bluuebunny/crossref_metadata_2025 huggingface dataset:
Green Analytical Approach for HPLC Method Development for Quantification of Sorafenib and Its Pharmacopeia Impurities: LC–MS/MS Characterization and Toxicity Prediction of Stress Degradation Products
Authors: Bhupatiraju Rajesh Varma , Peddi Pavani , Edla Subhashini , Rekha Kandula , Kasimala Bikshal Babu
Published: July 2024

This research presents the development and validation of chromatographic method for analyzing sorafenib and its pharmacopeial impurities, with a focus on stability studies and degradation product (DP) characterization. Initial method optimization involved exploring various column and buffer combinations, ultimately achieving optimal separation and peak symmetry using an ODS‐AQ YMC (150 mm) column with 0.6 mL/min gradient flow of 10 mM ammonium formate buffer adjusted to pH 3.4 with formic acid as solvent A, and ethanol as solvent B as mobile phase and 246 nm wavelength. Method exhibits calibration curve linear in 50–300 µg/mL for sorafenib and 0.050–0.30 µg/mL for impurities with a detection limit of 0.015 µg/mL for impurities. A structural elucidation of DPs was performed using LC–MS/MS, providing valuable insights into their molecular compositions, and was characterized as 4‐[4‐(carboxyamino)phenoxy]pyridine‐2‐carboxylic acid (DP 1) and 4‐(4‐aminophenoxy)pyridine‐2‐carboxamide (DP 2). Using AGREE and GAPI metrics, evaluation highlighted method sustainability through ethanol–water solvents and shorter column to reduce energy consumption. Toxicity assessments revealed differences in environmental impact and toxicological profiles of DPs, emphasizing importance of managing safety considerations for sorafenib and its DPs. This research offers novel insights into sorafenib analysis by addressing pharmacopeial impurities, characterizing DPs, and evaluating method sustainability and safety.
Activated carbon adsorption for mitigating the harmful effects of antibiotics on the biological activated sludge: Effect on heterotrophic kinetics through respirometry
Authors: Díaz Eva , García‐Menéndez Laura , Leyva‐Díaz Juan Carlos , Ordóñez Salvador
Published: July 2024

Conventional wastewater treatment plants (WWTPs) are not designed for the abatement of antibiotics, and their effluents are one of the main entry ways of these emerging contaminants to the aquatic environment, causing major concern due to their toxicity, persistence, and bioaccumulation. When wastewater containing antibiotics enters the bioreactor, they can impact microbial communities of the activated sludge, affecting biodegradation processes of organic matter and nutrients. There is scarce information about the effect of activated carbon on the activated sludge within the bioreactor in presence of antibiotics. In light of this, the effect of representative antibiotics, ciprofloxacin (CIP), nalidixic acid (NAL), and erythromycin (ERY), on the performance of a conventional activated sludge of a WWTP was analyzed by respirometry with and without activated carbon. NAL and ERY negatively affected the net heterotrophic biomass growth rate (r′x,H), with reduction percentages of 26%–90% and 31%–81%, respectively. The addition of activated carbon mitigated this effect, especially for ERY, with increments of even 8% in the r′x,H for the hybrid process when working with 5 ppm of ERY and 80 ppm of activated carbon compared with the value in the absence of antibiotic and activated carbon. This effect was attributed to the enhanced retention of ERY, in comparison to NAL, on the surface of the activated carbon, probably due to its higher molecular size and affinity towards the activated carbon (log Kow = 3.06). This effect was more marked at low sludge retention times (below 8 days).

Practitioner points

Ciprofloxacin (CIP), nalidixic acid (NAL), and erythromycin (ERY) were studied.

NAL and ERY exerted negative impact on heterotrophic growth rate.

Effect of antibiotics on microorganisms in the presence of activated carbon was studied.

Activated carbon was mainly relevant for ERY due to its adsorption retention.

Enhancement by activated carbon was more significant at low sludge retention times.
Maximizing synergies between state and non‐state actors to enhance water governance in the Cubango‐Okavango River basin
Authors: Shifidi Victoria , Sitas Nadia , Meissner Richard
Published: July 2024

The inherent complexity of governing transboundary social–ecological systems like the Cubango‐Okavango River Basin (CORB) has given rise to various governance frameworks like integrated water resource management (IWRM) and adaptive governance. While these may work in theory and some specific contexts, current discordance between formal (state) and informal (non‐state) governance systems, especially at the local level, still exists, resulting in significant inequities regarding water resource allocation, use, and sustainability. This research, therefore, is crucial in understanding why the disconnects between state and non‐state actors might be present in current governance arrangements and how they influence decision‐making processes linked to equitable and sustainable water governance. Through a mixed‐method, qualitative approach, this paper aimed to examine how state and non‐state actors influence water governance in the CORB from a Namibian perspective and explore current challenges and opportunities in governance structures to understand strategic intervention points for enhancing more just and sustainable governance outcomes. Data was collected from 63 participants through semi‐structured, in‐depth interviews, and an actor‐mapping questionnaire to understand key actors involved in the Namibian portion of the CORB and to determine the critical networks and relationships between them for enhancing water governance in the basin. Embedded within a grounded theory approach, thematic analysis was used to analyze data using Atlas.ti; a descriptive analysis was used to graphically organize, summarize, and present field data using Microsoft Excel; and a narrative analysis documented the participants' personal stories of water governance. The study identified key water governance breakdown points between state and non‐state actors, including resource grabs and inadequate bottom‐up approaches. The study further found that the active participation of non‐state actors in the water governance of the CORB is imperative for maximizing contextualized synergies between state and non‐state actors in transboundary water governance.
Introduction: Why Study the Governance of Gene Edited Agrifoods?
Authors: Clark Lisa F. , Hobbs Jill E.
Published: July 2024

