bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic admixture between Central European and Alpine wolf populations
Authors: Hulva Pavel , Collet Sebastian , Baránková Lucie , Valentová Kamila , Šrutová Jana , Bauer Harald , Gahbauer Martin , Mokrý Jan , Romportl Dušan , Smith Adam Francis , Vorel Aleš , Zýka Vladimír , Nowak Carsten , Černá Bolfíková Barbora , Heurich Marco
Published: March 2024

The recovery and expansion of formerly isolated wolf populations in Europe raise questions about the nature of their interactions and future consequences for population viability and conservation. Will fragmented populations fuse or maintain a certain level of isolation with migration? Central Europe is suitable for obtaining empirical data in this field as it represents a ‘crossroad' with the potential for contact among several phylogeographic lineages. In this study, non‐invasive genetic samples obtained during population monitoring in the Bohemian and Bavarian Forest (BBF) mountain ranges in the Czech Republic and Germany (Bohemian Massif) were analysed at different neutral markers including mitochondrial sequence, nuclear autosomal microsatellites and gonosomal sex markers. Resultant genetic profiles were compared with reference data to study population ancestry. Both cluster analyses of microsatellite genotypes and syntopic occurrence of haplotypes HW01 and HW22 showed genetic admixture between Central European and Alpine populations. This represents secondary contact and interbreeding of formerly allopatric populations with different phylogeographic histories and distant expansion centres in different biomes in the Baltic region versus the Apennine peninsula and Alps. Moreover, the study describes the founding event and genealogy of this admixed deme, inhabiting intermediate environmental conditions compared to parental forms, and emphasises the role of protected areas as stepping stones in the range recolonization process in endangered large mammals.
Development of a Model for the Application of the Circular Economy in Hotels and Restaurants Through the ‘Customer Journey Map’
Authors: Sánchez-Planelles Joaquín , Trujillo-Adriá Yolanda , Ribes-Giner Gabriela
Published: March 2024

This chapter explores the different activities associated with the use of food and hotel services—represented as the contact points of a customer journey map—to establish what type of circular practices could implement the stakeholders throughout the process—specifically, those that lead to more circular business models that integrate the seven Rs (redesign, reduce, reuse, renovate/repair, re-store/remanufacture, recover/return, and recycle) to achieve more efficient and sustainable performance. From the booking process to the evaluation of customer satisfaction, the interactions of hotels or restaurants with suppliers from different economic sectors determine a variety of activities in their value chain that create synergies, improve circularity and add value to the tourism sector through the implementation of sustainable practices or the acquisition of sustainable products and services. Based on the literature, reports and lessons learned in the sector through specific focus groups previously conducted by the research team, the proposed model can help hotel and restaurant managers to take steps towards the circular economy.
Artificial Intelligence in the Public Sector in Norway:
Authors: Corneliussen Hilde G. , Seddighi Gilda , Iqbal Aisha , Andersen Rudolf
Published: March 2024

This paper presents a study of the use of artificial intelligence (AI) in the Norwegian public sector. The study focused particularly on projects involving personal data, which adds a risk of discriminating against individuals and social groups. The study included a survey of 200 public sector organizations and 19 interviews with representatives for AI projects involving personal data. The findings suggest that AI development in the public sector is still immature, and few projects involving personal data have reached the stage of production. Political pressure to use AI in the sector is significant. Limited knowledge and focus on AI development among managements has made individuals and units with the resources and interest in experimenting with AI an important driving force. The study found that the journey from idea to production of AI in the public sector presents many challenges, which often leads to projects being temporarily halted or terminated. While AI can contribute to the streamlining and improvement of public services, it also involves risks and challenges, including the risk of producing incorrect or discriminatory results affecting individuals and groups when personal data is involved. The risk of discrimination was, however, not a significant concern in the public sector AI projects. Instead, other concepts such as ethics, fairness, and transparency took precedence in most of the project surveyed here.
Patient Self-reports for Explainable Machine Learning Predictions of Risks to Psychotherapy Outcomes
Authors: Westbye Hans Jacob , McAleavey Andrew A. , Moltu Christian
Published: March 2024

Prioritizing the right patients and providing personalized treatment in a timely manner is crucial to improve access to healthcare. In psychotherapy, at least 1 in 3 patients drop out of treatment, with therapeutic alliance among the common predictors. Recommendations to safeguard retention include strengthening the patient-therapist bond through developing shared goals and checking in on progress and treatment path. Using a sample of 11,095 mental health patients from the USA, we used machine learning to develop a clinical support tool for treatment personalization. A gradient-boosted decision tree was trained on patient-reported data to establish global and individual predictions/predictors for early treatment dropout, treatment length, and symptom outcomes conditional on different treatment lengths in out-of-sample patients. The models demonstrated marginal to moderate improvements in performance versus baseline predictions. The resulting decision support tool could assist in the collaborative selection of treatment goals, appropriate treatment intensity, and optimal allocation of resources. Results are discussed in the context of explainable AI emphasizing interpretability in a clinical context.
C=Anything and the switchback effect in Schwarzschild-de Sitter space
Authors: Aguilar-Gutierrez Sergio E.
Published: March 2024

