bluuebunny/crossref_metadata_2025 huggingface dataset:
Nation-Building in an Autonomous Community
Authors: McRoberts Kenneth
Published: June 2022

With the statute of autonomy enacted, Catalonia was at last able to elect its own parliament. But who was to lead Catalonia and in what direction? With the return of democracy to Catalonia, control of the Generalitat was captured by a conservative form of Catalan nationalism that focused on securing and expanding autonomy within Spain, as opposed to full independence. In the hands of conservative nationalists, the Generalitat apparently was not disposed even to pursue the full fiscal independence that the Basque Country had secured. Still, despite the weak constitutional basis of its autonomy and the prevalence of an integral Spanish nationalism in much of the country, the Generalitat was able to pursue a comprehensive program of ‘nation-building without a state’.
Japan’s Rise to Naval Prominence
Authors: Kowner Rotem
Published: June 2022

This chapter evaluates the way the battle affected the Japanese actions in the following years and the way it has been commemorated ever since. The battle established Japan’s naval supremacy in East Asian waters and brought it dramatically closer to its desired goal since the outbreak of hostilities: peace negotiations with Russia following their military triumph on sea and land. More importantly, the Battle of Tsushima became a prominent landmark in the rise of the Imperial Japanese Navy. It was celebrated throughout the country and instantly made Admiral Togo a national hero. Thereafter, this doctrine called for the use of a strong battleship force which would destroy an invading fleet in a single stroke as it approached Japan after suffering losses by attrition as it penetrated the nation’s perimeter defences. This chapter shows how the battle remained a reference point for the navy’s Decisive Battle Doctrine in subsequent years and discusses its implications. In addition, the chapter explores the three stages that mark the battle’s memory in Japan during the subsequent century: jubilation, amnesia, and pride.
Conclusion
Authors: Kowner Rotem
Published: June 2022

This chapter offers a comprehensive analysis of the outcomes of the Battle of Tsushima and its significance from historical and naval perspectives. It begins with the question of whether the battle was determined by Russian failure or Japanese success and argues that both sides contributed to the extreme outcomes. The Russians fulfilled all three basic categories of military failure, whereas the Japanese overcame these hurdles by learning, anticipating, and adapting. Despite the Russian inadequacies, the chapter concludes that Tsushima was a ‘great battle’, perhaps even greater than other notable great naval battles. Considering its decisiveness, immediate outcomes, and long-lasting repercussions, the Battle of Tsushima deserves a more central place in historical writing
Defeat and Internment
Authors: Moore Bob
Published: June 2022

The defeat and incarceration of the bulk of the French Army after June 1940 justifies separate treatment on account of its sheer scale. Having taken some 1.8 million French servicemen as prisoners, the Germans removed around 1.5 million of them to Germany to augment the agricultural labour force inside the Reich where most remained for the duration of the war. Although the terms of the Geneva Convention were largely adhered to, the prisoners’ captivity was also influenced by the bilateral treaties between Pétain’s Vichy regime and Berlin. The Germans also engaged in some largely unsuccessful attempts to encourage the French prisoners to become civilians with the promise of better pay and conditions, and at the same time used them as bargaining counters with the Vichy authorities to extract much more useful civilian skilled industrial labour from France—the so-called Relève. With so many men held as hostages, the Vichy regime also saw the prisoners as an important domestic political issue and went to great lengths to offer protection to their wives and families. There were wartime repatriations and some escapes, but the majority of the officers and soldiers of 1940 remained in Germany until their liberation
War of Annihilation
Authors: Moore Bob
Published: June 2022

Unlike the war in the West, the war of annihilation proclaimed by Hitler in the run-up to Operation Barbarossa and the attack on the Soviet Union also had a major impact on prisoner-taking and the treatment of captives. Debates on the barbarization of warfare essentially began with Christian Streit’s Keine Kameraden but have continued unabated since then, with much new evidence emerging from Soviet sources in the last fifteen years. The deaths of around two million Soviet captives in the first six months of the conflict from ill treatment and starvation ranks alongside any of the major war crimes of the twentieth century and has been attributed by different authors to deliberate policy, neglect, or a shortage of Wehrmacht resources. This chapter charts Hitler’s many interventions and the development of Wehrmacht policies towards captured Red Army personnel from the first directives, including the infamous Kommissarbefehl, before the war began through to the revisions made as a result of the overwhelming success of the early military campaigns in the East. It also looks at conditions on the ground and questions whether local initiatives might have ameliorated conditions that led to deaths on scale never seen before.
Soviet Prisoners in German Captivity 1942‒1945
Authors: Moore Bob
Published: June 2022

By early 1942 the Germans gradually saw the advantages of Soviet prisoners as cheap labour, and even as a source of additional manpower for the hard-pressed armed forces. They were therefore deployed in the eastern territories and even in the Reich itself—albeit still given much less consideration than their Allied counterparts. Despite their appalling treatment, there were examples of resistance by Soviet prisoners, including sabotage and even some cases of open insurrection. Ultimately anything up to 1.3 million prisoners were ostensibly persuaded to join German military formations, either as an escape from the appalling conditions of their captivity, or because they could not expect any mercy from their own side after the publication of Stalin’s Order No. 270, or because they had little sympathy for communism, or because they saw the war as a means of pursuing their own nationalist agendas against the forces of Russian imperialism. This helps to explain how large numbers of former Soviet soldiers were captured in NW Europe by the Western powers during and after 1944 which was later to create diplomatic and political problems when their repatriation was being contemplated.
Women as Prisoners of War
Authors: Moore Bob
Published: June 2022

