bluuebunny/crossref_metadata_2025 huggingface dataset:
Noncoding RNAs in diagnosis and prognosis of graft‐versus‐host disease (GVHD)
Authors: Vajari Mahdi K. , Moradinasab Susan , Yousefi Amir‐Mohammad , Bashash Davood
Published: July 2022

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a functional therapy for a plethora of hematologic malignancies and immune disorders. Graft‐versus‐host disease (GVHD), on the other hand, is one of the major complications ahead of a successful HSCT, contributing to transplant‐associated morbidity and mortality. Notably, little is known about the underlying mechanism of this event; therefore, exploring precise biomarkers and uncovering the molecular pathogenesis of GVHD is valuable for early diagnosis and treatment optimization. Thanks to the advances in sequencing techniques, the noncoding sequences of the human genome—formerly considered "junk"—are now identified as functional molecules. Noncoding RNAs (ncRNA) control cellular responses by regulating gene expression, and previous studies have shown that these tiny molecules, especially microRNAs (miRNAs), can affect allogeneic T cell responses in both animal models and clinical experiments. The present study gives an overview of the functions of various miRNAs in regulating T cell responses in GVHD. We also provide an outlook on miRNAs and long noncoding RNAs (lncRNAs) potential role in GVHD with the hope of providing a future research direction for expanding their application as the sensitive and noninvasive diagnostic or prognostic biomarkers and also the promising therapeutic targets for improving outcomes after allogeneic HSCT.
A novel thymidine phosphorylase mutation in a family with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Molecular docking, dynamic simulation and computational investigations
Authors: Ammar Marwa , Safi Wajdi , Tlili Abdelaziz , Alila‐Fersi Olfa , Frikha Fakher , Chouchen Jihen , Mnif Fatma , Kharrat Marwa , Maalej Marwa , Felhi Rahma , Abid Mohamed , Mnif‐Feki Mouna , Kacem Faten Hadj , Fakhfakh Faiza , Mkaouar‐Rebai Emna
Published: July 2022

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; OMIM 603041) is a rare inherited metabolic disorder mostly caused by mutations in TYMP gene encoding thymidine phosphorylase (TP) protein that affects the mitochondrial nucleotide metabolism. TP, functionally active as a homodimer, is involved in the salvage pathway of pyrimidine nucleosides. MNGIE‐like syndrome having an overlapping phenotype of MNGIE was also described and has been associated with mutations in POLG and RRM2B genes. In the present study, we report the molecular investigation of a consanguineous family including two patients with clinical features suggestive of MNGIE syndrome. Bioinformatics analyses were carried out in addition to mtDNA deletion screening and copy number quantification in the blood of the two patients. Whole exome sequencing and Sanger sequencing analyses revealed the segregation in the affected family a novel mutation c.1205T>A (p.L402Q) within the exon 9 of the TYMP gene. In addition, mtDNA analysis revealed the absence of mtDNA deletions and a decrease of the copy number in the blood of the two patients of the studied family. The p.Leu402Gln mutation was located in a conserved amino acid within the α/β domain of the TP protein and several software supported its pathogenicity. In addition, and based on docking and molecular dynamic simulation analyses, results revealed that L402Q caused a conformational change in TP mutated structure and could therefore alter its flexibility and stability. These changes prevent also the formation of stable homodimer leading to non‐functional protein with partial or complete loss of its catalytic activity.
Regional earth system model for CORDEX‐South Asia: A comparative assessment of RESM and ESM over the tropical Indian Ocean
Authors: Kumar Pankaj , Mallick Subrat , Mishra Alok Kumar , Dubey Aditya Kumar , Tiwari Gaurav , Sein Dimitry V. , Cabos William , Jacob Daniela
Published: July 2022

Understanding climate variability requires good quality high resolution spatially and temporally varying ocean fields due to its decisive role in regulating the region's climate, including the Indian summer monsoon. In this regard, we employed a new high‐resolution regional earth system model (RESM), namely ROM over CORDEX South Asia. We demonstrated the performance of the RESM and its added value over the global earth system model, namely MPI‐ESM, in simulating the hydrographic characteristics and associated mechanism over the tropical Indian Ocean (TIO). ROM shows better skill than MPI‐ESM in simulating the near‐surface and subsurface characteristics of the ocean. However, larger added values are noticed for subsurface (>350 m) thermal structure. MPI‐ESM's cold sea surface temperature (SST) bias is reduced in ROM which is associated with weaker winds, anomalous cyclonic wind stress curl, enhanced stratifications, and a shallower mixed layer, resulting in greater upper‐ocean heating. The reduced SST bias is also consistent with improved ocean meridional heat transport (OMHT) in ROM. For example, reduced southward export of OMHT over the Arabian Sea increases the surface warming by ~4%, reducing the RMSE by ~0.2–0.6°C and becoming closer to observation. The anomalous cyclonic wind stress curl, in turn, caused mixed layer stratifications in the western Indian Ocean. The advective heat transfer from the south‐eastern Indian Ocean to the western Indian Ocean reduced oceanic cooling by vertical processes, overcame the cooling by the net loss of surface heat fluxes, and favoured the TIO's surface warming.
Surface heat transfer changes over Arctic land and sea connected to Arctic warming
Authors: Kong Linlin , Zou Han , Zhou Libo , Zhu Jinhuan
Published: July 2022