Abstract

We investigate observables within the framework of the codimension-one C=Anything (CAny) proposal for Schwarzschild-de Sitter (SdS) space under the influence of shockwave sources. Within the proposal, there is a set of time-reversal invariant observables that display the same rate of growth at early and late times for a background with or without shockwave sources. Once we introduce shockwaves in the weak gravitational coupling regime, there is a decrease in the late-time complexity growth due to cancellations with early-time perturbations, known as the switchback effect. The result shows that some CAny observables in SdS may reproduce the same type of behavior found in anti-de Sitter black holes. We comment on how our results might guide us to new explorations in the putative quantum mechanical theory.
On the particle picture of Emergence
Authors: Hattab Jarod , Palti Eran
Published: March 2024

Abstract

The Emergence Proposal is the idea that all kinetic terms for fields in quantum gravity are emergent in the infrared from integrating out towers of states. It predicts that in a supersymmetric string theory context, the tree-level prepotential terms can be recovered precisely by integrating out a tower of non-perturbative states. In this note we present a new perspective, and associated quantitative evidence, for this proposal. We argue that the tree-level kinetic terms arise from integrating out the ultraviolet physics of each of the states in the tower. This ultraviolet physics is associated to extended objects, and cannot be captured by a standard particle Schwinger integral. Instead, we argue that it should be captured by a Schwinger-like integral where the proper time is analytically continued, and a contour is taken around the origin. This maps to certain integral representations for the moduli space periods, and indeed one recovers the tree-level prepotential exactly. This interpretation suggests that the ultraviolet physics which gives the leading contribution to the prepotential is localised on point intersections of the extended objects. We also argue that over special loci in moduli space there can exist a particle picture of the states, and an associated simple particle Schwinger integral, which leads to the full tree-level prepotential. These are loci with special degenerations, such as the singular limit of the resolved conifold.
CircAKT3 alleviates postoperative cognitive dysfunction by stabilizing the feedback cycle of miR-106a-5p/HDAC4/MEF2C axis in hippocampi of aged mice
Authors: Wang Xuan , Tang Xiaole , Zhu Pengfei , Hua Dongyu , Xie Zheng , Guo Mingke , Que Mengxin , Yan Jing , Li Xing , Xia Qian , Luo Xiaoxiao , Bi Jiangjiang , Zhao Yilin , Zhou Zhiqiang , Li Shiyong , Luo Ailin
Published: March 2024

Circular RNAs (circRNAs) have garnered significant attention in the field of neurodegenerative diseases including Alzheimer’s diseases due to their covalently closed loop structure. However, the involvement of circRNAs in postoperative cognitive dysfunction (POCD) is still largely unexplored. To identify the genes differentially expressed between non-POCD (NPOCD) and POCD mice, we conducted the whole transcriptome sequencing initially in this study. According to the expression profiles, we observed that circAKT3 was associated with hippocampal neuronal apoptosis in POCD mice. Moreover, we found that circAKT3 overexpression reduced apoptosis of hippocampal neurons and alleviated POCD. Subsequently, through bioinformatics analysis, our data showed that circAKT3 overexpression in vitro and in vivo elevated the abundance of miR-106a-5p significantly, resulting in a decrease of HDAC4 protein and an increase of MEF2C protein. Additionally, this effect of circAKT3 was blocked by miR-106a-5p inhibitor. Interestingly, MEF2C could activate the transcription of miR-106a-5p promoter and form a positive feedback loop. Therefore, our findings revealed more potential modulation ways between circRNA-miRNA and miRNA-mRNA, providing different directions and targets for preclinical studies of POCD.
PEBP4 deficiency aggravates LPS-induced acute lung injury and alveolar fluid clearance impairment via modulating PI3K/AKT signaling pathway
Authors: Shi Qiao-qing , Huang Yong-hong , Li Yu-fei , Zhen Shuang-yan , Li Yan-hong , Huang Jia-yi , Wang Jia-yang , Zhou Xiao-yan
Published: March 2024

Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase β1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.
The Janus-faced functions of Apolipoproteins L in membrane dynamics
Authors: Pays Etienne
Published: March 2024

