bluuebunny/crossref_metadata_2025 huggingface dataset:
Representing Disability in Tort Litigation: An Empirical Analysis of Judicial Discourse (1998–2018)
Authors: Mor Sagit , Pikkel Rina B. , Lankry Havi Inbar
Published: March 2023

This study empirically examines whether and how the introduction of disability rights impacted the portrayal of disability in personal injury court decisions in Israel and offers a method for doing such research in other legal realms and contexts. We conducted a quantitative content analysis of Israeli district court judicial rulings over twenty years to measure whether a discursive shift occurred from a medical-individual view of disability to a social constructionist and a rights-based understanding of disability. Our coding system included descriptive and conceptual indicators, forming two indexes: a conventional index and a progressive index. Our findings reveal a steady dominance of the conventional discourse and a gradual yet limited rise in progressive discourse. Moreover, individual court decisions often manifest both types of discourse but are still dominated by a conventional view of disability and rarely apply direct disability rights terminology. These findings provide pioneering empirical evidence that substantiates the disability critique of tort law, demonstrating that judicial decision making is slow to adopt a disability rights perspective. More broadly, our findings show that the infusion of a disability rights orientation does not necessarily replace the older medical-individual view of disability but adds to it, resulting in a mixed discourse that includes both conventional and progressive elements.
Future advanced technology rotorcraft
Authors: Lowson M. V. , Balmford D. E. H.
Published: March 2023

The ability of the helicopter to hover and therefore to take-off and land in confined areas has proven to be of significant value in an increasing range of applications. Rotorcraft have now established a significant role for specialist aeronautical applications both in the civil and military field.

Figure 1(a) shows a graph of the increase of helicopter usage in the civil market. To the traditional roles of point to point transport and special purpose public service operations has been added a massive increase in energy related use, particularly for off-shore oil exploration. Present fleet growth rate in the civil area is about 15% p.a. There is no sign that this demand will abate. There has also been a substantial increase in helicopter use on military operations, as illustrated in Fig. 1(b). Helicopters now account for between 40–50% of all service aircraft (excluding training and liaison) in both the United States and Britain. The flexibility offered by the helicopter has been critical in its tactical value for land operations. The ability of the helicopter to operate from small ships at sea in all weathers, and at night, has provided it with a unique role in naval applications. In Britain over 80% of naval aircraft are now helicopters.
Wing flapping with minimum energy
Authors: Jones R. T.
Published: March 2023

The interesting article by Archer, Sapuppo and Betteridge leads to the problem of determining the optimum lift distribution along the wing during flapping motion. Adopting the assumptions made in Ref. 1, the problem may be reduced to one of minimising the induced drag for a specified, periodically varying, bending moment at the wing root. The wing-root bending moment should be of primary importance to a bird or, for that matter, to a mechanical flapping-machine, since it is at this point that most of the flapping energy is introduced.
Behavioural evaluations of simulators: academic and practical issues
Authors: Stammers R. B.
Published: March 2023

The question posed by the symposium title is one of concern to many psychologists, especially those with interests in the study of high levels of human skill. The area of flight simulation does however present a number of challenges in terms of research questions, which are at present only partially answered.

There are at least three areas of simulator use where psychologists have interests and have a part to play:

Man-machine system development

Research simulators

Training simulators.
Airport operators' views
Authors: Payne Norman J.
Published: March 2023

Passenger traffic through the seven BAA airports, Heathrow, Gatwick and Stansted in the South-East and Glasgow, Edinburgh, Prestwick and Aberdeen in Scotland is predominantly in the leisure sector and this sector is most affected by low fares. In 1978 this sector formed 65% of all traffic at the three South-East airports and 55% at the four airports in Scotland.

As Ray Colegate and Adam Thomson have said low fares are no new choice for air travellers. Low fares for charter operations with a range of fare options have been the main feature of the rapid passenger growth at Gatwick Airport for many years. This is also the case at Luton Airport which is not owned by the BAA but serves the South-East.
Airport Operators Council International Inc.
Authors: Davis David W.
Published: March 2023

Both within the US, and on the North Atlantic, there has been a dramatic reduction in governmental control over airline pricing routeing and service policies. In the short run, the most visible and important development has been the substantial decrease in average fares, spearheaded by greatly reduced fares available in certain restricted circumstances.

Because decisions about price, routeing and service interact, I find it most useful to talk about the loosening of governmental strictures on them, collectively, as deregulation, and I want to concentrate my remarks on the impact of deregulation from my perspective as an observer of the industry, and as an airport operator. I hope also to develop the theme that loosening one of these strictures without attention to the others can adversely affect air service.
The Boeing Company
Authors: Steiner J. E.
Published: March 2023

The proliferation of discount fares and their understanding by the regulators, or for that matter, by the travelling public, is one of the most complex, if not bewildering aspects of today's airline industry. You may consider it presumptuous for me, representing an aeroplane manufacturer, to comment on airline fares policies. However, as part of an industry directly affected by whether or not airlines are profitable, we are very ‘interested parties'. This interest has invoved us in many discussions with airlines, as well as in Boeing-sponsored studies to understand discounted fares and the basis for their being profitable or unprofitable. Low fares, of course, are only one aspect of a rapidly evolving air transport industry—one which is seeing a new regulatory environment in the United States, new forms of bilateral agreements, and a whole host of fresh marketing ideas.
Greater London Council
Authors: Brew Richard M.
Published: March 2023

Tourism is both a growing industry and is also an increasingly competitive one. It has become an important factor in the social and economic life of this country, but it is the international visitors who form the growth sector in the market and make the greatest contribution to the national economy. In 1977 the United Kingdom attracted 4·7% of the world total of international travellers and its share of the growing world market has increased by half over the past 10 years. Figures from the Department of Trade show that in 1977 tourism was third in the league of invisible exports and seventh overall in export earnings.