The introduction to this book asks the question: why study the governance of genome editing in agrifood? We discuss current system-wide, and country specific policy changes that have increased interest in using genomic techniques to make improvements to agronomic, nutritional/functional traits and organoleptic qualities of plants used for human food and animal feed. We discuss why applying supply chain and systems approaches are useful ways to view how the pace and applications of technological innovations in this sector are tempered by the political and economic dynamics of risk governance. This introductory chapter also includes discussions of the methodology, a brief review of studies of gene editing in the agrifood system, and outlines the structure of the book.
What Is Gene Editing?
Authors: Clark Lisa F. , Hobbs Jill E.
Published: July 2024

This chapter begins with the basics. We explain what gene editing is, and how different techniques are used to achieve genomic edits, including Site-Directed Nucleases, Meganucleases, Zinc Finger Nuclease, TALENs, and CRISPR-Cas9. The chapter maps out a timeline of the development of genome-editing techniques, discussing the benefits and challenges of each, with most recently CRISPR-Cas9. We provide examples of applications of gene editing in agrifood plant breeding. Despite the advantages of CRISPR-Cas9, other genome editing techniques may offer useful tools to address the challenges of agrifood production in the twenty-first century. Nevertheless, CRISPR-Cas9 technology remains the dominant approach to genome editing.
Gewaltsames Othering (und seine Grenzen)
Authors: Breger Max
Published: July 2024

Das Kapitel fragt danach, welche Verweise auf Andersartigkeiten und Entmenschlichungen sich in der Foltergewalt des War on Terror zeigen und wie sie durch situative Elemente hergestellt werden. Grundsätzlich lassen sich zwei Richtungen des gewaltsamen Otherings in Foltersituationen unterscheiden. Zum einen adressiert die Gewalt Verletzungsoffenheiten auf Basis zugesprochener Spezifika muslimischer Männer. Hier wird das Wissen über vermeintliche kulturell-geschlechtliche Eigenarten der Feinde zu einem Mittel zur ‚Effektivierung‘ der Folter gewendet. Zum anderen stellt die Foltergewalt in ihrem Vollzug Andersartigkeiten der Unterworfenen performativ her und dar. Die beiden Aspekte sind jedoch nicht getrennt voneinander zu sehen und können bei Folterpraktiken zusammenfallen. Zugleich ist das Othering durch die Funktionsweise der Folter begrenzt, die eine absolute Dehumanisierung im Sinne eines vollständigen Aberkennens von Subjektivität der Gefolterten ausschließt.
Equivariant, safe and sensitive — graph networks for new physics
Authors: Bhardwaj Akanksha , Englert Christoph , Naskar Wrishik , Ngairangbam Vishal S. , Spannowsky Michael
Published: July 2024

Abstract

This study introduces a novel Graph Neural Network (GNN) architecture that leverages infrared and collinear (IRC) safety and equivariance to enhance the analysis of collider data for Beyond the Standard Model (BSM) discoveries. By integrating equivariance in the rapidity-azimuth plane with IRC-safe principles, our model significantly reduces computational overhead while ensuring theoretical consistency in identifying BSM scenarios amidst Quantum Chromodynamics backgrounds. The proposed GNN architecture demonstrates superior performance in tagging semi-visible jets, highlighting its potential as a robust tool for advancing BSM search strategies at high-energy colliders.
Is infrared-collinear safe information all you need for jet classification?
Authors: Athanasakos Dimitrios , Larkoski Andrew J. , Mulligan James , Płoskoń Mateusz , Ringer Felix
Published: July 2024

Abstract

Machine learning-based jet classifiers are able to achieve impressive tagging performance in a variety of applications in high-energy and nuclear physics. However, it remains unclear in many cases which aspects of jets give rise to this discriminating power, and whether jet observables that are tractable in perturbative QCD such as those obeying infrared-collinear (IRC) safety serve as sufficient inputs. In this article, we introduce a new classifier, Jet Flow Networks (JFNs), in an effort to address the question of whether IRC unsafe information provides additional discriminating power in jet classification. JFNs are permutation-invariant neural networks (deep sets) that take as input the kinematic information of reconstructed subjets. The subjet radius and a cut on the subjet’s transverse momenta serve as tunable hyperparameters enabling a controllable sensitivity to soft emissions and nonperturbative effects. We demonstrate the performance of JFNs for quark vs. gluon and Z vs. QCD jet tagging. For small subjet radii and transverse momentum cuts, the performance of JFNs is equivalent to the IRC-unsafe Particle Flow Networks (PFNs), demonstrating that infrared-collinear unsafe information is not necessary to achieve strong discrimination for both cases. As the subjet radius is increased, the performance of the JFNs remains essentially unchanged until physical thresholds that we identify are crossed. For relatively large subjet radii, we show that the JFNs may offer an increased model independence with a modest tradeoff in performance compared to classifiers that use the full particle information of the jet. These results shed new light on how machines learn patterns in high-energy physics data.
Baryon-number — flavor separation in the topological expansion of QCD
Authors: Frenklakh David , Kharzeev Dmitri , Rossi Giancarlo , Veneziano Gabriele
Published: July 2024