The functions of human Apolipoproteins L (APOLs) are poorly understood, but involve diverse activities like lysis of bloodstream trypanosomes and intracellular bacteria, modulation of viral infection and induction of apoptosis, autophagy, and chronic kidney disease. Based on recent work, I propose that the basic function of APOLs is the control of membrane dynamics, at least in the Golgi and mitochondrion. Together with neuronal calcium sensor-1 (NCS1) and calneuron-1 (CALN1), APOL3 controls the activity of phosphatidylinositol-4-kinase-IIIB (PI4KB), involved in both Golgi and mitochondrion membrane fission. Whereas secreted APOL1 induces African trypanosome lysis through membrane permeabilization of the parasite mitochondrion, intracellular APOL1 conditions non-muscular myosin-2A (NM2A)-mediated transfer of PI4KB and APOL3 from the Golgi to the mitochondrion under conditions interfering with PI4KB-APOL3 interaction, such as APOL1 C-terminal variant expression or virus-induced inflammatory signalling. APOL3 controls mitophagy through complementary interactions with the membrane fission factor PI4KB and the membrane fusion factor vesicle-associated membrane protein-8 (VAMP8). In mice, the basic APOL1 and APOL3 activities could be exerted by mAPOL9 and mAPOL8, respectively. Perspectives regarding the mechanism and treatment of APOL1-related kidney disease are discussed, as well as speculations on additional APOLs functions, such as APOL6 involvement in adipocyte membrane dynamics through interaction with myosin-10 (MYH10).
Ecological and environmental characteristics of a seagrass-dominated hypersaline coastal Mediterranean lagoon: a multidisciplinary approach
Authors: Ramfos A. , Alysandratou A. , Katsani O. , Faulwetter S. , Nikolakopoulos K. , Avramidis P.
Published: March 2024

In the present paper, sedimentological, water physicochemical data and biological benthic assemblages are compiled to provide an integrated environmental assessment of a protected shallow Mediterranean lagoon with a long history of management interventions (Klisova Lagoon, Western Greece). Satellite remote sensing techniques were used for mapping the seagrass Cymodocea nodosa (Ucria) Asch, which presents an extensive expansion in the study area. The results showed that Klisova is a hypersaline, well-oxygenated lagoon presenting changes in temperature, salinity, pH and dissolved oxygen over the course of 1 year, but largely lacks any spatial differentiation other than an east–west gradient in salinity in spring and summer. Sediment was classified as silty sand to silt, rich in total organic carbon (TOC), total nitrogen (TN) and total phosphorus (TP). The benthic community was characterised by a high species richness and the presence of marine species, without a clear spatial pattern. The multivariate-AZTI’s marine biotic index (M-AMBI) showed that the ecological quality of the macrobenthos was good in most stations. C. nodosa covered over 70% of the lagoon area and formed meadows even in the eastern part of the lagoon where salinity during spring and summer was close to the reported upper tolerance limit of the species (> 50). The present multidisciplinary approach provides valuable baseline information on various components of the ecosystem which can be used as a basis for management bodies and future conservation plans for the lagoon.
Functioning of a canopy-dominated intertidal community during emersion: highly productive but heterotrophic at the annual scale
Authors: Golléty Claire , Yearsley Jon , Migné Aline , Davoult Dominique
Published: March 2024

In order to address lack of data regarding coastal carbon budgets, we estimated the annual metabolic carbon budget of an intertidal rocky reef macroalgal community during emersion. This budget is based on direct in situ measurements during emersion and establishes the seasonal variations of the photosynthetic parameters of such a community. CO2 fluxes were measured hourly to study the response of community gross primary productivity (GPP) to irradiance and the variation of GPP and community respiration (CR) over the emersion period at different times of the year. These were combined together with existing monthly measures of GPP and CR hourly rates to model the variations of these fluxes as a function of irradiance and the tidal cycle throughout an entire calendar year. Daily, monthly and annual values of GPP, CR and net primary productivity (NPP) were calculated with a relatively low sensitivity to any of the parameters used. While GPP fluxes show comparable orders of magnitude to those measured in other systems, higher CR fluxes lead to a heterotrophic system during emersion, both under measured (NPP = −299 gC m−2 year−1) and theoretical irradiances (NPP = −119 gC m−2 year−1). This heterotrophy is directly linked to the light availability, varying according to combined daily, tidal and seasonal cycles, and to temperature at the seasonal scale. Measurements performed in situ at the community scale integrated interactions that are otherwise absent at the individual scale. This gives access to aspects of the functioning that cannot be otherwise identified.
An encoding of the $$\lambda $$-calculus in the String MultiSet Rewriting calculus
Authors: Bagossy Attila , Battyányi Péter
Published: March 2024

In this paper, we present an encoding of the $$\lambda $$
λ
-calculus in a multiset rewriting system and provide a few applications of the construction. For this purpose, we choose the calculus named String MultiSet Rewriting, which was introduced in Barbuti et al. (Electron Notes Theor Comput Sci 194:19–34, 2008) by Barbuti et al. With the help of our encoding, we give alternative proofs for the standardization and the finiteness of developments theorems in the $$\lambda $$
λ
-calculus.
Cardiac Rhabdomyomas Presenting with Critical Cardiac Obstruction in Neonates and Infants: Treatment Strategies and Outcome, A Single-Center Experience
Authors: Ng Li Yen , McGuinness Jonathan , Prendiville Terence , Franklin Orla , Walsh Mark , Kenny Damien , Nolke Lars , McMahon Colin J.
Published: March 2024