If the advent of cheap air fares is to lead to a tourist ‘explosion’ then the effects are likely to be dramatic in terms not only of the tourist industry but the social life of places visited as well as on the national economy. As the foremost tourist centre in Britain, London will feel the effects soonest and most dramatically. While this provides very welcome opportunities, the social and economic implications are far-reaching and need to be carefully considered.
A novel technique for obtaining aerodynamic data using simple, free flight trajectory measurements
Authors: Pope R. L. , Dudley R. E.
Published: March 2023

Free flight testing of missile designs is generally necessary to confirm that accurate estimates have been made of effects due to the change in size from wind tunnel model to full scale missile and of effects arising from the flight dynamic behaviour of the missile. The amount of such testing is generally limited by the high costs involved and so every effort is made to obtain the maximum information from each flight trial. During recent years parameter estimation techniques have been developed to provide superior methods for analysis of free flight tests. They enable the analyst to extract the required data with greater accuracy from fewer tests than has previously been possible. The old equation error methods relied on measuring all the variables characterising the projectile motion and using the equations of motion to obtain a relationship between aerodynamic forces and moments and translational and angular velocities of the vehicle.
The Bell Model 222
Authors: Garrison James R.
Published: March 2023

Bell's Model 222 is an 8-10 place helicopter powered by two Lycoming LTS101-650C2 engines. It is the result of extensive engineering design studies. These studies considered several configurations including fore and aft engines, laterally disposed engines, two across seating, fixed landing gear, skid landing gear and JetRanger growth versions. Two full-scale mockups were built and thoroughly evaluated prior to selecting the final configuration. The mockup selected was used extensively for evaluation by Bell and by commercial customers resulting in additional refinements. The final configuration is shown in flight in Fig. 1.
Least-weight design of carbon fibre honeycomb sandwich columns
Authors: Webber J. P. H.
Published: March 2023

In Ref. 1, an exact theoretical analysis is given for the buckling of sandwich columns in compression. The theory is able to predict both overall buckling and face wrinkling and the present paper extends this work by suggesting a design procedure for obtaining least column weight for a given end load and column length. It is shown how a family of optimum design curves can be obtained for given material properties, which encompass all of the geometrical parameters excepting column width. For a given end load, least weight is obtained with least width, but the limiting factor then becomes one of overall instability in the transverse direction of the column. The columns are not optimum in the sense that the buckling and compressive failure loads are made to occur at the same time. Generally speaking, it is not possible to design to this condition for given core and face plate materials and there is found to be a large margin of safety between the buckling stresses and the ultimate failure stresses.
A new method of boundary layer wall shear stress evaluation
Authors: Smith Peter D. , Franklin Raymond E.
Published: March 2023

It has long been suspected that the inner portion of any turbulent boundary layer velocity profile obeys a so-called law of the wall which takes the form:

where u is the boundary layer velocity at a distance y from the wall, uτ is the friction velocity given by √(τw/ρ) in which τw is the wall shearing stress and ρ is the fluid density, v is the kinematic viscosity and A and B are constants.
Design rules for small low speed wind tunnels
Authors: Mehta R.D. , Bradshaw P.
Published: March 2023

Even with today’s computers, a wind tunnel is an essential tool in engineering, both for model tests and basic research. Since the 1930s, when the strong effect of free-stream turbulence on shear layers became apparent, emphasis has been laid on wind tunnels with low levels of turbulence and unsteadiness. Consequently most high performance wind tunnels were designed as closed-circuit types (Fig. 1(a)) to ensure a controlled return flow. However, as will be seen below, it is possible with care to achieve high performance from an open-circuit tunnel, thus saving space and construction cost. ‘Blower’ tunnels (with the fan at entry to the tunnel, Fig. 1(b)) facilitate large changes in working section arrangements; to cope with the resulting large changes in operating conditions, a centrifugal fan is preferable to an axial one. For ease of changing working sections the exit diffuser is often omitted from small blower tunnels, at the cost of a power factor greater than unity. This paper concentrates on the design of small blower tunnels but most of the information is applicable to wind tunnels in general.
Outline of PADIS
Authors: Andrews David
Published: March 2023

PADIS is the acronym for the ‘procedure for analysing the design of interactive solutions ’.

If one may use the noun ‘paradigm ’ to mean that way of looking at a problem that permits a solution to that problem to be found, PADIS is both a paradigm for the design process, and a practical system of design management based on that paradigm, enabling important benefits to be realised.