Abstract

Gauge invariance of QCD dictates the presence of string junctions in the wave functions of baryons. In high-energy inclusive processes, these baryon junctions have been predicted to induce the separation of the flows of baryon number and flavor. In this paper we describe this phenomenon using the analog-gas model of multiparticle production proposed long time ago by Feynman and Wilson and adapted here to accommodate the topological expansion in QCD. In this framework, duality arguments suggest the existence of two degenerate junction-antijunction glueball Regge trajectories of opposite $$ \mathcal{C} $$
C
-parity with intercept close to 1/2. The corresponding results for the energy and rapidity dependence of baryon stopping are in reasonably good agreement with recent experimental findings from STAR and ALICE experiments. We show that accounting for correlations between the fragmenting strings further improves agreement with the data, and outline additional experimental tests of our picture at the existing (RHIC, LHC, JLab) and future (EIC) facilities.
Link-area commutators in AdS3 area-networks
Authors: Held Jesse , Kaplan Molly , Marolf Donald , Wu Jie-qiang
Published: July 2024

Abstract

Random tensor networks (RTNs) have proved to be fruitful tools for modelling the AdS/CFT correspondence. Due to their flat entanglement spectra, when discussing a given boundary region R and its complement $$ \overline{R} $$

R
¯

, standard RTNs are most analogous to fixed-area states of the bulk quantum gravity theory, in which quantum fluctuations have been suppressed for the area of the corresponding HRT surface. However, such RTNs have flat entanglement spectra for all choices of R,$$ \overline{R} $$

R
¯

, while quantum fluctuations of multiple HRT-areas can be suppressed only when the corresponding HRT-area operators mutually commute. We probe the severity of such obstructions in pure AdS3 Einstein-Hilbert gravity by constructing networks whose links are codimension-2 extremal-surfaces and by explicitly computing semiclassical commutators of the associated link-areas. Since d = 3, codimension-2 extremal-surfaces are geodesics, and codimension-2 ‘areas’ are lengths. We find a simple 4-link network defined by an HRT surface and a Chen-Dong-Lewkowycz-Qi constrained HRT surface for which all link-areas commute. However, the algebra generated by the link-areas of more general networks tends to be non-Abelian. One such non-Abelian example is associated with entanglement-wedge cross sections and may be of more general interest.
Small instanton effects on composite axion mass
Authors: Aoki Takafumi , Ibe Masahiro , Shirai Satoshi , Watanabe Keiichi
Published: July 2024

Abstract

This paper investigates the impact of small instanton effects on the axion mass in composite axion models. In particular, we focus on the Composite Accidental Axion (CAA) models, which are designed to address the axion quality problem, and where the Peccei-Quinn (PQ) symmetry emerges accidentally. In the CAA models, the QCD gauge symmetry is embedded in a larger gauge group at high energy. These models contain small instantons not included in low-energy QCD, which could enhance the axion mass significantly. However, in the CAA models, our analysis reveals that these effects on the axion mass are non-vanishing but are negligible compared to the QCD effects. The suppression of the small instanton effects originates from the global chiral U(1) symmetries which are not broken spontaneously and play a crucial role in eliminating θ-terms in the hidden sectors through anomalies. We find these U(1) symmetries restrict the impact of small instantons in hidden sectors on the axion mass. Our study provides crucial insights into the dynamics within the CAA models and suggests broader implications for understanding small instanton effects in other composite axion models.
Bone-muscle crosstalk under physiological and pathological conditions
Authors: Dong Yuechao , Yuan Hongyan , Ma Guixing , Cao Huiling
Published: July 2024

Anatomically connected bones and muscles determine movement of the body. Forces exerted on muscles are then turned to bones to promote osteogenesis. The crosstalk between muscle and bone has been identified as mechanotransduction previously. In addition to the mechanical features, bones and muscles are also secretory organs which interact closely with one another through producing myokines and osteokines. Moreover, besides the mechanical features, other factors, such as nutrition metabolism, physiological rhythm, age, etc., also affect bone-muscle crosstalk. What’s more, osteogenesis and myogenesis within motor system occur almost in parallel. Pathologically, defective muscles are always detected in bone associated diseases and induce the osteopenia, inflammation and abnormal bone metabolism, etc., through biomechanical or biochemical coupling. Hence, we summarize the study findings of bone-muscle crosstalk and propose potential strategies to improve the skeletal or muscular symptoms of certain diseases. Altogether, functional improvement of bones or muscles is beneficial to each other within motor system.
Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons
Authors: Petrova Veselina , Snavely Andrew R. , Splaine Jennifer , Zhen Shannon , Singh Bhagat , Pandey Roshan , Chen Kuchuan , Cheng Anya , Hermawan Crystal , Barrett Lee B. , Smith Jennifer A. , Woolf Clifford J.
Published: July 2024

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient’s quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles – AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.
ZMYND12 serves as an IDAd subunit that is essential for sperm motility in mice
Authors: Wang Chang , Xie Qingsong , Xia Xun , Zhang Chuanying , Jiang Shan , Wang Sihan , Zhang Xi , Hua Rong , Xue Jiangyang , Zheng Haoyu
Published: July 2024