Cardiac rhabdomyomas are the most common benign pediatric heart tumor in infancy, which are commonly associated with tuberous sclerosis complex (TSC). Most rhabdomyomas are asymptomatic and spontaneously regress over time. However, some cases especially in neonates or small infants can present with hemodynamic instability. Surgical resection of the tumor, which has been the gold standard in alleviating obstruction, is not always possible and may be associated with significant morbidity and mortality. Recently, mammalian target of rapamycin inhibitors (mTORi) have been shown to be safe and effective in the treatment of TSC. We present the outcomes of neonates and an infant who received treatment for symptomatic rhabdomyomas at a tertiary cardiology center. Medical records were reviewed to obtain clinical, demographic, and outcome data. Six patients received interventions for symptomatic rhabdomyomas, median age at presentation was 1 day old (range from 1 to 121 days old), and 67% of the patients had a pathogenic mutation in TSC gene. One patient underwent surgical resection of solitary tumor at right ventricular outflow tract (RVOT) successfully. In the four patients with left ventricular outflow tract (LVOT) obstruction, two patients received combined therapy of surgical debulking of LVOT tumor, Stage I palliation procedure, and mTORi and two patients received mTORi therapy. One patient with RVOT obstruction underwent ductal stenting and received synergistic mTORi. Four of the five patients had good response to mTORi demonstrated by the rapid regression of rhabdomyoma size. 83% of patients are still alive at their latest follow-up, at two to eight years of age. One patient died on day 17 post-LVOT tumor resection and Hybrid stage one due to failure of hemostasis, in the background of familial factor VII deficiency. Treatment of symptomatic rhabdomyoma requires individualized treatment strategy based on the underlying pathophysiology, with involvement of multidisciplinary teams. mTORi is effective and safe in inducing rapid regression of rhabdomyomas. A standardized mTORi prescription and monitoring guide will ensure medication safety in neonates and infants with symptomatic cardiac rhabdomyoma. Although the majority of tumors responded to mTORi, some prove to be resistant. Further studies are warranted, ideally involving multiple international centers with a larger number of patients.
HLA class I NK-epitopes and KIR diversities in patients with multiple myeloma
Authors: Beelen Nicky A. , Molenbroeck Stefan J. J. , Groeneveld Lisette , Voorter Christien E. , Bos Gerard M. J. , Wieten Lotte
Published: March 2024

Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of malignant plasma cells in the bone marrow. Myeloma cells are susceptible to killing by natural killer (NK) cells, but NK cells fail to control disease progression, suggesting immunosuppression. The activation threshold of NK-effector function is regulated by interaction between KIRs and self-HLA class I, during a process called “education” to ensure self-tolerance. NK cells can respond to diseased cells based on the absence of HLA class I expression (“Missing-self” hypothesis). The HLA and KIR repertoire is extremely diverse; thus, the present study aimed to characterize potential variances in genotypic composition of HLA Class I NK-epitopes and KIRs between MM patients and healthy controls. Genotypic expression of KIR and HLA (HLA-C group-C1/C2 and Bw4 motifs (including HLA-A*23, A*24, A*32) were analyzed in 172 MM patients and 195 healthy controls. Compared to healthy controls, we did not observe specific KIR genes or genotypes, or HLA NK-epitopes with higher prevalence among MM patients. The presence of all three HLA NK-epitopes (C1+C2+Bw4+) was not associated with MM occurrence. However, MM patients were more likely to be C1-/C2+/Bw4+ (p = 0.049, OR 1.996). In line with this, there was a trend of increased genetic co-occurrence of Bw4 and KIR3DL1 in MM patients (p = 0.05, OR 1.557). Furthermore, MM patients were more likely to genetically express both C2/KIR2DL1 and Bw4/KIR3DL1 (p = 0.019, OR 2.453). Our results reveal an HLA NK-epitope combination that is associated with the occurrence of MM. No specific KIR genotypes were associated with MM.
Pharmacokinetics and pharmacodynamics of antibacterial peptide NZX in Staphylococcus aureus mastitis mouse model
Authors: Zheng Xueling , Yang Na , Mao Ruoyu , Hao Ya , Teng Da , Wang Jianhua
Published: March 2024