Study of the requirements for a design management system had been under way since 1970, but after the fortuitous discovery of the paradigm early in 1977 it became possible to carry out focusing development, and in a succession of small scale experiments a much deeper understanding of the problem was obtained.
The static pressure in a vortex core
Authors: Dunham J.
Published: March 2023

Vortices are of interest in many situations in fluid mechanics. One type of vortex with which the gas turbine designer is concerned is the line vortex springing like a miniature tornado from a point on the ground (or from a nearby aircraft surface) and entering the engine intake. It is possible for these vortices to suck stones up into the engine (Refs. 1, 2) and also to reduce the compressor surge margin (Refs. 3, 4). They are unsteady, in that their point of origin wanders about and so does their point of entry into the intake. This unsteadiness makes it very difficult to measure them, and so far no one known to the author has reported measurements of ground vortex strength, in the course of several investigations of the phenomenon (Refs. 1-3, 5-8).
Crack free and cracked life of the pressurised cabin of the A300B—calculation, tests and design measurements to improve damage tolerance
Authors: Gökgöl O.
Published: March 2023

The A300B aircraft is a co-operative effort by France, Germany, Great Britain, USA, Spain and the Netherlands. The work sharing regarding manufacture of the structure is as follows:

MBB: Fuselage sections from the tail cone to section 16, upper shell of section 15, and the vertical tail.

VFW-Fokker: Fuselage sections 13 and 14.

AS: Flight compartment, fuselage sections 12, 15 (lower shell), wing centre box and pylons.

CASA: Horizontal tail and passenger compartment door No 1.

Fokker-VFW: Movable components on the wing, flap track fairings.

British Aerospace (HSA): Cantilever wing, slats.

General Electric: Engines.

Messier: Landing gears.

The design of the A300B was based on many years’ experience gained on aircraft like the Trident (HSA) and the Caravelle (AS). Furthermore, by means of extensive studies and tests, bases were created to ensure reliability of the structure and to achieve an optimum design regarding weight and cost.
Upper stage jet impingement on separated booster
Authors: Saxena Sushil K.
Published: March 2023

The knowledge about the position of the detached shock and the aerodynamic forces acting upon a booster front during upper stage (sustainer) jet impingement on a separated booster is needed in connection with the problem of stage separation in the atmosphere for a multistage launch vehicle. The jet flow is squeezed in by the free-stream and characterised by a non-uniform transverse variation of flow properties. The flow field analysis of a trailing blunt body in such a non-uniform flow has been limited to experimental studies only. Most of the prior analytical treatments were restricted to the study of the effect of free-stream non-uniformities such as source flow and wake-like free-stream velocities on blunt bodies. A somewhat related problem of supersonic, underexpanded jet impingement upon an infinite flat plate in the absence of external stream has been studied by Belov et al and Gummer and Hunt.
Advanced application of the MADGE approach aid offshore
Authors: Clarke R. W. G.
Published: March 2023

The MADGE aircraft approach aid is being supplied to Mobil for fitment to the Beryl ‘A’ Platform in the North Sea where multiple approach paths, offset in both azimuth and elevation are to be provided. Application has been made to the UK Civil Aviation Authority for approach limits of 150 ft (200 ft for Beryl ‘A’) Minimum Descent Altitude and 300 metres RVR equivalent.

MADGE was originally designed to meet a NATO requirement for a tactical approach aid which could be carried by two men, and set up in 15 minutes and give guidance to all aircraft types. This is a totally different application from the one at Beryl ‘A’ and yet it uses the standard MADGE production airborne equipment and standard MADGE production ground station units supplemented by ancillary ground equipment to provide offset tracks and monitoring facilities.
The development of multiple redundant flight control systems for high integrity applications
Authors: Corney J. M.
Published: March 2023

Multiple redundant flight control systems have been the subject of continuous development since the 1950s. Early examples include the automatic landing systems of the BAC 1–11 and the VC10; these were followed by the full flight envelope control systems fitted to the Concorde and Tornado. These examples all use analogue computing techniques, with redundancy levels appropriate to the individual fail-passive or fail-operational requirements of each system.

However, recent advances in digital technology have enabled highly sophisticated flight control systems to be implemented which would be wholly impractical using analogue computing methods. Furthermore, digital computing is amenable to self-monitoring techniques which can be used not only to improve system maintainability, but also to augment the cross comparison or majority voting algorithms which have been developed on analogue systems.
Analyst Coverage and Corporate Environmental Policies
Authors: Jing Chenxing , Keasey Kevin , Lim Ivan , Xu Bin
Published: March 2023

Exploiting two quasi-natural experiments, we find that firms increase emissions of toxic pollution following decreases in analyst coverage. The effects are stronger for firms with low initial analyst coverage, poor corporate governance, and firms subject to less stringent monitoring by environmental regulators. Decreases in environmental-related questions raised in conference calls, an increased cost of monitoring to institutional shareholders, reductions in pollution abatement investment, and the weakening of internal governance related to environmental performance are channels through which reduced analyst coverage contributes to increases in firm pollution. Our study highlights the monitoring role analysts play in shaping corporate environmental policies.
Creating colonisable land: Cartography, ‘blank spaces’, and imaginaries of empire in nineteenth-century Germany
Authors: Çapan Zeynep Gülşah , dos Reis Filipe
Published: March 2023