Inner dynein arms (IDAs) are formed from a protein complex that is essential for appropriate flagellar bending and beating. IDA defects have previously been linked to the incidence of asthenozoospermia (AZS) and male infertility. The testes-enriched ZMYND12 protein is homologous with an IDA component identified in Chlamydomonas. ZMYND12 deficiency has previously been tied to infertility in males, yet the underlying mechanism remains uncertain. Here, a CRISPR/Cas9 approach was employed to generate Zmynd12 knockout (Zmynd12−/−) mice. These Zmynd12−/− mice exhibited significant male subfertility, reduced sperm motile velocity, and impaired capacitation. Through a combination of co-immunoprecipitation and mass spectrometry, ZMYND12 was found to interact with TTC29 and PRKACA. Decreases in the levels of PRKACA were evident in the sperm of these Zmynd12−/− mice, suggesting that this change may account for the observed drop in male fertility. Moreover, in a cohort of patients with AZS, one patient carrying a ZMYND12 variant was identified, expanding the known AZS-related variant spectrum. Together, these findings demonstrate that ZMYND12 is essential for flagellar beating, capacitation, and male fertility.
The Sobolev Wavefront Set of the Causal Propagator in Finite Regularity
Authors: Sanchez Sanchez Yafet E. , Schrohe Elmar
Published: July 2024

Given a globally hyperbolic spacetime $$M={\mathbb {R}}\times \Sigma $$

M
=
R
×
Σ

of dimension four and regularity $$C^\tau $$

C
τ

, we estimate the Sobolev wavefront set of the causal propagator $$K_G$$

K
G

of the Klein–Gordon operator. In the smooth case, the propagator satisfies $$WF'(K_G)=C$$

W

F
′

(

K
G

)

=
C

, where $$C\subset T^*(M\times M)$$

C
⊂

T
∗

(
M
×
M
)

consists of those points $$(\tilde{x},\tilde{\xi },\tilde{y},\tilde{\eta })$$

(

x
~

,

ξ
~

,

y
~

,

η
~

)

such that $$\tilde{\xi },\tilde{\eta }$$

ξ
~

,

η
~

are cotangent to a null geodesic $$\gamma $$
γ
at $$\tilde{x}$$

x
~

resp. $$\tilde{y}$$

y
~

and parallel transports of each other along $$\gamma $$
γ
. We show that for $$\tau >2$$

τ
>
2

, $$\begin{aligned} WF'^{-2+\tau -{\epsilon }}(K_G)\subset C \end{aligned}$$

W

F

′
-
2
+
τ
-
ϵ

(

K
G

)

⊂
C

for every $${\epsilon }>0$$

ϵ
>
0

. Furthermore, in regularity $$C^{\tau +2}$$

C

τ
+
2

with $$\tau >2$$

τ
>
2

, $$\begin{aligned} C\subset WF'^{-\frac{1}{2}}(K_G)\subset WF'^{\tau -\epsilon }(K_G)\subset C \end{aligned}$$

C
⊂
W

F

′
-

1
2

(

K
G

)

⊂
W

F

′
τ
-
ϵ

(

K
G

)

⊂
C

holds for $$0<\epsilon <\tau +\frac{1}{2}$$

0
<
ϵ
<
τ
+

1
2

. In the ultrastatic case with $$\Sigma $$
Σ
compact, we show $$WF'^{-\frac{3}{2}+\tau -\epsilon }(K_G)\subset C$$

W

F

′
-

3
2

+
τ
-
ϵ

(

K
G

)

⊂
C

for $$\epsilon >0$$

ϵ
>
0

and $$\tau >2$$

τ
>
2

and $$WF'^{-\frac{3}{2}+\tau -\epsilon }(K_G)= C$$

W

F

′
-

3
2

+
τ
-
ϵ

(

K
G

)

=
C

for $$\tau >3$$

τ
>
3

and $$\epsilon <\tau -3$$

ϵ
<
τ
-
3

. Moreover, we show that the global regularity of the propagator $$K_G$$

K
G

is $$H^{-\frac{1}{2}-\epsilon }_{loc}(M\times M)$$

H

loc

-

1
2

-
ϵ

(
M
×
M
)

as in the smooth case.
Large Ozone Hole in 2023 and the Hunga Tonga Volcanic Eruption
Authors: Kozubek Michal , Krizan Peter , Ramatheerthan Sunil Kumar , Laštovička Jan
Published: July 2024

Polar stratospheric chemistry is highly sensitive to changes in water vapor content and temperature. We identified an unusual behavior of water vapor and temperature in the southern polar winter stratosphere in 2023. The relationships between the Hunga-Tonga eruption injection of water vapor (detected in the tropics) and its transport to SH high latitudes, temperature changes and ozone anomalies at southern high latitudes are discussed, as well as the roles of zonal wind and the meridional flux of zonal mean zonal momentum. These parameters exhibit a consistent pattern in anomalous year 2023. In the winter of 2023 in the Southern Hemisphere, an unexpected decrease in ozone levels and the emergence of an excessive ozone hole were observed. This event marked one of the deepest Antarctic ozone holes with the largest area since 2011. This appears to be associated with the Hunga Tonga eruption anomalous water vapor injection. This study highlights importance of water vapor for evolution of the Antarctic stratosphere.
Stable envelopes for slices of the affine Grassmannian
Authors: Danilenko Ivan
Published: July 2024