Turbulent heat transfer from surface to atmosphere is important in the atmospheric energy balance over the Arctic, thereby impacting the remarkable warming that occurs in this region. The impact of heat transfer over the Arctic land and sea (approximate Arctic Ocean) on Arctic warming could be distinct, owing to different heat sources and physical processes on the interfaces. This study sought to analyse the heat transfer and changes over the Arctic land and sea and their contributions to those over the entire Arctic, and discuss the connection between the heat transfer changes and Arctic warming based on ERA5 reanalysis. The Arctic surface releases heat to the atmosphere, with an annual average of 4.5 × 1014 W, which is mainly contributed by the Arctic land in summer and sea in winter. From 1979 to 2018, the amount of heat release was found to markedly increase, with an annual trend of 0.94 ± 0.31 W/(m2 decade). A faster increase occurred in summer and was contributed by both the Arctic land and sea. In contrast, a slower increase occurred in winter and was only contributed by the sea. The heat transfer changed heterogeneously over the Arctic land and sea, with three major changes: Northern Russia Increase over northern Russia in summer, Northern Barents Increase over the northern Barents Sea in winter, and Nordic Sea Decrease over the Nordic Sea and northern Greenland Sea in winter. Notably, the heat transfer change over the Arctic land and sea could be connected to Arctic warming, especially the three major changes, based on distinct feedback processes, which could impact future Arctic warming. Overall, the Arctic land and sea play distinct roles in the heat transfer change and connection to Arctic warming, with the land being more important in summer and the sea being more important in winter.
Hydrogen bond‐driven assembly of coral‐like soy protein isolate–tannic acid microcomplex for encapsulation of limonene
Authors: Wu Kaiwen , Wu Zhenglin , Kang Yuxuan , Su Chang , Yi Fengping
Published: July 2022

BACKGROUND

The encapsulation of flavor and aroma compounds has great potential in foods, while effective preparation in the food industry is still a great challenge. Inspired by leather tanning, tannic acid (TA) was used for deep crosslinking through hydrogen bond‐driven assembly on soy protein isolate for encapsulating limonene with a high loading ratio.

RESULTS

The added TA changed the protein structure and formed a limonene‐loaded microcomplex. The morphology of these microcomplexes changed from smooth to rough, followed by the formation of smooth nanoparticle aggregates, by changing the amount of TA. The encapsulation efficiency and loading ratio were increased from 0.78% and 4.30% to 59.32% and 45.78% after increasing TA from 1.875 to 60 mg mL−1. The result of confocal laser scanning microscopy indicated that limonene is evenly distributed in microcomplexes. Additionally, the results of thermal stability demonstrated protection of limonene by soy protein–tannic acid microcomplex.

CONCLUSION

It is suggested that the added TA improved the encapsulation efficiency and loading ratio. Limonene is loaded in the complex in two ways. The present research provides a new and easy path for the preparation of the non‐thermal soy protein aroma carrier. © 2022 Society of Chemical Industry.
A prospective study to evaluate the treatment effect of pulsed dye laser on thyroidectomy hypertrophic scars using 3D imaging analysis
Authors: Kim Jin Cheol , Choi Jee Woong , Kim You Chan
Published: July 2022

Objectives

The pulsed dye laser (PDL) is an effective modality for preventing and improving hypertrophic scars (HSs). However, the heterogeneity of the parameter settings of the laser and subjective scar assessment methods used in most studies resulting in uncertainty with treatment plans. Therefore, we investigated the treatment effect of the PDL (V‐beam; Candela Laser Corporation) on HSs in post‐thyroidectomy patients using three‐dimensional imaging analysis and intended to provide a systemic and optimal treatment protocol.

Methods

Nineteen patients with HS after thyroidectomy underwent eight treatment sessions with the 595 nm PDL (with the dose gradually increased by 0.5 J/cm2) at 4‐ to 6‐week intervals. Patients with an elevated lesion also received intralesional corticosteroid (ICS) treatment. After every two treatment sessions, we assessed the patients' HS using the Vancouver Scar Scale (VSS), a patient satisfaction questionnaire, and with a three‐dimensional (3D) skin imaging device (Antera 3D™; Miravex Limited).