The social sciences and humanities in general and International Relations (IR) specifically are organised around what has been called ‘analytic bifurcation’. Analytic bifurcations artificially structure and divide analytic spaces into, for example, Europe/non-Europe, inside/outside, state/empire, and metropole/colony. Recently, these bifurcations have been problematised within IR and adjacent fields. Our article contributes to and extends these discussions by foregrounding two interrelated aspects that have not received sufficient attention: first, connections between colonies rather than between metropole and colony and, second, the construction and reproduction of the bifurcation of Europe/non-Europe. We explore how technologies of power, in our case mapping and the use of ‘blank spaces’, were used to create imaginaries of colonisable land. To do so, we trace two episodes from nineteenth-century German colonial discourse. The first episode analyses imaginaries of exploration in the Humboldtian tradition and how these imaginaries depict spaces outside of Europe, namely in Africa, as blank spaces. The second episode reconstructs the cartographic work of Paul Langhans, who focused on mapping ‘Germandom’ (Deutschtum) in Central and Eastern Europe. Juxtaposing these two episodes shows the interconnectedness between these spaces (Africa and the European East) and how techniques such as blank spaces were applied to create colonisable land.
Raccoon rabies control and elimination in the northeastern USA and southern Québec, Canada
Authors: Davis Amy J. , Gagnier Marianne , Massé Ariane , Nelson Kathleen M. , Kirby Jordona D. , Wallace Ryan , Ma Xiaoyue , Fehlner-Gardiner Christine , Chipman Richard B. , Gilbert Amy T.
Published: March 2023

Rabies virus (RABV) is a deadly zoonosis that circulates in wild carnivore populations in North America. Intensive management within the USA and Canada has been conducted to control the spread of the raccoon (Procyon lotor) variant of RABV and work towards elimination. We examined RABV occurrence across the northeastern USA and southeastern Québec, Canada during 2008–2018 using a multi-method, dynamic occupancy model. Using a 10 km × 10 km grid overlaid on the landscape, we examined the probability that a grid cell was occupied with RABV and relationships with management activities (oral rabies vaccination (ORV) and trap-vaccinate-release efforts), habitat, neighbour effects and temporal trends. We compared raccoon RABV detection probabilities between different surveillance samples (e.g. animals that are strange acting, road-kill, public health samples). The management of RABV through ORV was found to be the greatest driver in reducing the occurrence of rabies on the landscape. Additionally, RABV occupancy declined further with increasing duration of ORV baiting programmes. Grid cells north of ORV management were at or near elimination (

$\hat{\psi }_{{\rm north}}$

= 0.00, s.e. = 0.15), managed areas had low RABV occupancy (

$\hat{\psi }_{{\rm managed}}$

= 0.20, s.e. = 0.29) and enzootic areas had the highest level of RABV occupancy (

$\hat{\psi }_{{\rm south}}$

= 0.83, s.e. = 0.06). These results provide evidence that past management actions have been being successful at the goals of reducing and controlling the raccoon variant of RABV. At a finer scale we also found that vaccine bait type and bait density impacted RABV occupancy. Detection probabilities varied; samples from strange acting animals and public health had the highest detection rates. Our results support the movement of the ORV zone south within the USA due to high elimination probabilities along the US border with Québec. Additional enhanced rabies surveillance is still needed to ensure elimination is maintained.
Engaging community pharmacists in tuberculosis-directly observed treatment: a mixed-methods study
Authors: Wong Yen Jun , Thum Chern Choong , Ng Khuen Yen , Lee Shaun Wen Huey
Published: March 2023

Aim:

This study aimed to evaluate the feasibility of implementing community pharmacy-based tuberculosis-directly observed treatment (TB-DOT) in Malaysia.

Background:

Tuberculosis (TB) eradication is one of the top priorities in the public health agenda in Malaysia. While public-private mix (PPM) initiatives have been launched, community pharmacists remain undervalued assets in TB management.

Methods:

A two-phase mixed-methods study targeting community pharmacists was conducted in Malaysia between March and October 2021. The first phase was an online self-administered survey developed according to the Consolidated Framework for Implementation Research (CFIR). The second phase was a semi-structured interview to allow deeper understanding on the quantitative results. Quantitative data were analysed using descriptive analysis while qualitative data were analysed using thematic analysis with a semi-inductive approach. The data were triangulated to enhance comprehensiveness and credibility of the findings.