The affine Grassmannian associated to a reductive group $${\textbf{G}}$$
G
is an affine analogue of the usual flag varieties. It is a rich source of Poisson varieties and their symplectic resolutions. These spaces are examples of conical symplectic resolutions dual to the Nakajima quiver varieties. We study the cohomological stable envelopes of Maulik and Okounkov (Astérisque 408:ix+209, 2019) in this family. We construct an explicit recursive relation for the stable envelopes in the $${\textbf{G}}= \textbf{PSL}_{2}$$

G
=

PSL
2

case and compute the first-order correction in the general case. This allows us to write an exact formula for multiplication by a divisor.
Profile transformations for reciprocal averaging and singular value decomposition
Authors: Wang Ting-Wu , Beh Eric J. , Lombardo Rosaria , Renner Ian W.
Published: July 2024

Power transformations of count data, including cell frequencies of a contingency table, have been well understood for nearly 100 years, with much of the attention focused on the square root transformation. Over the past 15 years, this topic has been the focus of some new insights into areas of correspondence analysis where two forms of power transformation have been discussed. One type considers the impact of raising the joint proportions of the cell frequencies of a table to a known power while the other examines the power transformation of the relative distribution of the cell frequencies. While the foundations of the graphical features of correspondence analysis rest with the numerical algorithms like reciprocal averaging, and other analogous techniques, discussions of the role of power transformations in reciprocal averaging have not been described. Therefore, this paper examines this link where a power transformation is applied to the cell frequencies of a two-way contingency table. In doing so, we show that reciprocal averaging can be performed under such a transformation to obtain row and column scores that provide the maximum association between the variables and the greatest discrimination between the categories. Finally, we discuss the connection between performing reciprocal averaging and singular value decomposition under this type of power transformation. The function, is included in the Appendix and performs reciprocal averaging of a power transformation of the cell frequencies of a two-way contingency table.
The Gradient Flow for Entropy on Closed Planar Curves
Authors: O’Donnell Lachlann , Wheeler Glen , Wheeler Valentina-Mira
Published: July 2024

In this paper we consider the steepest descent $$L^2$$

L
2

-gradient flow of the entropy functional. The flow expands convex curves, with the radius of an initial circle growing like the square root of time. Our main result is that, for any initial curve (either immersed locally strictly convex of class $$C^2$$

C
2

or embedded of class $$W^{2,2}$$

W

2
,
2

bounding a strictly convex body), the flow converges smoothly to a round expanding multiply-covered circle.
The Role of the European Reference Network for Rare Bone Diseases (ERN BOND) and European Registries for Rare Bone and Mineral Conditions (EuRR-Bone) in the Governance of the Management of Rare Bone and Mineral Diseases
Authors: Priego Zurita Ana Luisa , Boarini Manila , Casareto Lorena , Cherenko Mariya , Mordenti Marina , Moroni Alice , Ahmed S. Faisal , Appelman-Dijkstra Natasha M. , Sangiorgi Luca
Published: July 2024

Rare diseases (RDs) bear a significant challenge to individuals, healthcare systems, and societies. The European reference network on Rare BONe diseases (ERN BOND) is committed to improving multidisciplinary, patient-centred care for individuals with rare bone and mineral diseases (RBMDs). Its affiliated project, the European registries for rare bone and mineral conditions (EuRR-Bone) collects data using two different platforms, an electronic surveillance system (e-REC) that captures the occurrence of RBMDs and the Core Registry, a platform with the infrastructure for collecting Core data fields and longitudinal generic and condition-specific information. With emerging registries and the overlap with other ERNs, it is key to maintain the capability of the platforms to adapt to the needs of the network and the community whilst adhering to quality and FAIR (findable, accessible, interoperable, and reusable) principles. This binomial ensures long-term sustainability and potential advances in the care pathway of RBMDs whilst promoting good practice standards within Europe and beyond.
Influence of Menstrual Cycle and Oral Contraceptive Phases on Bone (re)modelling Markers in Response to Interval Running
Authors: Guisado-Cuadrado Isabel , Romero-Parra Nuria , Elliott-Sale Kirsty J. , Sale Craig , Díaz Ángel E. , Peinado Ana B.
Published: July 2024