Most Second World War historiography on female prisoners of war comes from the relatively small numbers of military nurses captured by the Japanese in the Far East. In Western Europe, women were mobilized into auxiliary services and were seldom anywhere near the front line. Indeed, there were only one or two cases of female prisoners of war falling into German hands. Towards the end of the war, the Germans mobilized huge numbers of women into auxiliary roles and into anti-aircraft units. They became prisoners alongside the rest of the German armed forces in May 1945—in either British, American, or Russian hands—and thus endured very different fates at the hands of their captors. On the Eastern Front, German forces encountered female Russian soldiers from the outset of Operation Barbarossa and captured large numbers—many of whom shared the deprivations, ill treatment, and death meted out to their male counterparts.
Conclusions
Authors: Moore Bob
Published: June 2022

Summing up the elements discussed in the previous chapters there are reflections on the nature of surrender and the ‘conventional’ German treatment of Western prisoners – as well some anomalies, most notably the colonial troops of the French and British. This is nevertheless in stark contrast to the murderous disregard for Soviet captives and the huge death-toll this created. Female prisoners were also a feature of the conflict. Initially demonized by the Germans, they were later afforded some protection as military prisoners, as were both male and female francs-tireurs in several theatres of war. There are also reflections on the very different experiences of repatriation of British, American, French and Soviet prisoners to their respective homelands, as well as discussion of the continuing incarceration of Axis prisoners by all the powers before the final repatriations from the Soviet Union in 1956.
Denmark
Authors: Grønborg Ulrik , Ravn-Petersen Kristian
Published: June 2022

This chapter focuses on the legal system in Denmark: the civil law system. It reports that the law of Denmark covers only Denmark and not the Faroe Islands or Greenland. The EU Regulation may, however, be applicable to the estates of Danish citizens who are resident of another EU member state. The chapter then illustrates the four types of wills described in the Danish Inheritance Act: wills signed before a notary, wills signed before two witnesses, emergency wills, and wills that only concern household items and personal effects. It also elaborates on the intestate succession which is governed by the Inheritance Act of 1 January 2008. Ultimately, the chapter examines the compulsory shares for husband/wife/common law wife, civil partner, and children under Danish law. It also looks at the specific rules relating to maintenance for the descendants or the spouse of the deceased as well as the community property and the deceased’s share of jointly owned property.
Light at night in older age is associated with obesity, diabetes, and hypertension
Authors: Kim Minjee , Vu Thanh-Huyen , Maas Matthew B , Braun Rosemary I , Wolf Michael S , Roenneberg Till , Daviglus Martha L , Reid Kathryn J , Zee Phyllis C
Published: June 2022

Light at night (LAN) has been associated with negative health consequences and metabolic risk factors. Little is known about the prevalence of LAN in older adults in the United States and its association with CVD risk factors. We tested the hypothesis that LAN in older age is associated with higher prevalence of individual CVD risk factors. Five hundred and fifty-two community-dwelling adults aged 63−84 years underwent an examination of CVD risk factor profiles and 7-day actigraphy recording for activity and light measures. Associations between actigraphy-measured LAN, defined as no light vs. light within the 5-hour nadir (L5), and CVD risk factors, including obesity, diabetes, hypertension, and hypercholesterolemia, were examined, after adjusting for age, sex, race, season of recording, and sleep variables. LAN exposure was associated with a higher prevalence of obesity (multivariable-adjusted odds ratio [OR] 1.82 [95% CI 1.26−2.65]), diabetes (OR 2.00 [1.19−3.43]), and hypertension (OR 1.74 [1.21−2.52]) but not with hypercholesterolemia. LAN was also associated with (1) later timing of lowest light exposure (L5-light) and lowest activity (L5-activity), (2) lower inter-daily stability and amplitude of light exposure and activity, and (3) higher wake after sleep onset. Habitual LAN in older age is associated with concurrent obesity, diabetes, and hypertension. Further research is needed to understand long-term effects of LAN on cardiometabolic risks.
Brain morphometric similarity and flexibility
Authors: Vuksanović Vesna
Published: June 2022

Background

The cerebral cortex is represented through multiple multilayer morphometric similarity networks to study their modular structures. The approach introduces a novel way for studying brain networks' metrics across individuals, and can quantify network properties usually not revealed using conventional network analyses.

Methods

A total of 8 combinations or types of morphometric similarity networks were constructed – 4 combinations of the inter-regional cortical features on 2 brain atlases. The networks' modular structures were investigated by identifying those modular interactions that stay consistent across the combinations of inter-regional morphometric features and individuals.