Findings:

The survey was completed by 388 community pharmacists, and 23 pharmacists participated in the interview. Most community pharmacists indicated their willingness to serve as TB-DOT supervisors (70.1%). Qualitative results supported the findings. Community pharmacy-based TB-DOT service was perceived as an avenue to improve TB management and outcomes and to enhance the professional role of pharmacists in TB service at primary care settings. This was also perceived as a feasible intervention with the potential to strengthen the National TB Control programme. This initiative needs be reinforced with adequate support from the public healthcare sector for a strong partnership in ensuring success.
Mapping of QTLs for flood tolerance in rice using recombinant inbred lines of Indra and a new plant genetic resource AC 39416 A
Authors: Girija Rani M. , Satyanarayana P. V. , Chamundeswari N. , Ramana Rao P. V. , Prabhakar M. , Ravikumar B. N. V. S. R. , Nagakumari P. , Kalpana K.
Published: March 2023

Rice crop is affected by different types of floods at different stages of the crop cycle. Constant efforts of researchers resulted in the development of rice varieties for anaerobic germination, flash floods and stagnant flooding by both conventional and molecular breeding approaches. Detection of QTLs for different types of floods in new genetic source (AC39416A) is needed to combat adverse effects of climate change. Present investigation was carried out to identify QTLs for flood tolerance using recombinant inbred lines derived from Indra and AC39416A. QTL mapping resulted in identification of QTLs, qAG3.1 on chromosome 3 for anaerobic germination and qSF10.1 on chromosome 10 for plant survival % under stagnant flooding. These QTLs explain 59.08 and 13.21% of phenotypic variance respectively. Two candidate genes were identified in qAG3.1 region, LOC_Os03g42130 gibberellin 20 oxidase2 and LOC_Os03g44170 glutathione S-transferase. The underlying mechanism might be the inhibition of gibberellic acid synthesis and thereby protecting seedlings from oxidative stress under anoxia condition. Genomic region of qSF10.1 revealed LOC_Os10g35020 glycosyltransferase and LOC_Os10g35050 aquaporin protein loci, which might be responsible for adaptive mechanism for plant survival % under stagnant flooding. This indicates that the new genetic resource AC39416A has an ability to adopt to different types of flood tolerance in response to environmental stress. Unveiling physiological and molecular mechanisms for flood tolerance in AC39416A using advanced omics studies would help in precise genomic selections for sustained production in flood-prone areas.
A New Method to Estimate Slab Dip Direction Using Receiver Functions and Its Application in Revealing Slab Geometry and a Diffuse Plate Boundary Beneath Sumatra
Authors: Feng Mingye , Chen Ling , Wei Shengji , Wang Xin , Wang Xu , Wu Zimu
Published: March 2023

While dip direction is a fundamental parameter of slab geometry, it is rarely estimated quantitatively. Here, we develop a new method, Dip Direction Searching (DDS), of receiver functions (RFs) that reduces the uncertainty of slab dip direction estimation from tens to several degrees. DDS can also resolve the thickness and depth of a dipping structure. We then apply DDS to the RFs in the Sumatran subduction zone. Travel time differences of the converted phases from the upper and lower (oceanic Moho) boundaries of the dipping low‐velocity layer (LVL) along the plate interface show a thickness of 10–14 km. The results also show increased dip direction of the slab Moho from 47 ± 5.3° in southern Sumatra to 70 ± 10.7° in northern Sumatra, indicating a complicated slab geometry and internal deformation along strike. Similar dip directions are obtained for the upper and lower LVL boundaries beneath Nias and Enggano forearc islands in the north and south, whereas we find a larger discrepancy of ∼14–23° beneath Siberut and Pagai in between. The thicker LVL with a non‐negligible difference in the dip directions of its upper and lower bounds in the center of Sumatra is interpreted as a partially serpentinized mantle layer above the oceanic crust, forming a distinct channel atop the subducting slab. Our results provide basic observational constraints on the structure and geometry of the oceanic slab and associated subduction processes. Both synthetics and data analyses also indicate DDS can be applied in other subduction zones and for other dipping interfaces.
Cloud‐Radiation Feedback Facilitates Secondary Eyewall Formation of Tropical Cyclones
Authors: Wang Yi‐Fan , Yang Bolei , Tan Zhe‐Min
Published: March 2023

Recent studies show that the formation of outer rainbands (ORBs) is essence to secondary eyewall formation (SEF) of tropical cyclones (TCs). This study reveals that cloud‐radiation feedback (CRF) facilitates SEF of TCs by promoting the formation of ORBs and their stratiform sectors. In detail, CRF engenders an upper‐level anomalous radiative warming in the outer‐core region, which induces a secondary circulation that accelerates the release of microphysical heating above the freezing level. The enhanced upper‐level latent heating further promotes the outer‐core convection and the top‐down development of the ORBs. Moreover, CRF promotes a broader stratiform precipitation area and stronger stratiform heating profiles of the ORBs, which forces convective updrafts at the radially inward edge of the stratiform precipitation area and eventually leads to SEF. On the contrary, when the anomalous radiative warming is removed, the organization of ORBs and the development of stratiform precipitation are suppressed due to the absence of the radiation‐induced upper‐level secondary circulation, thus inhibiting SEF.
Perovskite photodetector-based single pixel color camera for artificial vision
Authors: Chen Chaohao , Li Ziyuan , Fu Lan
Published: March 2023