To explore how sex hormone fluctuations may affect bone metabolism, this study aimed to examine P1NP and β-CTX-1 concentrations across the menstrual and oral contraceptive (OC) cycle phases in response to running. 17β-oestradiol, progesterone, P1NP and β-CTX-1 were analysed pre- and post-exercise in eight eumenorrheic females in the early-follicular, late-follicular, and mid-luteal phases, while 8 OC users were evaluated during the withdrawal and active pill-taking phases. The running protocol consisted of 8 × 3min treadmill runs at 85% of maximal aerobic speed. 17β-oestradiol concentrations (pg·ml−1) were lower in early-follicular (47.22 ± 39.75) compared to late-follicular (304.95 ± 235.85;p =  < 0.001) and mid-luteal phase (165.56 ± 80.6;p = 0.003) and higher in withdrawal (46.51 ± 44.09) compared to active pill-taking phase (10.88 ± 11.24;p < 0.001). Progesterone (ng·ml−1) was higher in mid-luteal (13.214 ± 4.926) compared to early-follicular (0.521 ± 0.365; p < 0.001) and late-follicular phase (1.677 ± 2.586;p < 0.001). In eumenorrheic females, P1NP concentrations (ng·ml−1) were higher in late-follicular (69.97 ± 17.84) compared to early-follicular (60.96 ± 16.64;p = 0.006;) and mid-luteal phase (59.122 ± 11.77;p = 0.002). β-CTX-1 concentrations (ng·ml−1) were lower in mid-luteal (0.376 ± 0.098) compared to late-follicular (0.496 ± 0.166; p = 0.001) and early-follicular phase (0.452 ± 0.148; p = 0.039). OC users showed higher post-exercise P1NP concentrations in withdrawal phase (61.75 ± 8.32) compared to post-exercise in active pill-taking phase (45.45 ± 6;p < 0.001). Comparing hormonal profiles, post-exercise P1NP concentrations were higher in early-follicular (66.91 ± 16.26;p < 0.001), late-follicular (80.66 ± 16.35;p < 0.001) and mid-luteal phases (64.57 ± 9.68;p = 0.002) to active pill-taking phase. These findings underscore the importance of studying exercising females with different ovarian hormone profiles, as changes in sex hormone concentrations affect bone metabolism in response to running, showing a higher post-exercise P1NP concentrations in all menstrual cycle phases compared with active pill-taking phase of the OC cycle.
Evaluation of the Nordic Musculoskeletal Questionnaire for Measuring Prevalence and the Consequence of Pain in a Danish Adult OI Population: A Pilot Study
Authors: Horn Camilla Gehling , Jensen Karsten , Hartvigsen Jan , Wekre Lena Lande , Skou Søren T. , Folkestad Lars
Published: July 2024

Pain is a challenge in persons with OI and causes much concern in the Osteogenesis Imperfecta (OI) population. We aim to evaluate the usability of the Nordic Musculoskeletal Questionnaire (NMQ) to identify painful sites in adults with OI and to describe the occurrence of musculoskeletal (MSK) pain and its impact on their work and daily activities. This cross-sectional pilot study uses the OI-NMQ to study MSK pain prevalence in nine separate anatomical regions (neck, upper back, lower back, shoulder, elbow, hand/wrist, hip, knee, and ankle/foot) and its impact on regular work and daily activities in adults with OI. The questionnaire was distributed among participants of the 2023 annual meeting of The Danish OI Society. The response rate was 68%, and all participants considered the OI-NMQ helpful in assessing the presence of pain and its consequences. The analysis included 27 adults with OI type I, III, or IV above 18 years. Among all 27 participants, MSK pain was present in 15–56% of the 9 sites within the last 7 days and 33–89% of the nine anatomical regions during the last 12 months. In 7–48% of all the participants, their regular work and daily activities had been affected by the presence of MSK pain. The OI-NMQ was feasible in assessing MSK pain among adults with OI and displayed a high prevalence of MSK pain with a moderate impact on their regular work and daily activities in this OI population. A larger and repeated measurement of MSK pain in adults with OI is needed to confirm these results.
Cones of orthogonal Shimura subvarieties and equidistribution
Authors: Zuffetti Riccardo
Published: July 2024

Let X be an orthogonal Shimura variety, and let $$\mathcal {C}^{\textrm{ort}}_{r}(X)$$

C

r
ort

(
X
)

be the cone generated by the cohomology classes of orthogonal Shimura subvarieties in X of dimension r. We investigate the asymptotic properties of the generating rays of $$\mathcal {C}^{\textrm{ort}}_{r}(X)$$

C

r
ort

(
X
)

for large values of r. They accumulate towards rays generated by wedge products of the Kähler class of X and the fundamental class of an orthogonal Shimura subvariety. We also compare $$\mathcal {C}^{\textrm{ort}}_{r}(X)$$

C

r
ort

(
X
)

with the cone generated by the special cycles of dimension r. The main ingredient to achieve the results above is the equidistribution of orthogonal Shimura subvarieties.
EAR-Q outcomes in healthy adults: determining normative data
Authors: Wolters Alex Jacobus Petrus , de Henau Melissa , Piatkowski de Grzymala Andrzej A.
Published: July 2024

Background

Patient reported outcome measures (PROMs) are gaining importance in research and as a clinical tool to measure pre- and post-surgical patient satisfaction. The EAR-Q, an example of a clinically used PROM, focuses on patient satisfaction regarding their ears. However, the absence of EAR-Q scores in adults without external ear conditions causes challenging interpretation of the results in patients with ear conditions. Therefore, this study aims to find normative data for scales of the EAR-Q in healthy adults.

Methods

This cross-sectional, single centre study included 515 healthy adults without conditions of the external ears. The participants filled in an online questionnaire with questions from the EAR-Q scales. A Rasch score between 0 and 100 was calculated, in which higher scores correlate with more satisfaction of that particular scale.

Results

Mean scores for the EAR-Q ± standard deviation were: appearance 74 ± 20, adverse effects 94 ± 9, appearance distress 78 ± 14, psychological 64 ± 15 and social 66 ± 13. There was no difference in appearance scale between males and females; however, females scored lower on the appearance distress scale and psychological scale. Participants aged 30 and older scored higher on the appearance scale and appearance distress scale.