Results

The results provide evidence of the community structures as the property of (i) cortical lobar divisions, and also as (ii) the product of different combinations of morphometric features used for the construction of the multilayer representations of the cortex. For the first time, this study has mapped out flexible and inflexible morphometric similarity hubs, and evidence has been provided about variations of the modular network topology across the multilayers with age and IQ.

Conclusions

The results contribute to understanding of intra-regional characteristics in cortical interactions, which potentially can be used to map heterogeneous neurodegeneration patterns in diseased brains.
Gene copy number variations at the within-host population level modulate gene expression in a multipartite virus
Authors: Gallet Romain , Di Mattia Jérémy , Ravel Sébastien , Zeddam Jean-Louis , Vitalis Renaud , Michalakis Yannis , Blanc Stéphane
Published: June 2022

Multipartite viruses have a segmented genome, with each segment encapsidated separately. In all multipartite virus species for which the question has been addressed, the distinct segments reproducibly accumulate at a specific and host-dependent relative frequency, defined as the ‘genome formula’. Here, we test the hypothesis that the multipartite genome organization facilitates the regulation of gene expression via changes of the genome formula and thus via gene copy number variations. In a first experiment, the faba bean necrotic stunt virus (FBNSV), whose genome is composed of eight DNA segments each encoding a single gene, was inoculated into faba bean or alfalfa host plants, and the relative concentrations of the DNA segments and their corresponding messenger RNAs (mRNAs) were monitored. In each of the two host species, our analysis consistently showed that the genome formula variations modulate gene expression, the concentration of each genome segment linearly and positively correlating to that of its cognate mRNA but not of the others. In a second experiment, twenty parallel FBNSV lines were transferred from faba bean to alfalfa plants. Upon host switching, the transcription rate of some genome segments changes, but the genome formula is modified in a way that compensates for these changes and maintains a similar ratio between the various viral mRNAs. Interestingly, a deep-sequencing analysis of these twenty FBNSV lineages demonstrated that the host-related genome formula shift operates independently of DNA-segment sequence mutation. Together, our results indicate that nanoviruses are plastic genetic systems, able to transiently adjust gene expression at the population level in changing environments, by modulating the copy number but not the sequence of each of their genes.
The Development of a Comprehensive Mental Health Service for Medical Trainees
Authors: Hasan Samia , Pozdol Stacie L. , Nichelson Brian K. , Cunningham Stephanie J. , Lasek Dana G. , Dankoski Mary E.
Published: June 2022

Mental distress in medical learners and its consequent harmful effects on personal and professional functioning, a well-documented concern, draws attention to the need for solutions. The authors review the development of a comprehensive mental health service within a large and complex academic medical education system, created with special attention to offering equitable, accessible, and responsive care to all trainees. From the inception of the service in January 2017, the authors placed particular emphasis on eliminating obstacles to learners’ willingness and ability to access care, including concerns related to cost, session limits, privacy, and flexibility with modality of service delivery. Development of outreach initiatives included psychoeducational programming, consultation services, and cultivation of liaison relationships with faculty and staff. Significant utilization of clinical services occurred in the first year of the program and increased further over the course of 4 academic years (2017–2021); with a 2.2 times increase in trainees served and a 2.4 times increase in visits annually. In the 2020–2021 academic year, 821 medical learners received services (for a total 5,656 visits); 30% of all medical students and 25% of house staff and fellows sought treatment in that year. In 2021, 38% of graduating medical school students and 27% of graduating residents and fellows had used mental health services at some point in their training. Extensive use of services combined with very high patient satisfaction ratings by medical learners within this system demonstrate the perceived value of these services and willingness to pursue mental health care when offered a resource that is cognizant of, and responsive to, their unique needs. The authors reflect on potential factors promoting utilization of services—institutional financial support, outreach efforts, and design of services to increase accessibility and reduce barriers to seeking treatment—and propose future areas for investigation.
Diet and vascular risk
Authors: Gomez-Delgado Francisco , Romero-Cabrera Juan Luis , Perez-Martinez Pablo
Published: June 2022

Purpose of review

The basis for the prevention and treatment of cardiovascular disease (CVD) inevitably involves lifestyle modification, including dietary pattern (DP). The aim of this review is to address the different models of healthy DP with their peculiarities and nutritional components as well as their importance in the management of CVD.

Recent findings

Classical cardiovascular risk factors such as hypertension, dyslipidaemia and diabetes are strongly influenced by diet and physical activity. However, current evidence supports the role of emerging risk factors such as inflammatory status, oxidative stress and endothelial function in the development of CVD. Likewise, recent evidence explores how healthy DP can modulate CVD risk through these risk factors.