Narrowband red, green, blue self-filtering perovskite photodetectors and a broadband white photodetector are incorporated into a single pixel imaging camera to mimic the long-, medium-, and short-wavelength cone cells and rod cells in human visual system, leading to the demonstration of high-resolution color images in diffuse mode.
Node of Ranvier remodeling in chronic psychosocial stress and anxiety
Authors: Koskinen Maija-Kreetta , Laine Mikaela , Abdollahzadeh Ali , Gigliotta Adrien , Mazzini Giulia , Journée Sarah , Alenius Varpu , Trontti Kalevi , Tohka Jussi , Hyytiä Petri , Sierra Alejandra , Hovatta Iiris
Published: March 2023

Differential expression of myelin-related genes and changes in myelin thickness have been demonstrated in mice after chronic psychosocial stress, a risk factor for anxiety disorders. To determine whether and how stress affects structural remodeling of nodes of Ranvier, another form of myelin plasticity, we developed a 3D reconstruction analysis of node morphology in C57BL/6NCrl and DBA/2NCrl mice. We identified strain-dependent effects of chronic social defeat stress on node morphology in the medial prefrontal cortex (mPFC) gray matter, including shortening of paranodes in C57BL/6NCrl stress-resilient and shortening of node gaps in DBA/2NCrl stress-susceptible mice compared to controls. Neuronal activity has been associated with changes in myelin thickness. To investigate whether neuronal activation is a mechanism influencing also node of Ranvier morphology, we used DREADDs to repeatedly activate the ventral hippocampus-to-mPFC pathway. We found reduced anxiety-like behavior and shortened paranodes specifically in stimulated, but not in the nearby non-stimulated axons. Altogether, our data demonstrate (1) nodal remodeling of the mPFC gray matter axons after chronic stress and (2) axon-specific regulation of paranodes in response to repeated neuronal activity in an anxiety-associated pathway. Nodal remodeling may thus contribute to aberrant circuit function associated with anxiety disorders.
Clinical evidence for immune-based strategies in early-line multiple myeloma: current challenges in decision-making for subsequent therapy
Authors: Raje Noopur , Mateos María-Victoria , Iida Shinsuke , Reece Donna
Published: March 2023

Almost all patients with multiple myeloma (MM) will eventually develop disease that has relapsed with or become refractory to available treatments and will require additional therapy. However, data are still lacking on how best to sequence regimens in the relapsed/refractory (RR) setting after the failure of early-line lenalidomide, bortezomib, and/or daratumumab, the most commonly used agents in clinical practice today. With the treatment landscape rapidly changing in response to emerging clinical trial data and approvals of several new drugs and additional combinations, it is critically important to focus on patients with RRMM. Variability in patient baseline characteristics, such as the number of prior lines of treatment, refractoriness to prior treatments, prior stem cell transplant, and timing and dosing of prior lenalidomide, makes it difficult to select the best options for patients with RRMM for whom first-line treatments have failed. The aim of this review is to provide both an overview of current therapies and future directions within the RRMM treatment landscape, and a framework for clinicians to choose the most promising next treatment option.
USP10 deubiquitinates RUNX1 and promotes proneural-to-mesenchymal transition in glioblastoma
Authors: Qiu Wenjin , Xiao Zumu , Yang Yushi , Jiang Lishi , Song Shibin , Qi Xiaolan , Chen Yimin , Yang Hua , Liu Jian , Chu Liangzhao
Published: March 2023

The mesenchymal (MES) subtype of glioblastoma (GBM) is a highly aggressive, malignant and proliferative cancer that is resistant to chemotherapy. Runt-related transcription factor 1 (RUNX1) was shown to support MES GBM, however, its underlying mechanisms are unclear. Here, we identified USP10 as a deubiquitinating enzyme that regulates RUNX1 stabilization and is mainly expressed in MES GBM. Overexpression of USP10 upregulated RUNX1 and induced proneural-to-mesenchymal transition (PMT), thus maintaining MES properties in GBM. Conversely, USP10 knockdown inhibited RUNX1 and resulted in the loss of MES properties. USP10 was shown to interact with RUNX1, with RUNX1 being stabilized upon deubiquitylation. Moreover, we found that USP10 inhibitor Spautin-1 induced RUNX1 degradation and inhibited MES properties in vitro and in vivo. Furthermore, USP10 was strongly correlated with RUNX1 expression in samples of different subtypes of human GBM and had prognostic value for GBM patients. We identified USP10 as a key deubiquitinase for RUNX1 protein stabilization. USP10 maintains MES properties of GBM, and promotes PMT of GBM cells. Our study indicates that the USP10/RUNX1 axis may be a potential target for novel GBM treatments.
Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination
Authors: Zahaf Amina , Kassoussi Abdelmoumen , Hutteau-Hamel Tom , Mellouk Amine , Marie Corentine , Zoupi Lida , Tsouki Foteini , Mattern Claudia , Bobé Pierre , Schumacher Michael , Williams Anna , Parras Carlos , Traiffort Elisabeth
Published: March 2023

Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences.
Bitter taste cells in the ventricular walls of the murine brain regulate glucose homeostasis
Authors: Yu Qiang , Gamayun Igor , Wartenberg Philipp , Zhang Qian , Qiao Sen , Kusumakshi Soumya , Candlish Sarah , Götz Viktoria , Wen Shuping , Das Debajyoti , Wyatt Amanda , Wahl Vanessa , Ectors Fabien , Kattler Kathrin , Yildiz Daniela , Prevot Vincent , Schwaninger Markus , Ternier Gaetan , Giacobini Paolo , Ciofi Philippe , Müller Timo D. , Boehm Ulrich
Published: March 2023

