizations of subgrid physics is a growing research area. A key question is whether traditional ML methods such as feed‐forward neural networks (FNNs) are better suited for representing only specific processes. Radiation schemes are an interesting example, because they compute radiative flows through the atmosphere using well‐established physical equations. The sequential aspect of the problem implies that FNNs may not be well‐suited for it. This study explores whether emulating the entire radiation scheme is more difficult than its components without vertical dependencies. FNNs were trained to replace a shortwave radiation scheme, its gas optics component, and its reflectance‐transmittance computations. In addition, a novel recurrent NN (RNN) method was developed to structurally incorporate the vertical dependence and sequential nature of radiation computations. It is found that a bidirectional RNN with an order of magnitude fewer model parameters than FNN is considerably more accurate, while offering a smaller but still significant 4‐fold speedup over the original code on CPUs, and a larger speedup on GPUs. The RNN predicts fluxes with less than 1% error, and heating rates computed from fluxes have a root‐mean‐square‐error of 0.16 K day−1 in offline tests using a year of global data. Finally, FNNs emulating gas optics are very accurate while being several times faster. As with RNNs emulating radiative transfer, the smaller dimensionality may be crucial for developing models that are general enough to be used as parameterizations.
Provenance of Inorganic Carbon Sinks in Closed Basins
Authors: Li Yu , Hao Lu , Han Qin , Zhang Yuxin , Peng Simin , Zhang Xinzhong
Published: March 2022

Much dissolved inorganic carbon (DIC) may exist in lacustrine carbonates in the terminal lakes of closed basins in arid areas, and inorganic carbon sinks in arid regions are an important hypothesis of global carbon cycle research in recent years. Previous studies have made significant progress in estimating the inorganic carbon content. However, the source of inorganic carbon sinks remains unclear. Here, we choose four typical arid closed basins in North China to investigate the provenance of inorganic carbon sinks. The results show that CO2 absorbed by saline‐alkaline soil is the main source of groundwater DIC in the study area, with a contribution rate of approximately 50%. Forty‐three groundwater radiocarbon ages from arid closed basins indicate that the DIC in groundwater is transported along the direction of water flow and deposited in terminal lakes, forming inorganic carbon sinks. Our study suggests that the total inorganic carbon contents of Zhuye Lake, Yanchi Lake, Huahai Lake, and Qinghai Lake in the Holocene are 0.318 Pg, 0.003 Pg, 0.160 Pg, and 3.289 Pg, respectively. The results demonstrate that inorganic carbon sinks are much larger than lake organic carbon storage, thereby serving as an important carbon cycle factor in arid regions.
Indoxyl sulfate- and P-cresol-induced monocyte adhesion and migration is mediated by integrin-linked kinase-dependent podosome formation
Authors: Campillo Sofía , Bohorquez Lourdes , Gutiérrez-Calabrés Elena , García-Ayuso Diego , Miguel Verónica , Griera Mercedes , Calle Yolanda , de Frutos Sergio , Rodríguez-Puyol Manuel , Rodríguez-Puyol Diego , Calleros Laura
Published: March 2022

Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate (IS), are poorly removed during hemodialysis, leading to vascular endothelial dysfunction and leukocyte extravasation. These processes can be related to dynamic adhesion structures called podosomes. Several studies have indicated the role of integrin-linked kinase (ILK) in the accumulation of integrin-associated proteins in podosomes. Here, we investigated the involvement of ILK and podosome formation in the adhesion and extravasation of monocytes under p-cresol (pc) and IS exposure. Incubation of THP-1 human monocyte cells with these toxins upregulated ILK kinase activity. Together, both toxins increased cell adhesion, podosome formation, extracellular matrix degradation, and migration of THP-1 cells, whereas ILK depletion with specific small interfering RNAs suppressed these processes. Interestingly, F-actin colocalized with cortactin in podosome cores, while ILK was colocalized in podosome rings under toxin stimulation. Podosome Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP) and AKT protein depletion demonstrated that monocyte adhesion depends on podosome formation and that the ILK/AKT signaling pathway is involved in these processes. Ex vivo experiments showed that both toxins induced adhesion and podosome formation in leukocytes from wild-type mice, whereas these effects were not observed in leukocytes of conditional ILK-knockdown animals. In summary, under pc and IS stimulation, monocytes increase podosome formation and transmigratory capacity through an ILK/AKT signaling pathway-dependent mechanism, which could lead to vascular injury. Therefore, ILK could be a potential therapeutic target for the treatment of vascular damage associated with CKD.
Region-based analysis of rare genomic variants in whole-genome sequencing datasets reveal two novel Alzheimer’s disease-associated genes: DTNB and DLG2
Authors: Prokopenko Dmitry , Lee Sanghun , Hecker Julian , Mullin Kristina , Morgan Sarah , Katsumata Yuriko ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Weiner Michael W. , Fardo David W. , Laird Nan , Bertram Lars , Hide Winston , Lange Christoph , Tanzi Rudolph E.
Published: March 2022