Staphylococcus aureus is associated with dairy mastitis, which causes serious economic losses to dairy farming industry. Antibacterial peptide NZX showed good antibacterial activity against S. aureus. This study aimed to evaluate pharmacokinetics and pharmacodynamics of NZX against S. aureus-induced mouse mastitis. NZX exhibited potent in vitro antibacterial activity against the test S. aureus strains (minimal inhibitory concentration (MIC): 0.23–0.46 μM), low mutant prevention concentration (MPC: 1.18–3.68 μM), and a long post antibiotic effect (PAE: 2.20–8.84 h), which was superior to those of lincomycin and ceftiofur. Antibacterial mechanisms showed that NZX could penetrate the cell membrane, resulting in obvious cell membrane perforation and morphological changes, and bind to intracellular DNA. Furthermore, NZX had a good stability in milk environment (retention rate: 85.36%, 24 h) than that in mammary homogenate (47.90%, 24 h). In mouse mastitis model, NZX (25–400 μg/gland) could significantly reduce the bacterial load of mammary tissue in a dose-dependent manner. In addition, NZX (100 μg/gland) could relieve the inflammatory symptoms of mammary tissue, and significantly decreased its pathological scores. The concentration–time curve of NZX (100 μg/gland) in the mammary tissue was plotted and the corresponding pharmacokinetic parameters were obtained by non-compartment model calculation. Those parameters of Tmax, T1/2, Cmax and AUC were 0.5 h, 35.11 h, 32.49 μg/g and 391 μg·h/g, respectively. Therefore, these results suggest that NZX could act as a promising candidate for treating dairy mastitis disease caused by S. aureus.

Key points

• NZX could kill S. aureus by dual mechanism involved in membrane and DNA disruption

• NZX could relieve S. aureus-induced mouse mastitis

• Pharmacokinetic parameters of NZX in mouse mammary gland were obtained
Automatic estimation of hallux valgus angle using deep neural network with axis-based annotation
Authors: Takeda Ryutaro , Mizuhara Hiroyasu , Uchio Akihiro , Iidaka Toshiko , Makabe Kenta , Kasai Taro , Omata Yasunori , Yoshimura Noriko , Tanaka Sakae , Matsumoto Takumi
Published: March 2024

Objectives

We developed the deep neural network (DNN) model to automatically measure hallux valgus angle (HVA) and intermetatarsal angle (IMA) on foot radiographs. The objective is to assess the accuracy of the model by comparing to the manual measurement of foot and ankle surgeons.

Materials and methods

A DNN was developed to predict the bone axes of the first proximal phalanx and all metatarsals from the first to the fifth in foot radiographs. The dataset used for model development consisted of 1798 radiographs collected from a population-based cohort and patients at our foot and ankle clinic. The retrospective validation cohort comprised of 92 radiographs obtained from 92 consecutive patients visiting our foot and ankle clinic. The mean absolute error (MAE) between automatic measurements by the model and the median of manual measurements by three foot and ankle surgeons was compared to 3° using one-tailed t-test and was also compared to the inter-rater difference in manual measurements among the three surgeons using two-tailed paired t-test.

Results

The MAE for HVA was 1.3° (upper limit of 95% CI 1.6°), and this was significantly smaller than the inter-rater difference of 2.0 ± 0.2° among the surgeons, demonstrating the superior accuracy of the model. In contrast, the MAE for IMA was 0.8° (upper limit of 95% CI 1.0°) that showed no significant difference from the inter-rater difference of 1.0 ± 0.1° among the surgeons.

Conclusion

Our model demonstrated the ability to measure the HVA and IMA with an accuracy comparable to that of specialists.
Neuropathy of the suprascapular and axillary nerves in rotator cuff arthropathy: a prospective electrodiagnostic study
Authors: Lopiz Yaiza , Rodríguez-González Alberto , Martín-Albarrán Susana , Herzog Raul , García-Fernández Carlos , Marco Fernando
Published: March 2024

Purpose

Prevalence of axillary (AN) and/or suprascapular (SSN) neuropathy in rotator cuff tear arthropathy (RCTA) is unknown. We aimed to prospectively evaluate for preoperative neurodiagnostic abnormalities in order to determine their prevalence, location, and influence on reverse shoulder arthroplasty (RSA) outcomes.

Methods

Patients who underwent RSA for RCTA were prospectively included. An electromyography and nerve conduction study were performed pre and post-surgery. Clinical situation: VAS, Relative Constant-Murley Score (rCMS) and ROM over a minimum of two years follow-up.

Results

Forty patients met the inclusion criteria; mean follow-up was 28.4 months (SD 4.4). Injuries in RCTA were present in 83.9% (77.4% in AN and 45.2% in SSN). There were no differences on preoperative VAS, ROM, and rCMS between patients with and without preoperative nerve injuries. Four acute postoperative neurological injuries were registered under chronic preoperative injuries. Six months after RSA, 69% of preoperative neuropathies had improved (82.14% chronic injuries and 77.7% disuse injuries). No differences in improvement between disuse and chronic injuries were found, but patients with preoperative neuropathy that had not improved at the postoperative electromyographic study at six months, scored worse on the VAS (1.44 vs 2.66; p .14) and rCMS (91.6 vs 89.04; p .27).