Although the Mediterranean diet (MedDiet) is the paradigm of the healthy DP in the light of current scientific evidence, there are other DP that we should be aware of due to their results in epidemiological studies, randomized clinical trials (RCTs) and meta-analyses on CVD risk modulation. The best-analysed DP are the MedDiet, Dietary Approaches to Stop Hypertension (DASH), the Nordic DP, the Vegetarian DP, the Portfolio DP, the Low-carbohydrate DP and the Planetary Health diet initiative.
Image-free ultrasound for local and regional vascular stiffness assessment: the ARTSENS Plus
Authors: Nabeel P. M. , Raj Kiran V. , Joseph Jayaraj
Published: June 2022

Objective:

The combined assessment of vascular health markers is crucial for identifying the cumulative burden of vascular risk factors early on, as well as the extent of vascular aging for effective prediction of future cardiovascular events. This work addresses the need for a currently nonexistent device or system that facilitates such combined assessment in clinical practice and large-scale screening settings. We report an image-free ultrasound device – ARTSENS Plus – developed for the measurement of local and regional arterial stiffness, central and peripheral blood pressure (BP), and vessel dimensions, all in one examination.

Methods:

A preclinical study on 90 asymptomatic individuals verified the device's functionality under ARTERY Society guidelines. The device's accuracy of stiffness measures was validated against the reference measures.

Results:

The interoperator and intraoperator variability was less than 7%. Carotid artery's lumen diameter and local stiffness indices and carotid–femoral regional pulse wave velocity showed excellent agreement with the references (absolute errors were less than 4.1, 9, and 4.1%, respectively). The carotid SBP was 10.02% lower than that of the brachial artery, as expected.

Conclusion:

The study demonstrated the device's ability to perform an effortless and reliable evaluation of the local and regional vascular stiffness and central BP with an accuracy that meets clinical standards.
All-Cause Health Care and Work Loss Burden Associated With Nonsteroidal Anti-Inflammatory Drug and Opioid Treatment in Employed Patients With Osteoarthritis
Authors: Silverman Stuart , Thakkar Sheena , Sell Heather , White Alan G. , Downes Nathaniel , Pajerowski William , Robinson Rebecca L. , Beck Craig G. , Emir Birol , Schepman Patricia
Published: June 2022

Introduction

This study estimated all-cause health care resource utilization (HRU) and costs and work loss outcomes associated with pain management of employed patients with osteoarthritis of the hip and/or knee.

Methods

Optum Health Care Solutions data were analyzed for employed patients prescribed nonsteroidal anti-inflammatory drugs, tramadol, or nontramadol opioids following diagnoses of osteoarthritis of the hip and/or knee. A pre-post design was used to evaluate changes in all-cause HRU and costs, and work loss days and associated costs.

Results

Costs rose for patients in all three cohorts (up to 198.3% for health care costs [tramadol] and up to 178.7% for work loss costs [tramadol]). Greatest increases in all-cause HRU included inpatient visits (237.9% [nonsteroidal anti-inflammatory drugs]; 600% [tramadol]).

Conclusions

Study results provide evidence of increases in all-cause HRU and costs and work loss days and associated costs.
Diversity of opinions promotes herding in uncertain crowds
Authors: Navajas Joaquin , Armand Oriane , Moran Rani , Bahrami Bahador , Deroy Ophelia
Published: June 2022

Classic and recent studies demonstrate how we fall for the ‘tyranny of the majority' and conform to the dominant trend when uncertain. However, in many social interactions outside of the laboratory, there is rarely a clearly identified majority and discerning who to follow might be challenging. Here, we asked whether in such conditions herding behaviour depends on a key statistical property of social information: the variance of opinions in a group. We selected a task domain where opinions are widely variable and asked participants (
N
= 650) to privately estimate the price of eight anonymous paintings. Then, in groups of five, they discussed and agreed on a shared estimate for four paintings. Finally, they provided revised individual estimates for all paintings. As predicted (
https://osf.io/s89w4
), we observed that group members converged to each other and boosted their confidence following social interaction. We also found evidence supporting the hypothesis that the more diverse groups show greater convergence, suggesting that the variance of opinions promotes herding in uncertain crowds. Overall, these findings empirically examine how, in the absence of a clear majority, the distribution of opinions relates to subjective feelings of confidence and herding behaviour.
Change in prey genotype frequency rescues predator from extinction
Authors: Hermann Ruben Joseph , Becks Lutz
Published: June 2022

Indirect evolutionary rescue (IER) is a mechanism where a non-evolving species is saved from extinction in an otherwise lethal environment by evolution in an interacting species. This process has been described in a predator–prey model, where extinction of the predator is prevented by a shift in the frequency of defended towards undefended prey when reduced predator densities lower selection for defended prey. We test here how increased mortality and the initial frequencies of the prey types affect IER. Combining the analysis of model simulations and experiments with rotifers feeding on algae we show IER in the presence of increased predator mortality. We found that IER was dependent on the ability of the prey to evolve as well as on the frequency of the defended prey. High initial frequencies of defended prey resulted in predator extinction despite the possibility for prey evolution, as the increase in undefended prey was delayed too much to allow predator rescue. This frequency dependency for IER was more pronounced for higher predator mortalities. Our findings can help informing the development of conservation and management strategies that consider evolutionary responses in communities to environmental changes.
The wave function as a true ensemble
Authors: Hance Jonte R. , Hossenfelder Sabine
Published: June 2022