Conclusions

This is the first study to generate normative data for the EAR-Q in an adult population without ear conditions. The presented findings and normal scores support future research and clinical implementation of the EAR-Q. Clinicians can guide decision-making with these normative data as a reference point. Level of Evidence: Not gradable
Cranial and spinal nerve enhancement in SURF1-associated Leigh syndrome
Authors: Dupré Mhairi , Warne Richard , Shipman Peter , Kava Maina , Ghia Twinkle , Loughman Lily , Lakshmanan Rahul
Published: July 2024

A 23-month-old boy with poor growth, developmental delay, and hypotonia presented with acute onset of ataxia and fatigue. Magnetic resonance imaging (MRI) of the brain and spinal cord was performed as part of diagnostic work-up. MRI showed bilateral symmetrical lesions in basal ganglia, midbrain, and brainstem consistent with Leigh syndrome. Signal abnormalities were also present within the cervical cord, with enhancement of multiple cranial, spinal, and cauda equina nerve roots. Genetic testing confirmed compound heterozygosity for two pathogenic variants in SURF1 implicated in Leigh syndrome. Whilst nerve root enhancement has been described in other mitochondrial disorders, we believe this is the first published case of both cranial and spinal nerve root enhancement in Leigh syndrome.

Graphical Abstract
Strong Saharan Dust Deposition Events Alter Microbial Diversity and Composition in Sediments of High-Mountain Lakes of Sierra Nevada (Spain)
Authors: Castellano-Hinojosa Antonio , Tortosa Germán , Fernández-Zambrano Alejandra , Correa-Galeote David , Bedmar Eulogio J. , Medina-Sánchez Juan M.
Published: July 2024

Mediterranean high-mountain lakes are being increasingly affected by strong Saharan dust deposition events. However, the ecological impacts of these severe atmospheric episodes remain largely unknown. We examined the effects of a strong Saharan dust intrusion to the Iberian Peninsula in 2022 on the physicochemical parameters and prokaryotic communities in sediments of nine high-mountain lakes of Sierra Nevada (Spain) located above 2800 m.a.s.l and in different orientations (north vs. south). A previous year (2021), with lower Saharan dust deposition with respect to 2022, was used for interannual comparisons. The strong dust deposition to the high-mountain lakes resulted in a significant increase in sediment nutrient availability which was linked to changes in the composition of prokaryotic communities. Decreases in alpha diversity and changes in beta diversity of prokaryotic communities were mainly observed in lakes located in the south compared to the north orientation likely because the former was more affected by the atmospheric dust deposition episode. Dust intrusion to the high-mountain lakes resulted in significant changes in the relative abundance of specific genera involved in important nutrient cycling processes such as phosphate solubilization, nitrogen fixation, nitrification, and denitrification. Saharan dust deposition also increased predicted microbial functionality in all lakes. Our findings show that severe atmospheric dust inputs to remote high-mountain lakes of Sierra Nevada can have significant biogeochemical and biodiversity consequences through changes in nutrient availability and prokaryotic communities in sediments of these freshwater ecosystems. This information contributes to understanding how Mediterranean high-mountain lakes of Sierra Nevada face strong intrusions of Saharan dust and their ecological consequences.
A novel Saclayvirus Acinetobacter baumannii phage genomic analysis and effectiveness in preventing pneumonia
Authors: Li Shibin , Wei Bingdong , Xu Le , Cong Cong , Murtaza Bilal , Wang Lili , Li Xiaoyu , Li Jibin , Xu Mu , Yin Jiajun , Xu Yongping
Published: July 2024

Acinetobacter baumannii, which is resistant to multiple drugs, is an opportunistic pathogen responsible for severe nosocomial infections. With no antibiotics available, phages have obtained clinical attention. However, since immunocompromised patients are often susceptible to infection, the appropriate timing of administration is particularly important. During this research, we obtained a lytic phage vB_AbaM_P1 that specifically targets A. baumannii. We then assessed its potential as a prophylactic treatment for lung infections caused by clinical strains. The virus experiences a period of inactivity lasting 30 min and produces approximately 788 particles during an outbreak. Transmission electron microscopy shows that vB_AbaM_P1 was similar to the Saclayvirus. Based on the analysis of high-throughput sequencing and bioinformatics, vB_AbaM_P1 consists of 107537 bases with a G + C content of 37.68%. It contains a total of 177 open reading frames and 14 tRNAs. No antibiotic genes were detected. In vivo experiments, using a cyclophosphamide-induced neutrophil deficiency model, tested the protective effect of phage on neutrophil-deficient rats by prophylactic application of phage. The use of phages resulted in a decrease in rat mortality caused by A. baumannii and a reduction in the bacterial burden in the lungs. Histologic examination of lung tissue revealed a decrease in the presence of immune cells. The presence of phage vB_AbaM_P1 had a notable impact on preventing A. baumannii infection, as evidenced by the decrease in oxidative stress in lung tissue and cytokine levels in serum. Our research offers more robust evidence for the early utilization of bacteriophages to mitigate A. baumannii infection.

Key points

•A novel Saclayvirus phage infecting A. baumannii was isolated from sewage.

•The whole genome was determined, analyzed, and compared to other phages.

•Assaying the effect of phage in preventing infection in neutrophil-deficient models.
The true history of the Hueter-Volkmann law
Authors: Bartoníček Jan , Naňka Ondřej
Published: July 2024

Introduction

The Hueter-Volkmann law (HVL) of the response of growth plate to compression load is a basic concept in orthopaedics. However, little is known about the origin of HVL and its history.