The median eminence (ME) is a circumventricular organ at the base of the brain that controls body homeostasis. Tanycytes are its specialized glial cells that constitute the ventricular walls and regulate different physiological states, however individual signaling pathways in these cells are incompletely understood. Here, we identify a functional tanycyte subpopulation that expresses key taste transduction genes including bitter taste receptors, the G protein gustducin and the gustatory ion channel TRPM5 (M5). M5 tanycytes have access to blood-borne cues via processes extended towards diaphragmed endothelial fenestrations in the ME and mediate bidirectional communication between the cerebrospinal fluid and blood. This subpopulation responds to metabolic signals including leptin and other hormonal cues and is transcriptionally reprogrammed upon fasting. Acute M5 tanycyte activation induces insulin secretion and acute diphtheria toxin-mediated M5 tanycyte depletion results in impaired glucose tolerance in diet-induced obese mice. We provide a cellular and molecular framework that defines how bitter taste cells in the ME integrate chemosensation with metabolism.
Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas
Authors: Murakami Shigekazu , White Shannon M. , McIntosh Alec T. , Nguyen Chan D. K. , Yi Chunling
Published: March 2023

Lineage plasticity has been proposed as a major source of intratumoral heterogeneity and therapeutic resistance. Here, by employing an inducible genetic engineered mouse model, we illustrate that lineage plasticity enables advanced Pancreatic Ductal Adenocarcinoma (PDAC) tumors to develop spontaneous relapse following elimination of the central oncogenic driver - Yap. Transcriptomic and immunohistochemistry analysis of a large panel of PDAC tumors reveals that within high-grade tumors, small niches of PDAC cells gradually evolve to re-activate pluripotent transcription factors (PTFs), which lessen their dependency on Yap. Comprehensive Cut&Tag analysis demonstrate that although acquisition of PTF expression is coupled with the process of epithelial-to-mesenchymal transition (EMT), PTFs form a core transcriptional regulatory circuitry (CRC) with Jun to overcome Yap dependency, which is distinct from the classic TGFb-induced EMT-TF network. A chemical-genetic screen and follow-up functional studies establish Brd4 as an epigenetic gatekeeper for the PTF-Jun CRC, and strong synergy between BET and Yap inhibitors in blocking PDAC growth.
Interoperable slide microscopy viewer and annotation tool for imaging data science and computational pathology
Authors: Gorman Chris , Punzo Davide , Octaviano Igor , Pieper Steven , Longabaugh William J. R. , Clunie David A. , Kikinis Ron , Fedorov Andrey Y. , Herrmann Markus D.
Published: March 2023

The exchange of large and complex slide microscopy imaging data in biomedical research and pathology practice is impeded by a lack of data standardization and interoperability, which is detrimental to the reproducibility of scientific findings and clinical integration of technological innovations. We introduce Slim, an open-source, web-based slide microscopy viewer that implements the internationally accepted Digital Imaging and Communications in Medicine (DICOM) standard to achieve interoperability with a multitude of existing medical imaging systems. We showcase the capabilities of Slim as the slide microscopy viewer of the NCI Imaging Data Commons and demonstrate how the viewer enables interactive visualization of traditional brightfield microscopy and highly-multiplexed immunofluorescence microscopy images from The Cancer Genome Atlas and Human Tissue Atlas Network, respectively, using standard DICOMweb services. We further show how Slim enables the collection of standardized image annotations for the development or validation of machine learning models and the visual interpretation of model inference results in the form of segmentation masks, spatial heat maps, or image-derived measurements.
Population dynamics of head-direction neurons during drift and reorientation
Authors: Ajabi Zaki , Keinath Alexandra T. , Wei Xue-Xin , Brandon Mark P.
Published: March 2023

The head direction (HD) system functions as the brain’s internal compass1,2, classically formalized as a one-dimensional ring attractor network3,4. In contrast to a globally consistent magnetic compass, the HD system does not have a universal reference frame. Instead, it anchors to local cues, maintaining a stable offset when cues rotate5–8 and drifting in the absence of referents5,8–10. However, questions about the mechanisms that underlie anchoring and drift remain unresolved and are best addressed at the population level. For example, the extent to which the one-dimensional description of population activity holds under conditions of reorientation and drift is unclear. Here we performed population recordings of thalamic HD cells using calcium imaging during controlled rotations of a visual landmark. Across experiments, population activity varied along a second dimension, which we refer to as network gain, especially under circumstances of cue conflict and ambiguity. Activity along this dimension predicted realignment and drift dynamics, including the speed of network realignment. In the dark, network gain maintained a ‘memory trace’ of the previously displayed landmark. Further experiments demonstrated that the HD network returned to its baseline orientation after brief, but not longer, exposures to a rotated cue. This experience dependence suggests that memory of previous associations between HD neurons and allocentric cues is maintained and influences the internal HD representation. Building on these results, we show that continuous rotation of a visual landmark induced rotation of the HD representation that persisted in darkness, demonstrating experience-dependent recalibration of the HD system. Finally, we propose a computational model to formalize how the neural compass flexibly adapts to changing environmental cues to maintain a reliable representation of HD. These results challenge classical one-dimensional interpretations of the HD system and provide insights into the interactions between this system and the cues to which it anchors.
Structural basis of mitochondrial membrane bending by the I–II–III2–IV2 supercomplex
Authors: Mühleip Alexander , Flygaard Rasmus Kock , Baradaran Rozbeh , Haapanen Outi , Gruhl Thomas , Tobiasson Victor , Maréchal Amandine , Sharma Vivek , Amunts Alexey
Published: March 2023