Alzheimer’s disease (AD) is a genetically complex disease for which nearly 40 loci have now been identified via genome-wide association studies (GWAS). We attempted to identify groups of rare variants (alternate allele frequency <0.01) associated with AD in a region-based, whole-genome sequencing (WGS) association study (rvGWAS) of two independent AD family datasets (NIMH/NIA; 2247 individuals; 605 families). Employing a sliding window approach across the genome, we identified several regions that achieved association p values <10−6, using the burden test or the SKAT statistic. The genomic region around the dystobrevin beta (DTNB) gene was identified with the burden and SKAT test and replicated in case/control samples from the ADSP study reaching genome-wide significance after meta-analysis (pmeta = 4.74 × 10−8). SKAT analysis also revealed region-based association around the Discs large homolog 2 (DLG2) gene and replicated in case/control samples from the ADSP study (pmeta = 1 × 10−6). In conclusion, in a region-based rvGWAS of AD we identified two novel AD genes, DLG2 and DTNB, based on association with rare variants.
Colorectal liver metastasis: molecular mechanism and interventional therapy
Authors: Zhou Hui , Liu Zhongtao , Wang Yongxiang , Wen Xiaoyong , Amador Eric H. , Yuan Liqin , Ran Xin , Xiong Li , Ran Yuping , Chen Wei , Wen Yu
Published: March 2022

Colorectal cancer (CRC) is one of the most frequently occurring malignancy tumors with a high morbidity additionally, CRC patients may develop liver metastasis, which is the major cause of death. Despite significant advances in diagnostic and therapeutic techniques, the survival rate of colorectal liver metastasis (CRLM) patients remains very low. CRLM, as a complex cascade reaction process involving multiple factors and procedures, has complex and diverse molecular mechanisms. In this review, we summarize the mechanisms/pathophysiology, diagnosis, treatment of CRLM. We also focus on an overview of the recent advances in understanding the molecular basis of CRLM with a special emphasis on tumor microenvironment and promise of newer targeted therapies for CRLM, further improving the prognosis of CRLM patients.
Schizophrenia risk loci from xMHC region were associated with antipsychotic response in chronic schizophrenic patients with persistent positive symptom
Authors: Li Jiang , Yoshikawa Akane , Alliey-Rodriguez Ney , Meltzer Herbert Y.
Published: March 2022

We examined whether common variants from the extended major histocompatibility complex (xMHC) region contribute to the response to antipsychotic drugs (APDs) in patients with schizophrenia with persistent psychosis. Subjects participated in a prospective longitudinal study of the effect of APDs on psychopathology were temporally split into discovery (n = 88) and replication (n = 42) cohorts. The primary endpoint was a change in Brief Psychiatric Rating Scale at 6-week or 6-month after treatment. rs204991 (β = 3.917, p = 3.72 × 10−6), the strongest signal associated with response at 6-week was located near C4A/C4B after a linear regression adjusted for covariates. xMHC SNP imputation disclosed much stronger signals (rs9268469, β = 5.140, p = 1.57 × 10−7) and other weaker signals (p < 1 × 10−5) spanning the entire xMHC region. All the variants were previously identified schizophrenia risk loci. Conditional fine-mapping revealed three subgroups of SNPs which were the eQTLs (p < 1 × 10−7) for C4A, HLA-C, and BTN3A2 in disease-relevant tissue. Epistasis between HLA-C and C4A was observed (p = 0.019). Minor allele (G) carriers of rs204991, eQTL for C4A, having decreased risk for schizophrenia and lower imputed expression of C4A, had a better response to APDs. Some imputed HLA alleles associated with a decreased risk for schizophrenia had a positive association with improvement in psychotic symptoms. An independent cohort validated the association of change in psychosis with C4A. We provide evidence that genetic risk factors for schizophrenia from the xMHC region are associated with response to APDs and those variants significantly alter the imputed expression of C4A, HLA-C, and BTN3A2. The minor alleles predicting higher C4A level are associated with diminished improvement in psychotic symptoms after APD treatment.
Identification of the estrogen receptor beta as a possible new tamoxifen-sensitive target in diffuse large B-cell lymphoma
Authors: Langendonk Myra , de Jong Mathilde R. W. , Smit Nienke , Seiler Jonas , Reitsma Bart , Ammatuna Emanuele , Glaudemans Andor W. J. M. , van den Berg Anke , Huls Gerwin A. , Visser Lydia , van Meerten Tom
Published: March 2022