Conclusions

The frequency of axillary and suprascapular neuropathies in RCTA is much higher than expected. Most of these injuries improve after surgery, with almost complete neurophysiological recovery and little functional impact on RSA. However, those patients with preoperative neuropathies and absence of neurophysiological improvement six months after surgery have lower functional results.
Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation
Authors: Hsu Te-Lin , Tsai Chun-Kuang , Liu Chun-Yu , Yeh Chiu-Mei , Lin Fen-Lan , Hsiao Liang-Tsai , Liu Yao-Chung , Chien Sheng-Hsuan , Wang Hao-Yuan , Ko Po-Shen , Lin Ting-An , Chen Wen-Chun , Chen Po-Min , Liu Jin-Hwang , Gau Jyh-Pyng , Liu Chia-Jen
Published: March 2024

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post–ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08–3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53–4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31–0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32–0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05–4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03–7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45–34.59), post–ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09–28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23–6.17) experienced shorter OS. In contrast, post–ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17–0.79) and post–ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24–0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post–ASCT outcome prediction beyond clinical trials.
Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera: the “RAMP” Italian multicenter prospective study
Authors: Palandri F. , Auteri G. , Abruzzese E. , Caocci G. , Bonifacio M. , Mendicino F. , Latagliata R. , Iurlo A. , Branzanti F. , Garibaldi B. , Trawinska M. M. , Cattaneo D. , Krampera M. , Mulas O. , Martino E. A. , Cavo M. , Vianelli N. , Impera S. , Efficace F. , Heidel F. , Breccia M. , Elli E. M. , Palumbo G. A.
Published: March 2024

Ruxolitinib is beneficial in patients with myelofibrosis (MF) and polycythemia vera (PV). Information on ruxolitinib adherence is scant. The Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera (RAMP) prospective multicenter study (NCT06078319) included 189 ruxolitinib-treated patients. Patients completed the Adherence to Refills and Medications Scale (ARMS) and Distress Thermometer and Problem List (DTPL) at the earliest convenience, after registration in the study, and at later timepoints. At week-0, low adherence (ARMS > 14) and high distress (DT ≥ 4) were declared by 49.7% and 40.2% of patients, respectively. The main reason for low adherence was difficult ruxolitinib supply (49%), intentional (4.3%) and unintentional (46.7%) non-take. In multivariable regression analysis, low adherence was associated to male sex (p = 0.001), high distress (p < 0.001), and treatment duration ≥ 1 year (p = 0.03). Over time, rates of low adherence and high distress remained stable, but unintentional non-take decreased from 47.9% to 26.0% at week-48. MF patients with stable high adherence/low distress were more likely to obtain/maintain the spleen response at week-24. Low adherence to ruxolitinib represents an unmet clinical need that require a multifaceted approach, based on reason behind it (patients characteristics and treatment duration). Its recognition may help distinguishing patients who are truly refractory and those in need of therapy optimization.
Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy)
Authors: Huang Xiao , Bao Huihui , Ding Congcong , Li Junpei , Cao Tianyu , Liu Lishun , Wei Yaping , Zhou Ziyi , Zhang Nan , Song Yun , Chen Ping , Jiang Chongfei , Xie Liling , Qin Xianhui , Zhang Yan , Li Jianping , Sun Ningling , Tang Genfu , Wang Xiaobin , Wang Hong , Huo Yong , Cheng Xiaoshu ,   for the Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy) Trial Investigators
Published: March 2024

Background

While folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes.

Methods

This multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment.

Results

The intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0–1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2–1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering.

Conclusions

This randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg.

ClinicalTrials.gov Identifier

NCT03472508 (Registration Date: March 21, 2018).
MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons
Authors: Xu Hong , Qiu Qi , Hu Peng , Hoxha Kevt’her , Jang Elliot , O’Reilly Mia , Kim Christopher , He Zhuohao , Marotta Nicholas , Changolkar Lakshmi , Zhang Bin , Wu Hao , Schellenberg Gerard D. , Kraemer Brian , Luk Kelvin C. , Lee Edward B. , Trojanowski John Q. , Brunden Kurt R. , Lee Virginia M.-Y.
Published: March 2024

Inclusions comprised of microtubule-associated protein tau (tau) are implicated in a group of neurodegenerative diseases, collectively known as tauopathies, that include Alzheimer’s disease (AD). The spreading of misfolded tau “seeds” along neuronal networks is thought to play a crucial role in the progression of tau pathology. Consequently, restricting the release or uptake of tau seeds may inhibit the spread of tau pathology and potentially halt the advancement of the disease. Previous studies have demonstrated that the Mammalian Suppressor of Tauopathy 2 (MSUT2), an RNA binding protein, modulates tau pathogenesis in a transgenic mouse model. In this study, we investigated the impact of MSUT2 on tau pathogenesis using tau seeding models. Our findings indicate that the loss of MSUT2 mitigates human tau seed-induced pathology in neuron cultures and mouse models. In addition, MSUT2 regulates many gene transcripts, including the Adenosine Receptor 1 (A1AR), and we show that down regulation or inhibition of A1AR modulates the activity of the “ArfGAP with SH3 Domain, Ankyrin Repeat, and PH Domain 1 protein” (ASAP1), thereby influencing the internalization of pathogenic tau seeds into neurons resulting in reduction of tau pathology.
Survival and hormone production of isolated mouse follicles in three-dimensional artificial scaffolds after stimulation with bpV(HOpic)
Authors: Keckstein Philip , Dittrich Ralf , Bleisinger Nathalie , Hoffmann Inge , Beckmann Matthias W. , Gebhardt Albrecht , Schmid Benjamin , Keckstein Simon
Published: March 2024