Results

In repeated‐measures analysis of variance, the mean VSS and patient satisfaction significantly improved (p < 0.001), with significant differences in these values observed until the sixth and eighth treatment sessions, respectively. In the quantitative analysis using Antera 3D™, the mean height, pigmentation, and vascularity scores were observed to be significantly improved (p < 0.001). Significant differences in these values were observed until the fourth, second, and eighth treatment sessions, respectively. Subgroup analysis according to ICS treatment showed no significant differences in scar characteristics between those with and without ICS treatment.

Conclusions

In this study, we found that the PDL was effective in reducing scar height, vascularity, and pigmentation in patients with thyroidectomy HS using 3D imaging analysis. Furthermore, we have suggested a cost‐effective treatment plan with the 595 nm PDL.
Precisely Tailoring and Renewing Polymers: An Efficient Strategy for Polymer Recycling
Authors: Yao Hongxin , Zuo Yongkang , Song Yiye , Huang Wenyan , Jiang Qimin , Xue Xiaoqiang , Jiang Li , Xu Jinbao , Yang Hongjun , Jiang Bibiao
Published: July 2022

Plastic wastes have contaminated both land and ocean environments throughout the world and hence, it is urgent to explore feasible yet cost‐effective recycling and reuse strategies for plastic wastes in order to solve this menacing problem. The so‐called “back‐to‐oligomer” chemical recycling process may be an efficient and affordable strategy to solve this global issue. However, structural control of the produced oligomers has never been achieved using this strategy until now. Here, it is reported that polymeric blends with different structures and molecular weights can be successfully tailored to homo‐/co‐ oligomers with a predesigned molecular weight (MW) and an acceptable MW distribution, just by changing the feed ratio or adding a predetermined amount of alcohol. Moreover, the molecular weight of the produced oligomers can be further increased by in situ addition of the corresponding monomers into the reaction system. This recycling strategy provides an efficient method for the preparation of high‐value polymers from plastic wastes without prior sorting of mixed plastic wastes. The newly developed process through polymer chemistry and environmental engineering not only helps with the selective recycling of polyester blends, but it can also enable the recycling of polymeric mixtures composed of polyester and polycarbonate.
A Review: Current Status and Emerging Developments on Natural Polymer‐Based Electrospun Fibers
Authors: Han Weisen , Wang Liangyu , Li Qin , Ma Bomou , He Chunju , Guo Xuefeng , Nie Jun , Ma Guiping
Published: July 2022

In recent years, natural polymer‐based electrospun fibers (EFs) with huge specific surface area, good biocompatibility, and biological activity obtained from electrospinning process exhibit tremendous vitality in the field of biomedical areas. Herein, the parameters of electrospinning from two perspectives, polymer solution such as solvent, polymeric relative molecular mass, concentration, viscosity, and conductivity of the solution, and electrospinning process such as spinning voltage, spinning flow rate, needle tip to collector distance, temperature, and humidity are first detailed. Next, the raw materials consisting of polysaccharides such as cellulose, hyaluronic acid, alginate, and chitosan as well as proteins such as collagen, gelatin, silk fibroin, and keratin are summarized. The preparation method and related characteristics of EFs with multistage structures such as porous, core–shell, Janus, bamboo‐like and other structures are introduced. The biomedical applications of these natural polymer‐based EFs mainly including tissue engineering, drug sustained release, wound dressings, and biomedical sensors are systematically recapitulated. Finally, the outlook on natural EFs is further proposed.
Deep learning in ultrasound elastography imaging: A review
Authors: Li Hongliang , Bhatt Manish , Qu Zhen , Zhang Shiming , Hartel Martin C. , Khademhosseini Ali , Cloutier Guy
Published: July 2022

It is known that changes in the mechanical properties of tissues are associated with the onset and progression of certain diseases. Ultrasound elastography is a technique to characterize tissue stiffness using ultrasound imaging either by measuring tissue strain using quasi‐static elastography or natural organ pulsation elastography, or by tracing a propagated shear wave induced by a source or a natural vibration using dynamic elastography. In recent years, deep learning has begun to emerge in ultrasound elastography research. In this review, several common deep learning frameworks in the computer vision community, such as multilayered perceptron, convolutional neural network, and recurrent neural network, are described. Then, recent advances in ultrasound elastography using such deep learning techniques are revisited in terms of algorithm development and clinical diagnosis. Finally, the current challenges and future developments of deep learning in ultrasound elastography are prospected.
Endometrial glycogen metabolism during early pregnancy in mice
Authors: Chen Ziting , Sandoval Kassandra , Dean Matthew
Published: July 2022