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Despite the proven efficacy of combined immunochemotherapy (R-CHOP) in the majority of patients, ~40% of DLBCL patients do not respond or will relapse and consequently have a very poor prognosis. The development of targeted therapies has not improved patient survival, underscoring the need for new treatment approaches. Using an unbiased genome-wide CD20 guilt-by-association approach in more than 1800 DLBCL patients, we previously identified the estrogen receptor beta (ERβ) as a new target in DLBCL. Here, we demonstrate that ERβ is expressed at significantly higher levels in DLBCL compared to normal B cells, and ERβ plays a role in the protection against apoptosis in DLBCL. Targeting of the ERβ with the selective estrogen receptor modulator tamoxifen reduces cell viability in all tested DLBCL cell lines. Tamoxifen-induced cell death was significantly decreased in an ERβ knock-out cell line. The activity of tamoxifen was confirmed in a xenograft human lymphoma model, as tumor growth decreased, and survival significantly improved. Finally, tamoxifen-treated breast cancer (BC) patients showed a significantly reduced risk of 38% for DLBCL compared to BC patients who did not receive tamoxifen. Our findings provide a rationale to investigate tamoxifen, a hormonal drug with a good safety profile, in DLBCL patients.
Heterogeneity induced GZMA-F2R communication inefficient impairs antitumor immunotherapy of PD-1 mAb through JAK2/STAT1 signal suppression in hepatocellular carcinoma
Authors: Gao Yuxue , Xu Qingguo , Li Xinqiang , Guo Yuan , Zhang Bowen , Jin Yan , zhu Cunle , Shen Yuntai , Yang Pengxiang , Shi Ying , Jin Rifeng , Liu Daojie , Ouyang Yabo , Liu Xiaoni , Wang Wenjing , Chen Dexi , Yang Tongwang
Published: March 2022

Tumor heterogeneity has been associated with immunotherapy and targeted drug resistance in hepatocellular carcinoma (HCC). However, communications between tumor and cytotoxic cells are poorly understood to date. In the present study, thirty-one clusters of cells were discovered in the tumor tissues and adjacent tissues through single-cell sequencing. Moreover, the quantity and function exhaustion of cytotoxic cells was observed to be induced in tumors by the TCR and apoptosis signal pathways. Furthermore, granzyme failure of cytotoxic cells was observed in HCC patients. Importantly, the GZMA secreted by cytotoxic cells was demonstrated to interact with the F2R expressed by the tumor cells both in vivo and in vitro. This interaction induced tumor suppression and T cell-mediated killing of tumor cells via the activation of the JAK2/STAT1 signaling pathway. Mechanistically, the activation of JAK2/STAT1 signaling promoted apoptosis under the mediating effect of the LDPRSFLL motif at the N-terminus of F2R, which interacted with GZMA. In addition, GZMA and F2R were positively correlated with PD-1 and PD-L1 in tumor tissues, while the expressions of F2R and GZMA promoted PD-1 mAb-induced tumor suppression in both mouse model and HCC patients. Finally, in HCC patients, a low expression of GZMA and F2R in the tumor tissues was correlated with aggressive clinicopathological characteristics and poor prognosis. Collectively, GZMA-F2R communication inefficient induces deficient PD-1 mAb therapy and provide a completely novel immunotherapy strategy for tumor suppression in HCC patients.
Geographically dispersed zoonotic tuberculosis in pre-contact South American human populations
Authors: Vågene Åshild J. , Honap Tanvi P. , Harkins Kelly M. , Rosenberg Michael S. , Giffin Karen , Cárdenas-Arroyo Felipe , Leguizamón Laura Paloma , Arnett Judith , Buikstra Jane E. , Herbig Alexander , Krause Johannes , Stone Anne C. , Bos Kirsten I.
Published: March 2022