In quantum mechanics, the wave function predicts probabilities of possible measurement outcomes, but not which individual outcome is realized in each run of an experiment. This suggests that it describes an ensemble of states with different values of a hidden variable. Here, we analyse this idea with reference to currently known theorems and experiments. We argue that the ψ-ontic/epistemic distinction fails to properly identify ensemble interpretations and propose a more useful definition. We then show that all local ψ-ensemble interpretations which reproduce quantum mechanics violate statistical independence. Theories with this property are commonly referred to as superdeterministic or retrocausal. Finally, we explain how this interpretation helps make sense of some otherwise puzzling phenomena in quantum mechanics, such as the delayed choice experiment, the Elitzur–Vaidman bomb detector and the extended Wigner’s friends scenario.
Asymptotic anatomy of the Berry phase for scalar waves in two-dimensional periodic continua
Authors: Guzina Bojan B. , Oudghiri-Idrissi Othman , Meng Shixu
Published: June 2022

We deploy an asymptotic model for the interaction between nearby dispersion surfaces and respective eigenstates towards explicit evaluation of the Berry phase governed by the scalar wave equation in two-dimensional periodic media. The model, featuring a pair of coupled Dirac equations, entails a four-dimensional parametric space and endows the interacting Bloch eigenstates with an explicit gauge that caters for analytical integration in the wavenumber domain. Among the featured parameters, the one (

s

∈
[
0
,

1
2

]

) that synthesizes the phase information on the coupling term is shown to decide whether the Berry connection round the loop is singular (

s

=
0

) or analytic (

s

>
0

). The analysis demonstrates that the Berry phase for two-dimensional lattices is

π

-quantal and topological when

s

=
0

, equalling

π

when the contour encloses a Dirac point and zero in all other situations (avoided crossings or line crossings). The analogous result is obtained, up to an

O
(

s

)

residual, when

s

≃
0

and similarly for

s

≃

1
2

. In the interior of the

s

-domain, we find that the Berry phase either approximately equals

π

or is not quantal. Beyond shedding light on the anatomy of the Berry phase in periodic continua, the analysis carries a practical benefit as it permits a single-wavenumber evaluation of this geometrical phase quantity. The asymptotic estimates of the Berry phase are found to be in agreement with their numerical counterparts. For generality, we also include an application to a Dirac-like, three-energy-level system.
Tailored acoustic metamaterials. Part I. Thin- and thick-walled Helmholtz resonator arrays
Authors: Smith Michael J. A. , Abrahams I. David
Published: June 2022

We present a novel multipole formulation for computing the band structures of two-dimensional arrays of cylindrical Helmholtz resonators. This formulation is derived by combining existing multipole methods for arrays of ideal cylinders with the method of matched asymptotic expansions. We construct asymptotically close representations for the dispersion equations of the first band surface, correcting and extending an established lowest-order (isotropic) result in the literature for thin-walled resonator arrays. The descriptions we obtain for the first band are accurate over a relatively broad frequency and Bloch vector range and not simply in the long-wavelength and low-frequency regime, as is the case in many classical treatments. Crucially, we are able to capture features of the first band, such as low-frequency anisotropy, over a broad range of filling fractions, wall thicknesses and aperture angles. In addition to describing the first band we use our formulation to compute the first band gap for both thin- and thick-walled resonators, and find that thicker resonator walls correspond to both a narrowing of the first band gap and an increase in the central band gap frequency.
Integrative deep learning analysis improves colon adenocarcinoma patient stratification at risk for mortality
Authors: Zhou Jie , pour Ali Foroughi , Deirawan Hany , Daaboul Fayez , Aung Thazin , Beydoun Rafic , Ahmed Fahad Shabbir , Chuang Jeffrey H.
Published: June 2022

Colorectal cancers are the fourth most commonly diagnosed cancer and the second leading cancer in number of deaths. Many clinical variables, pathological features, and genomic signatures are associated with patient risk, but reliable patient stratification in the clinic remains a challenging task. Here we assess how image, clinical, and genomic features can be combined to predict risk. We first observe that deep learning models based only on whole slide images (WSIs) from The Cancer Genome Atlas accurately separate high risk (OS<3years, N=38) from low risk (OS>5years, N=25) patients (AUC=0.81±0.08, 5year survival p-value=2.13e-25, 5year relative risk=5.09±0.05) though such models are less effective at predicting OS for moderate risk (3years<OS<5years, N=45) patients (5year survival p-value=0.5, 5year relative risk=1.32±0.09). However, we find that novel integrative models combining whole slide images, clinical variables, and mutation signatures can improve patient stratification for moderate risk patients (5year survival p-value=6.69e-30, 5year relative risk=5.32±0.07). Our integrative model combining image and clinical variables is also effective on an independent pathology dataset generated by our team (3year survival p-value=1.14e-09, 5year survival p-value=2.15e-05, 3year relative risk=3.25±0.06, 5year relative-risk=3.07±0.08). The integrative model substantially outperforms models using only images or only clinical variables, indicating beneficial cross-talk between the data types. Pathologist review of image-based heatmaps suggests that nuclear shape, nuclear size pleomorphism, intense cellularity, and abnormal structures are associated with high risk, while low risk regions tend to have more regular and small cells. The improved stratification of colorectal cancer patients from our computational methods can be beneficial for preemptive development of management and treatment plans for individual patients, as well as for informed enrollment of patients in clinical trials.
Ebonyunderpins Batesian mimicry in an insect melanic polymorphism
Authors: Foster Brodie J. , McCulloch Graham A. , Foster Yasmin , Kroos Gracie C. , Waters Jonathan M.
Published: June 2022