Materials and methods

A literature search was performed in original publications and historical sources.

Results

An analysis of all Volkmann´s and Hueter´s texts has shown that none of their publications was based on experiments, but on the data in the literature and their own clinical observations. They did not deal at all with the effect of pressure on the growth plate and mentioned this structure only marginally. The authors coined the opinion that increased pressure retards and decreased pressure accelerates bone growth. Julius Wolff criticized the HVL and concentrated all his arguments in the book “The law of bone remodeling”. According to him, increased pressure leads to bone formation, decreased pressure to its resorption. The Wolff-Volkmann dispute was addressed in the German literature by a number of authors. Walther Müller in his monograph “The normal and pathological physiology of the bone” criticized Wolff for his concept of interstitial bone growth. In Müller´s view, HVL applies to the growing bone and Wolff confuses growth with hypertrophy of the mature bone.

Conclusion

The circumstances of the emergence of HVL are inaccurately and incompletely described in the current literature, as they are mostly taken from secondary sources. HVL, as it is presented today, is not the original formulation, but the result of a long historical evolution.
Performance of an Anti-Phase Technology-Powered Microwave Ablation System on Ex Vivo Liver, Lung and Kidney: Analysis of Temperature Trend, Ablation Size and Sphericity
Authors: Namakshenas Pouya , Arcaini Tommaso , Cesare Benedetta , Dorato Alessandro , Durante Elena , Ricci Milena , Santucci Domiziana , Saccomandi Paola , Faiella Eliodoro
Published: July 2024

Purpose

Investigating the performance of the new Dophi™ M150E Microwave Ablation System, in terms of temperature distribution, ablation size and shape, reproducibility.

Materials and Methods

The Dophi™ M150E Microwave Ablation System was tested on ex vivo liver, lung and kidney, at 6 different settings of time, power and number of MW antennas (single antenna: 50 and 100 W at 5 and 10 min; double antenna: 75 W at 5 and 10 min). The temperature distribution was recorded by Fiber Bragg Grating sensors, placed at different distances from the antennas. The ablation axes were measured and the sphericity index was calculated.

Results

The standard deviation of ablation axes was < 5 mm, except at the highest energy and time setting for the lung. A maximum temperature rise of ~ 80 °C was measured. The measured ablation axes are overall comparable with the manufacture’s values, especially at lower power and with one MW antenna (average maximum difference is 7 mm). The mean sphericity index of 0.95, 0.79 and 0.9 was obtained for the liver, lung and kidney, respectively, with a single antenna. With double antenna setup, the sphericity index was closer to 1 when 75 W for 10 min were used.

Conclusions

Dophi™ M150E allows good reproducibility of ablation axes for all cases except in the lung at the highest energy level. With one antenna, an almost spherical ablation area for the liver and kidney was obtained. Using double antenna results in more homogeneous temperature distribution within the tissue compared to single antenna.

Graphical Abstract
Use of 3D foot and ankle puzzle enhances student understanding of the skeletal anatomy in the early years of medical school
Authors: Al-Ani Sami A. , Chandla Danny , Delieu John , Yu Sinling Tiffany , Fratini Antonio , Gkountiou Renia , Stocker Claire J.
Published: July 2024

Purpose

3D visualization is an important part of learning anatomy with cadavers generally used to effectuate this. However, high cost, ethical considerations, and limited accessibility can often limit the suitability of cadavers as teaching tools. Anatomical 3D printed models offer an alternative tool for teaching gross anatomy due to their low cost and accessibility. This study aims to investigate if combing gamification with 3D printed models can enhance the learning experience and be effective for teaching anatomy.

Methods

3D printed models of the bones of the foot and ankle were generated, and 267 first-year medical students from 2 consecutive cohorts worked in groups to put it together as a puzzle. Participants completed a questionnaire regarding perceptions of 3D models and their knowledge of foot anatomy, before and after the session and were asked to provide comments.

Results

Analysis of the responses showed a significant increase in the confidence of the learners in their anatomy knowledge and an increased appreciation of the role that 3D models have in enhancing the learning experience. After the session, there were many comments saying how enjoyable and engaging 3D models were.

Conclusion

Through the puzzle element of the session, the students were challenged mentally to work out the anatomical features of the foot and ankle. The combined elements of the puzzle and the features of the 3D model assembly made the activity fun and conducive to active learning. The possibility of having fun was not something the students had considered before the session.
Early-life risk factors which govern pro-allergic immunity
Authors: Ptaschinski Catherine , Gibbs Bernhard F.
Published: July 2024

Allergic diseases affect up to 40% of the global population with a substantial rise in food allergies, in particular, over the past decades. For the majority of individuals with allergy fundamental programming of a pro-allergic immune system largely occurs in early childhood where it is crucially governed by prenatal genetic and environmental factors, including their interactions. These factors include several genetic aberrations, such as filaggrin loss-of-function mutations, early exposure to respiratory syncytial virus, and various chemicals such as plasticizers, as well as the influence of the gut microbiome and numerous lifestyle circumstances. The effects of such a wide range of factors on allergic responses to an array of potential allergens is complex and the severity of these responses in a clinical setting are subsequently not easy to predict at the present time. However, some parameters which condition a pro-allergic immune response, including severe anaphylaxis, are becoming clearer. This review summarises what we currently know, and don’t know, about the factors which influence developing pro-allergic immunity particularly during the early-life perinatal period.