Previous ancient DNA research has shown that Mycobacterium pinnipedii, which today causes tuberculosis (TB) primarily in pinnipeds, infected human populations living in the coastal areas of Peru prior to European colonization. Skeletal evidence indicates the presence of TB in several pre-colonial South and North American populations with minimal access to marine resources— a scenario incompatible with TB transmission directly from infected pinnipeds or their tissues. In this study, we investigate the causative agent of TB in ten pre-colonial, non-coastal individuals from South America. We reconstruct M. pinnipedii genomes (10- to 15-fold mean coverage) from three contemporaneous individuals from inland Peru and Colombia, demonstrating the widespread dissemination of M. pinnipedii beyond the coast, either through human-to-human and/or animal-mediated routes. Overall, our study suggests that TB transmission in the pre-colonial era Americas involved a more complex transmission pathway than simple pinniped-to-human transfer.
Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer
Authors: Lopez Andrea , Reyna Denis E. , Gitego Nadege , Kopp Felix , Zhou Hua , Miranda-Roman Miguel A. , Nordstrøm Lars Ulrik , Narayanagari Swathi-Rao , Chi Ping , Vilar Eduardo , Tsirigos Aristotelis , Gavathiotis Evripidis
Published: March 2022

Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.
Topological charge-entropy scaling in kagome Chern magnet TbMn6Sn6
Authors: Xu Xitong , Yin Jia-Xin , Ma Wenlong , Tien Hung-Ju , Qiang Xiao-Bin , Reddy P. V. Sreenivasa , Zhou Huibin , Shen Jie , Lu Hai-Zhou , Chang Tay-Rong , Qu Zhe , Jia Shuang
Published: March 2022

In ordinary materials, electrons conduct both electricity and heat, where their charge-entropy relations observe the Mott formula and the Wiedemann-Franz law. In topological quantum materials, the transverse motion of relativistic electrons can be strongly affected by the quantum field arising around the topological fermions, where a simple model description of their charge-entropy relations remains elusive. Here we report the topological charge-entropy scaling in the kagome Chern magnet TbMn6Sn6, featuring pristine Mn kagome lattices with strong out-of-plane magnetization. Through both electric and thermoelectric transports, we observe quantum oscillations with a nontrivial Berry phase, a large Fermi velocity and two-dimensionality, supporting the existence of Dirac fermions in the magnetic kagome lattice. This quantum magnet further exhibits large anomalous Hall, anomalous Nernst, and anomalous thermal Hall effects, all of which persist to above room temperature. Remarkably, we show that the charge-entropy scaling relations of these anomalous transverse transports can be ubiquitously described by the Berry curvature field effects in a Chern-gapped Dirac model. Our work points to a model kagome Chern magnet for the proof-of-principle elaboration of the topological charge-entropy scaling.
Tropical extreme droughts drive long-term increase in atmospheric CO2 growth rate variability
Authors: Luo Xiangzhong , Keenan Trevor F.
Published: March 2022

The terrestrial carbon sink slows the accumulation of carbon dioxide (CO2) in the atmosphere by absorbing roughly 30% of anthropogenic CO2 emissions, but varies greatly from year to year. The resulting variations in the atmospheric CO2 growth rate (CGR) have been related to tropical temperature and water availability. The apparent sensitivity of CGR to tropical temperature ($${{{{{{\rm{\gamma }}}}}}}_{{{{{{\rm{CGR}}}}}}}^{{{{{{\rm{T}}}}}}}$$

γ

CGR

T

) has changed markedly over the past six decades, however, the drivers of the observation to date remains unidentified. Here, we use atmospheric observations, multiple global vegetation models and machine learning products to analyze the cause of the sensitivity change. We found that a threefold increase in $${{{{{{\rm{\gamma }}}}}}}_{{{{{{\rm{CGR}}}}}}}^{{{{{{\rm{T}}}}}}}$$

γ

CGR

T

emerged due to the long-term changes in the magnitude of CGR variability (i.e., indicated by one standard deviation of CGR; STDCGR), which increased 34.7% from 1960-1979 to 1985-2004 and subsequently decreased 14.4% in 1997-2016. We found a close relationship (r2 = 0.75, p < 0.01) between STDCGR and the tropical vegetated area (23°S – 23°N) affected by extreme droughts, which influenced 6-9% of the tropical vegetated surface. A 1% increase in the tropical area affected by extreme droughts led to about 0.14 Pg C yr−1 increase in STDCGR. The historical changes in STDCGR were dominated by extreme drought-affected areas in tropical Africa and Asia, and semi-arid ecosystems. The outsized influence of extreme droughts over a small fraction of vegetated surface amplified the interannual variability in CGR and explained the observed long-term dynamics of $${{{{{{\rm{\gamma }}}}}}}_{{{{{{\rm{CGR}}}}}}}^{{{{{{\rm{T}}}}}}}$$