The evolution of Batesian mimicry – whereby harmless species avoid predation through their resemblance to harmful species – has long intrigued biologists. In rare cases, such mimicry systems can be highly dynamic, being maintained via frequency-dependent selection on intraspecific polymorphisms, in which only some individuals within a population resemble a noxious ‘model’. Here, we use genomic approaches to identify the genetic basis of a striking mimicry polymorphism within a widespread New Zealand stonefly complex. Specifically, highly melanised specimens ofZelandoperlaclosely resemble an aposematic stonefly (Austroperla cyrene) well-known for its production of hydrogen cyanide. We assess convergence in the colour pattern of these two species, compare their relative palatability to predators, and use genome-wide association mapping to elucidate the genetic basis of this mimicry polymorphism. Our analysis reveals that melanisedZelandoperlaoverlap significantly withAustroperlain colour space, but are significantly more palatable to predators, indicating that they are indeed Batesian mimics. Analysis of 194,773 genome-wide SNPs reveals a strong outlier locus (ebony) differentiating melanic (mimic) versus non-melanic phenotypes. Asebonyhas a well-documented role in insect melanin biosynthesis, our findings highlight its conserved function across deeply divergent hexapod lineages. Distributional records suggest a link between the occurrence ofZelandoperlamimics and forested ecosystems where the modelAustroperlais abundant, suggesting the potential for adaptive shifts in this system underpinned by environmental change.
GM-CSF drives immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12
Authors: Paust Hans-Joachim , Song Ning , De Feo Donatella , Asada Nariaki , Tuzlak Selma , Zhao Yu , Riedel Jan-Hendrik , Hellmig Malte , Sivayoganathan Amirrtavarshni , Peters Anett , Kaffke Anna , Borchers Alina , Wenzel Ulrich O. , Steinmetz Oliver M. , Tiegs Gisa , Meister Elisabeth , Lindenmeyer Maja T. , Hoxha Elion , Stahl Rolf A.K. , Huber Tobias B. , Bonn Stefan , Meyer-Schwesinger Catherine , Wiech Thorsten , Turner Jan-Eric , Becher Burkhard , Krebs Christian F. , Panzer Ulf
Published: June 2022

Glomerulonephritis is a group of immune-mediated diseases that cause inflammation within the glomerulus and adjacent compartments of the kidney and is a major cause of end-stage renal disease. T cells are among the main drivers of glomerulonephritis. However, the T cell subsets, cytokine networks, and downstream effector mechanisms that lead to renal tissue injury are largely unknown, which has hindered the development of targeted therapies.

Here we identify a population of GM-CSF-producing T cells that accumulates in the kidneys of patients with ANCA-associated glomerulonephritis, infiltrates the renal tissue in a mouse model of glomerulonephritis, and promotes tissue destruction and loss of renal function. Mechanistically, we show that GM-CSF producing T cells licence monocyte-derived cells to produce matrix metalloproteinase 12 (MMP12), which cleaves components of the glomerular basement membrane and exacerbates renal pathology. These findings provide a mechanistic rationale for the immunopathology of T cell-mediated diseases and identify the “GM-CSF – monocyte-derived cells – MMP12” pathway as a promising therapeutic target in treatment of glomerulonephritis.
Suppression of YAP Safeguards Human Naïve Pluripotency
Authors: Dattani Anish , Huang Tao , Smith Austin , Guo Ge
Published: June 2022

Propagation of human naïve pluripotent stem cells (nPSCs) requires inhibition of MEK/ERK signalling. However, MEK/ERK inhibition also induces differentiation into trophectoderm (TE). Therefore, robust self-renewal requires active suppression of TE fate. Tankyrase inhibition using XAV939 has been shown to stabilise human nPSCs. Here we dissect the mechanism of this effect. Tankyrase inhibition blocks canonical Wnt/β-catenin signalling. However, nPSCs depleted of β-catenin remain dependent on XAV939. We show that XAV939 prevents TE induction by suppressing YAP activity independent of β-catenin. Tankyrase inhibition stabilises angiomotin, which reduces nuclear translocation of YAP1/TAZ. Upon deletion of Angiomotin-family members AMOT and AMOTL2, nuclear YAP increases and XAV939 fails to prevent TE induction. Conversely, nPSCs lacking YAP1 fail to undergo TE differentiation and sustain efficient self-renewal without XAV939. These findings explain the distinct requirement for tankyrase inhibition in human but not mouse naïve PSCs and highlight the pivotal role of YAP in human naïve pluripotency.
Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies
Authors: Preger Charlotta , Notarnicola Antonella , Hellström Cecilia , Wigren Edvard , Fernandes-Cerqueira Cátia , Idborg Helena , Lundberg Ingrid E. , Persson Helena , Gräslund Susanne , Jakobsson Per-Johan
Published: June 2022

Objectives

Autoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to all known myositis-specific autoantibodies (MSAs). We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM.