Mitochondrial energy conversion requires an intricate architecture of the inner mitochondrial membrane1. Here we show that a supercomplex containing all four respiratory chain components contributes to membrane curvature induction in ciliates. We report cryo-electron microscopy and cryo-tomography structures of the supercomplex that comprises 150 different proteins and 311 bound lipids, forming a stable 5.8-MDa assembly. Owing to subunit acquisition and extension, complex I associates with a complex IV dimer, generating a wedge-shaped gap that serves as a binding site for complex II. Together with a tilted complex III dimer association, it results in a curved membrane region. Using molecular dynamics simulations, we demonstrate that the divergent supercomplex actively contributes to the membrane curvature induction and tubulation of cristae. Our findings highlight how the evolution of protein subunits of respiratory complexes has led to the I–II–III2–IV2 supercomplex that contributes to the shaping of the bioenergetic membrane, thereby enabling its functional specialization.
An investigation of zinc isotope fractionation in cacao (Theobroma cacao L.) and comparison of zinc and cadmium isotope compositions in hydroponic plant systems under high cadmium stress
Authors: Barati Elnaz , Moore Rebekah E. T. , Ullah Ihsan , Kreissig Katharina , Coles Barry J. , Dunwell Jim M. , Rehkämper Mark
Published: March 2023

This study aims to establish whether zinc (Zn) and cadmium (Cd) share similar physiological mechanisms for uptake and translocation in cacao plants (Theobroma cacao L.). Multiple-collector ICP-MS was used to determine the Zn stable isotope compositions in the roots, stems and leaves of 19 diverse cacao genotypes grown in hydroponics with 20 µmol L−1 CdCl2. Additional plants of one genotype were grown in hydroponic solutions containing lower Cd concentrations (0 and 5 µmol L−1 added CdCl2). Regardless of the Cd concentration used in the exposures, the Zn stable isotope compositions show the same systematic patterns in plant organs, with δ66Znroot > δ66Znstem > δ66Znleaf (δ66Zn denotes relative differences in 66Zn/64Zn ratios in parts per thousand). The mean Zn stable isotope fractionation between the plants and the hydroponic solutions was ε66Znuptake = –1.15 ± 0.36‰ (2SD), indicating preferential uptake of isotopically light Zn by plants from the hydroponic solution. The mean  stable isotope fractionation factor associated with translocation of Zn from roots to shoots, ε66Znseq-mob =  + 0.52 ± 0.36‰ (2SD), shows that isotopically heavy Zn is preferentially sequestered in the cacao roots, whilst isotopically light Zn is mobilised to the leaves. A comparison with the Cd stable isotope compositions of the same plants shows that both isotopically light Zn and Cd are preferentially taken up by cacao plants. In contrast to Zn, however, the cacao roots retain isotopically light Cd and transfer isotopically heavy Cd to the leaves.
Comparing the effectiveness and lubricity of a novel Shea lubricant to 2% lidocaine gel for digital rectal examination: a randomized non-inferiority trial
Authors: Adanu Kekeli Kodjo , Iroko Davidson , Amegan-Aho Kokou , Adedia David , Ndudiri Orish Verner , Ali Mahamudu Ayamba , Oyortey Mawuenyo Attawa , Kpodonu Jacques
Published: March 2023

This study compared the level of lubricity and pain reduction of a novel shea lubricant to 2% lidocaine gel during digital rectal examination (DRE). Our research group performed a 9-week single-blind non-inferiority trial at the Ho Teaching Hospital involving 153 patients. The primary outcome measure was the mean pain difference during the procedure using a Visual Analogue Scale. 75 and 78 patients were randomized to the shea lubricant and 2% lidocaine gel groups respectively. The analysis considered the per-protocol population. The mean pain difference at endpoint was Δ − 0.01. The 95% lower confidence interval was a -0.595 difference in means, above the non-inferiority (NI) limit of − 0.720, thus establishing non-inferiority (Δ − 0.01, 95% CI − 0.59 to 0.57, NI − 0.72). With secondary outcome measures, perianal pruritus (p = 0.728), discomfort (p = 0.446), bowel urgency (p = 0.077) and urinary urgency (p = 0.841) were similar during the procedure. Shea lubricant had better lubricity and ease of use (p = 0.002). While the novel shea lubricant achieved similar level of pain reduction as obtained with 2% lidocaine gel, it had better ease of performance and lubricity.