Purpose

To preserve fertility before gonadotoxic therapy, ovarian tissue can be removed, cryopreserved, and transplanted back again after treatment. An alternative is the artificial ovary, in which the ovarian follicles are extracted from the tissue, which reduces the risk of reimplantation of potentially remaining malignant cells. The PTEN inhibitor bpV(HOpic) has been shown to activate human, bovine and alpacas ovarian follicles, and it is therefore considered a promising substance for developing the artificial ovary. The purpose of this study was to examine the impact of different scaffolds and the vanadate derivative bpV(HOpic) on mice follicle survival and hormone secretion over 10 days.

Methods

A comparative analysis was performed, studying the survival rates (SR) of isolated mice follicle in four different groups that differed either in the scaffold (polycaprolactone scaffold versus polyethylene terephthalate membrane) or in the medium—bpV(HOpic) versus control medium. The observation period of the follicles was 10 days. On days 2, 6, and 10, the viability and morphology of the follicles were checked using fluorescence or confocal microscopy. Furthermore, hormone levels of estrogen (pmol/L) and progesterone (nmol/L) were determined.

Results

When comparing the SR of follicles among the four groups, it was observed that on day 6, the study groups utilizing the polycaprolactone scaffold with bpV(HOpic) in the medium (SR: 0.48 ± 0.18; p = 0.004) or functionalized in the scaffold (SR: 0.50 ± 0.20; p = 0.003) exhibited significantly higher survival rates compared to the group using only the polyethylene terephthalate membrane (SR: 0). On day 10, a significantly higher survival rate was only noted when comparing the polycaprolactone scaffold with bpV(HOpic) in the medium to the polyethylene terephthalate membrane group (SR: 0.38 ± 0.20 versus 0; p = 0.007). Higher levels of progesterone were only significantly associated with better survival rates in the group with the polycaprolactone scaffold functionalized with bpV(HOpic) (p = 0.017).

Conclusion

This study demonstrates that three-dimensional polycaprolactone scaffolds improve the survival rates of isolated mice follicles in comparison with a conventional polyethylene terephthalate membrane. The survival rates slightly improve with added bpV(HOpic). Furthermore, higher rates of progesterone were also partly associated with improved survival.
Moyamoya disease in Southeast Asians: genetic and autopsy data, new cases, systematic review, and meta-analysis of all patients from the literature
Authors: Strunk Daniel , Bauer Peter , Keyvani Kathy , Diehl Rolf R. , Veltkamp Roland , Berlit Peter , Meuth Sven G. , Timmermann Lars , Schwitalla Jan Claudius , Kraemer Markus
Published: March 2024

Background

Moyamoya disease (MMD) is a rare disorder causing ischemic and hemorrhagic juvenile stroke. It is associated with the founder susceptibility variant p.R4810K in the RNF213 gene in East Asia. Our aim was to enhance understanding of MMD in so far poorly characterized Southeast Asians and exploring differences with Caucasian Europeans.

Methods

By retrospective analysis of medical records and systematic database search on PubMed for all published cases, we identified Southeast Asian patients with MMD. We extracted and pooled proportions using fixed-effects models. Our own cohort was tested for the East Asian RNF213 founder variant p.R4810K. One of our Southeast Asian patients underwent post-mortem histopathological examination.

Results

The study cohort comprised 32 Southeast Asians. Mean age at onset in the entire cohort was 32.5 ± 20.3 years (n = 24), 43.4 ± 8.7 years in patients admitted to our center (n = 11), and 23.4 ± 22.4 years in patients from the international literature (n = 13). Female-to-male ratio was 1.6:1. MMD predominantly affected bilateral anterior intracranial vessels. Cerebral ischemia outnumbered transient ischemic attacks (TIAs) and intracranial hemorrhage. TIAs, arterial hypertension and obesity were significantly less frequent in Southeast Asian patients compared to Caucasian Europeans. p.R4810K was absent in all examined Southeast Asians despite of typical histopathological signs of MMD in one autopsy case.