Methods

Plasma samples and clinical data from 217 patients with, 50 patients with ASSD, 165 without, and two with unknown ASSD status were included retrospectively, as well as serum from 156 age/sex-matched population controls. Samples were screened using a multiplex bead array assay for presence of autoantibodies against a panel of 118 recombinant protein variants, representing 33 myositis-related proteins, including all 19 cytoplasmic aaRS.

Results

We identified reactivity towards 16 aaRS in 72 of the 217 patients. Twelve patients displayed reactivity against nine novel aaRS. The novel autoantibody specificities were detected in four patients previously seronegative for MSAs and in eight with previously detected MSAs. We also confirmed reactivity to four of the most common aaRS (Jo1, PL12, PL7, and EJ (n=45)) and identified patients positive for anti-Zo, -KS, and -HA (n=10) that were not previously tested. A low frequency of anti-aaRS autoantibodies was detected in controls.

Conclusion

Our results suggest that most, if not all, cytoplasmic aaRS may become autoantigenic. Autoantibodies against new aaRS may be found in plasma of patients previously classified as seronegative with potential high clinical relevance.
Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult in mice
Authors: Yiew Nicole K.H. , Vazquez Joel H. , Martino Michael R. , Kennon-McGill Stefanie , Price Jake R. , Allard Felicia D. , Yee Eric U. , James Laura P. , McCommis Kyle S. , Finck Brian N. , McGill Mitchell R.
Published: June 2022

Pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, as well as NADH production. As a result, there is growing interest in targeting the mitochondrial pyruvate carrier (MPC) complex in liver and metabolic diseases. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress. We report that MPC inhibition does indeed sensitize the liver to APAP-induced injury in vivo, but only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacologic and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) of these proteins significantly worsened the liver damage. Further investigation confirmed that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis. Furthermore, APAP toxicity was exacerbated by inhibition of both the MPC and ALT in vitro. Thus, increased glutaminolysis and susceptibility to oxidative stress requires loss of both the MPC and ALT2 in vivo and exacerbates them in vitro. Finally, induction of ALT2 reduced APAP-induced injury.
Measuring Neuronal Avalanches to inform Brain-Computer Interfaces
Authors: Corsi Marie-Constance , Sorrentino Pierpaolo , Schwartz Denis , George Nathalie , Gollo Leonardo L. , Chevallier Sylvain , Hugueville Laurent , Kahn Ari E. , Dupont Sophie , Bassett Danielle S. , Jirsa Viktor , De Vico Fallani Fabrizio
Published: June 2022

Large-scale interactions among multiple brain regions manifest as bursts of activations called neuronal avalanches, which reconfigure according to the task at hand and, hence, might constitute natural candidates to design brain-computer interfaces (BCI). To test this hypothesis, we used source-reconstructed magneto/electroencephalography, during resting state and a motor imagery task performed within a BCI protocol. To track the probability that an avalanche would spread across any two regions we built an avalanche transition matrix (ATM) and demonstrated that the edges whose transition probabilities significantly differed between conditions hinged selectively on premotor regions in all subjects. Furthermore, we showed that the topology of the ATMs allows task-decoding above the current gold standard. Hence, our results suggest that Neuronal Avalanches might capture interpretable differences between tasks that can be used to inform brain-computer interfaces.
Genome-wide identification of loss of heterozygosity generated by mitotic homologous recombination reveals its possible association with spatial positioning of chromosomes
Authors: Kim Hyeonjeong , Suyama Mikita
Published: June 2022

Loss of heterozygosity (LOH) is a genetic alteration that results from the loss of one allele at a heterozygous locus. Some LOH events are generated by mitotic homologous recombination after monoallelic defection, then the novel homozygous locus has two copies of the normal counterpart allele. This phenomenon can serve as a source of genome diversity and is associated with various diseases. To clarify the nature of the LOH such as the frequency, genomic distribution, and inheritance pattern, we made use of whole-genome sequencing data of the three-generation CEPH/Utah family cohort, with the pedigree consisting of grandparents, parents, and offspring. We identified an average of 40.7 LOH events per individual taking advantage of 285 healthy individuals from 33 families in the cohort. On average 65% of them were classified as gonosomal-mosaicism-associated LOH, which exists in both germline and somatic cells. We also confirmed that the incidence of the LOH has little to do with the parents’ age and sex. Furthermore, through the analysis of the genomic region including the LOH, we found that the chance of the occurrence of the LOH tends to increase at the GC-rich locus and/or on the chromosome having a relatively close inter-homolog distance. We expect that these results provide significant insights into the association between genetic alteration and spatial position of chromosomes as well as the intrinsic genetic property of the LOH.