γ

CGR

T

.
A bottom-up reward pathway mediated by somatostatin neurons in the medial septum complex underlying appetitive learning
Authors: Shen Li , Zhang Guang-Wei , Tao Can , Seo Michelle B. , Zhang Nicole K. , Huang Junxiang J. , Zhang Li I. , Tao Huizhong W.
Published: March 2022

Valence detection and processing are essential for the survival of animals and their life quality in complex environments. Neural circuits underlying the transformation of external sensory signals into positive valence coding to generate appropriate behavioral responses remain not well-studied. Here, we report that somatostatin (SOM) subtype of GABAergic neurons in the mouse medial septum complex (MS), but not parvalbumin subtype or glutamatergic neurons, specifically encode reward signals and positive valence. Through an ascending pathway from the nucleus of solitary tract and then parabrachial nucleus, the MS SOM neurons receive rewarding taste signals and suppress the lateral habenula. They contribute essentially to appetitive associative learning via their projections to the lateral habenula: learning enhances their responses to reward-predictive sensory cues, and suppressing their responses to either conditioned or unconditioned stimulus impairs acquisition of reward learning. Thus, MS serves as a critical hub for transforming bottom-up sensory signals to mediate appetitive behaviors.
Surface loss calculations and design of a superconducting transmon qubit with tapered wiring
Authors: Martinis John M.
Published: March 2022

Analytical formulas are presented for simplified but useful qubit geometries that predict surface dielectric loss when its thickness is much less than the metal thickness, the limiting case needed for real devices. These formulas can thus be used to precisely predict loss and optimize the qubit layout. Surprisingly, a significant fraction of surface loss comes from the small wire that connects the Josephson junction to the qubit capacitor. Tapering this wire is shown to significantly lower its loss. Also predicted are the size and density of the two-level state (TLS) spectrum from individual surface dissipation sites.
Experimental implementation of secure anonymous protocols on an eight-user quantum key distribution network
Authors: Huang Zixin , Joshi Siddarth Koduru , Aktas Djeylan , Lupo Cosmo , Quintavalle Armanda O. , Venkatachalam Natarajan , Wengerowsky Sören , Lončarić Martin , Neumann Sebastian Philipp , Liu Bo , Samec Željko , Kling Laurent , Stipčević Mario , Ursin Rupert , Rarity John G.
Published: March 2022

Anonymity in networked communication is vital for many privacy-preserving tasks. Secure key distribution alone is insufficient for high-security communications. Often, knowing who transmits a message to whom and when must also be kept hidden from an adversary. Here, we experimentally demonstrate five information-theoretically secure anonymity protocols on an eight user city-wide quantum network using polarisation entangled photon pairs. At the heart of these protocols is anonymous broadcasting, which is a cryptographic primitive that allows one user to reveal one bit of information while keeping their identity anonymous. For a network of n users, the protocols retain anonymity for the sender, given that no more than n − 2 users are colluding. This is an implementation of genuine multi-user cryptographic protocols beyond standard QKD. Our anonymous protocols enhance the functionality of any fully-connected Quantum Key Distribution network without trusted nodes.
In vivo lensless microscopy via a phase mask generating diffraction patterns with high-contrast contours
Authors: Adams Jesse K. , Yan Dong , Wu Jimin , Boominathan Vivek , Gao Sibo , Rodriguez Alex V. , Kim Soonyoung , Carns Jennifer , Richards-Kortum Rebecca , Kemere Caleb , Veeraraghavan Ashok , Robinson Jacob T.
Published: March 2022

The simple and compact optics of lensless microscopes and the associated computational algorithms allow for large fields of view and the refocusing of the captured images. However, existing lensless techniques cannot accurately reconstruct the typical low-contrast images of optically dense biological tissue. Here we show that lensless imaging of tissue in vivo can be achieved via an optical phase mask designed to create a point spread function consisting of high-contrast contours with a broad spectrum of spatial frequencies. We built a prototype lensless microscope incorporating the ‘contour’ phase mask and used it to image calcium dynamics in the cortex of live mice (over a field of view of about 16 mm2) and in freely moving Hydra vulgaris, as well as microvasculature in the oral mucosa of volunteers. The low cost, small form factor and computational refocusing capability of in vivo lensless microscopy may open it up to clinical uses, especially for imaging difficult-to-reach areas of the body.