Conclusion

Clinical and histopathological manifestations of MMD in Southeast Asians are similar to those in Caucasian Europeans. The genotype of MMD in Southeast Asians differs from that of most East Asian patients.
Thylakoid ultrastructural variations in chlorophyll-deficient wheat: aberrations or structural acclimation?
Authors: Aliprandi Elisabetta , Demaria Sara , Colpo Andrea , Brestič Marian , Živčak Marek , Martina Angela , Pancaldi Simonetta , Baldisserotto Costanza , Ferroni Lorenzo
Published: March 2024

Main conclusion

A structural re-modeling of the thylakoid system, including granum size and regularity, occurs in chlorophyll-deficient wheat mutants affected by photosynthetic membrane over-reduction.

In the chloroplast of land plants, the thylakoid system is defined by appressed grana stacks and unstacked stroma lamellae. This study focuses on the variations of the grana organization occurring in outdoor-grown wheat mutants characterized by low chlorophyll content and a tendency for photosynthetic membrane over-reduction. Triticum aestivum ANK-32A and Triticum durum ANDW-7B were compared to their corresponding WT lines, NS67 and LD222, respectively. Electron micrographs of chloroplasts were used to calculate grana ultrastructural parameters. Photosynthetic parameters were obtained by modulated chlorophyll fluorescence and applying Light Curves (LC) and Rapid Light Curves (RLC) protocols. For each photosynthetic parameter, the difference Δ(RLC–LC) was calculated to evaluate the flexible response to light in the examined lines. In the mutants, fewer and smaller disks formed grana stacks characterized by a marked increase in lateral and cross-sectional irregularity, both negatively correlated with the number of layers per granum. A relationship was found between membrane over-reduction and granum structural irregularity. The possible acclimative significance of a greater proportion of stroma-exposed grana domains in relieving the excess electron pressure on PSI is discussed.
A pan-cancer analysis of the oncogenic and immunological roles of transglutaminase 1 (TGM1) in human cancer
Authors: Wu Ruicheng , Li Dengxiong , Zhang Shuxia , Wang Jie , Chen Kai , Tuo Zhouting , Miyamoto Akira , Yoo Koo Han , Wei Wuran , Zhang Chi , Feng Dechao , Han Ping
Published: March 2024

Background

There is currently a limited number of studies on transglutaminase type 1 (TGM1) in tumors. The objective of this study is to perform a comprehensive analysis across various types of cancer to determine the prognostic significance of TGM1 in tumors and investigate its role in the immune environment.

Method

Pan-cancer and mutational data were retrieved from the TCGA database and analyzed using R (version 3.6.4) and its associated software package. The expression difference and prognosis of TGM1 were examined, along with its correlation with tumor heterogeneity, stemness, mutation landscape, and RNA modification. Additionally, the relationship between TGM1 expression and tumor immunity was investigated using the TIMER method.

Results

TGM1 is expressed differently in various tumors and normal samples and is associated with the overall survival and progression-free time of KIRC, ACC, SKCM, LIHC, and STES. In LICH, we found a negative correlation between TGM1 expression and 6 indicators of tumor stemness. The mutation frequencies of BLCA, LIHC, and KIRC were 1.7%, 0.3%, and 0.3% respectively. In BLCA and BRCA, there was a significant correlation between TGM1 expression and the infiltration of CD4 + T cells, CD8 + T cells, neutrophils, and dendritic cells.

Conclusion

TGM1 has the potential to serve as both a prognostic marker and a drug target.
N-fertilization and disturbance exert long-lasting complex legacies on subarctic ecosystems
Authors: Manninen Outi H. , Myrsky Eero , Tolvanen Anne , Stark Sari
Published: March 2024

Subarctic ecosystems are subjected to increasing nitrogen (N) enrichment and disturbances that induce particularly strong effects on plant communities when occurring in combination. There is little experimental evidence on the longevity of these effects. We applied N-fertilization (40 kg urea-N ha−1 year−1 for 4 years) and disturbance (removal of vegetation and organic soil layer on one occasion) in two plant communities in a subarctic forest-tundra ecotone in northern Finland. Within the first four years, N-fertilization and disturbance increased the share of deciduous dwarf shrubs and graminoids at the expense of evergreen dwarf shrubs. Individual treatments intensified the other’s effect resulting in the strongest increase in graminoids under combined N-fertilization and disturbance. The re-analysis of the plant communities 15 years after cessation of N-fertilization showed an even higher share of graminoids. 18 years after disturbance, the total vascular plant abundance was still substantially lower and the share of graminoids higher. At the same point, the plant community composition was the same under disturbance as under combined N-fertilization and disturbance, indicating that multiple perturbations no longer reinforced the other’s effect. Yet, complex interactions between N-fertilization and disturbance were still detected in the soil. We found higher organic N under disturbance and lower microbial N under combined N-fertilization and disturbance, which suggests a lower bioavailability of N sources for soil microorganisms. Our findings support that the effects of enhanced nutrients and disturbance on subarctic vegetation persist over decadal timescales. However, they also highlight the complexity of plant–soil interactions that drive subarctic ecosystem responses to multiple perturbations across varying timescales.