Author Summary

Loss of heterozygosity (LOH) is a common genetic alteration that a heterozygous locus becomes a homozygous locus. In some cases, if a monoallelic defection accompanying homologous recombination between inter-homolog occurs, it results in copy-neutral LOH having two copies of the allele. Although the LOH is potentially important in understanding pathogenesis of various diseases, its fundamental features have received scant attention. To characterize the nature of the LOH, data from single individuals and their parents are required. This is because it would be difficult to discriminate between the LOH and a normal homozygous allelic state using genomic data obtained only from a single individual. Whole-genome sequencing data of 33 CEPH/Utah families, which comprise large three-generation family units, motivated us to perform a genome-wide identification of the LOH. Using this dataset, we successfully identified the LOH and analyzed its frequency, genomic distribution, and inheritance pattern. Moreover, we revealed that the occurrence of the LOH was affected by the inter-homolog distances, which reflect the chromosome territory. Our findings pertaining to the LOH provide insight into the association between genetic alteration and spatial positioning of chromosomes.
Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis
Authors: Maserumule Charlotte , Passemar Charlotte , Oh Olivia S H , Hegyi Kriztina , Brown Karen , Weimann Aaron , Dinan Adam , Davila Sonia , Klapholz Catherine , Bryant Josephine , Verma Deepshikha , Gadwa Jacob , Krishnananthasivam Shivankari , Vongtongsalee Kridakorn , Kendall Edward , Trelles Andres , Hibberd Martin L , Prados-Rosales Rafael , Andi Kaliappan , Kumar S Siva , Ordway Diane , MacAry Paul A , Floto R. Andres
Published: June 2022

Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) are poorly understood but could provide insights into critical pathways involved in infection, informing host-directed therapies and enabling risk stratification at individual and population levels. Through a genome-wide forward genetic screen, we identify the Toll-like Receptor 8 (TLR8), as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances killing of phylogenetically diverse clinical isolates of drug-susceptible and multidrug-resistant Mtb by macrophages and during in vivo infection in mice. TLR8 is activated by phagosomal mycobacterial RNA released by extracellular membrane vesicles, and enhances xenophagy-dependent Mtb killing. We find that the TLR8 variant, M1V, common in far eastern populations, enhances intracellular killing of Mtb through preferential signal-dependent trafficking to phagosomes. TLR8 signalling may therefore both regulate susceptibility to tuberculosis and provide novel drug targets.

Single sentence summary

RNA released from Mycobacterium tuberculosis in the macrophage phagosome is sensed by the pattern recognition receptor TLR8 controlling host susceptibility to tuberculosis and revealing a druggable pathway for host-directed therapy.
Temporally and regionally distinct morphogenetic processes govern zebrafish tail fin blood vessel network expansion
Authors: Leonard Elvin V. , Hasan Sana Safatul , Siekmann Arndt F.
Published: June 2022

Blood vessels form elaborate networks depending on tissue-specific signalling pathways and anatomical structures to guide their growth. However, it is not clear which morphogenetic principles organize the stepwise assembly of the vasculature. We thus performed a longitudinal analysis of zebrafish tail fin vascular assembly, revealing the existence of temporally and spatially distinct morphogenetic processes. Initially, vein-derived endothelial cells (ECs) generated arteries in a reiterative process requiring Vascular Endothelial Growth Factor (VEGF), Notch and cxcr4a signalling. Subsequently, veins produced veins in more proximal fin regions, transforming pre-existing artery-vein loops into a three-vessel pattern consisting of an artery and two veins. A distinct set of vascular plexuses formed at the base of the fin. They differed by virtue of diameter, flow magnitude and marker gene expression. At later stages, intussusceptive angiogenesis occurred from veins in distal fin regions. In proximal fin regions, we observed new vein sprouts crossing the inter-ray tissue through sprouting angiogenesis. Together, our results reveal a surprising diversity among the mechanisms generating the mature fin vasculature and suggest that these might be driven by separate local cues.
Therapeutic activation of endothelial sphingosine 1-phosphate receptor-1 by chaperone-bound S1P suppresses proliferative retinal vasculopathy
Authors: Niaudet Colin , Jung Bongnam , Kuo Andrew , Swendeman Steven , Bull Edward , Seno Takahiro , Crocker Reed , Fu Zhongjie , Smith Lois E. H. , Hla Timothy
Published: June 2022

Sphingosine-1-phosphate (S1P), a bioactive lipid mediator that signals via G protein-coupled S1P receptors (S1PR), is required for normal vascular development. The role of this signaling axis in vascular retinopathies is largely unexplored. Here we show in a mouse model of oxygen-induced retinopathy (OIR) that endothelial overexpression of S1pr1 suppresses while endothelial knockout (KO) of S1pr1 worsens neovascular tuft formation. Furthermore, neovascular tufts are increased in Apom KO mice which lack HDL-bound S1P while they are suppressed in Apom TG mice which has more circulating HDL-S1P. These results suggest that circulating HDL-S1P activation of endothelial S1PR1 specifically suppresses proliferative retinal vasculopathy. Moreover, systemic administration of ApoM-Fc-bound S1P or a small molecule Gi-biased S1PR1 agonist suppressed neovascular tuft formation. Circulating HDL-S1P activation of endothelial S1PR1 may be a key protective mechanism to guard against neovascular retinopathies that occur not only in premature infants but also in diabetes and aging.