Glucose is critical during early pregnancy. The uterus can store glucose as glycogen but uterine glycogen metabolism is poorly understood. This study analyzed glycogen storage and localization of glycogen metabolizing enzymes from proestrus until implantation in the murine uterus. Quantification of diastase‐labile periodic acid–Schiff (PAS) staining showed glycogen in the glandular epithelium decreased 71.4% at 1.5 days postcoitum (DPC) and 62.13% at DPC 3.5 compared to proestrus. In the luminal epithelium, glycogen was the highest at proestrus, decreased 46.2% at DPC 1.5 and 63.2% at DPC 3.5. Immunostaining showed that before implantation, glycogen metabolizing enzymes were primarily localized to the glandular and luminal epithelium. Stromal glycogen was low from proestrus to DPC 3.5. However, at the DPC 5.5 implantation sites, stromal glycogen levels increased sevenfold. Similarly, artificial decidualization resulted in a fivefold increase in glycogen levels. In both models, decidualization increased expression of glycogen synthase as determine by immunohistochemistry and western blot. In conclusion, glycogen levels decreased in the uterine epithelium before implantation, indicating that it could be used to support preimplantation embryos. Decidualization resulted in a dramatic increase in stromal glycogen levels, suggesting it may have an important, but yet undefined, role in pregnancy.
Altered bladder‐related brain network in multiple sclerosis women with voiding dysfunction
Authors: Shi Zhaoyue , Karmonik Christof , Soltes Amelia , Tran Khue , Lincoln John A. , Boone Timothy , Khavari Rose
Published: July 2022

Objectives

A number of neurourology imaging studies have mainly focused on investigating the brain activations during micturition in healthy and neuropathic patients. It is, however, also necessary to study brain functional connectivity (FC) within bladder‐related regions to understand the brain organization during the execution of bladder function. This study aims to identify the altered brain network associated with bladder function in multiple sclerosis (MS) women with voiding dysfunction through comparisons with healthy subjects via concurrent urodynamic study (UDS)/functional magnetic resonance imaging (fMRI).

Materials and Methods

Ten healthy adult women and nine adult ambulatory women with clinically stable MS for ≥6 months and symptomatic voiding phase neurogenic lower urinary tract dysfunction (NLUTD) underwent UDS/fMRI evaluation with a task of bladder filling/emptying that was repeated three to five times. We quantitatively compared their FC within 17 bladder‐related brain regions during two UDS phases: “strong desire to void” and “(attempt at) voiding initiation.”

Results

At “strong desire to void,” the healthy group showed significantly stronger FC in regions involved in bladder filling and suppression of voiding compared to the patient group. These regions included the bilateral anterior cingulate cortex, right supplementary motor area, and right middle frontal gyrus. During “(attempt at) voiding initiation,” healthy subjects exhibited stronger FC in the right inferior frontal gyrus compared to MS patients.

Conclusion

Our study offers a new way to identify alterations in the neural mechanisms underlying NLUTD and provides potential targets for clinical interventions (such as cortical neuromodulation) aimed at restoring bladder functions in MS patients.
Uncivil society and social policies in Brazil: The backlash in the gender, sexual, and reproductive rights and ethnic and racial relations fields
Authors: Segatto Catarina Ianni , Alves Mario Aquino , Pineda Andrea
Published: July 2022

This paper analyzes how dynamics between Brazil's right‐wing populist government and civil and uncivil organizations affected the role of civil organizations, especially rights‐based ones, and Brazil's democratization process. These dynamics contributed to stripping policies of their progressive nature and rejecting the values of diversity, freedom, and equality. Our analysis relies on the inhabited institutions approach to comprehend the role of action, interaction, and meaning in institutionalized spaces. We analyzed two policy fields—gender, sexual, and reproductive rights, and ethnic and racial relations—through documents and in‐depth interviews. Our analysis shows that Bolsonaro's government mobilized mechanisms related to institutional changes, the replacement of actors, and their interactions to inhibit civil society organizations' influence in policy formulation and provision and strengthen the participation of uncivil groups, thereby legitimating conservative ideas and discourses, and closing civic space for NGOs with rights‐based agendas.
Effect of stacking sequence and silicon carbide nanoparticles on properties of carbon/glass/Kevlar fiber reinforced hybrid polymer composites
Authors: Karthik Krishnasamy , Prakash Jayavelu Udaya , Binoj Joseph Selvi , Mansingh Bright Brailson
Published: July 2022

Synthetic fibers as reinforcement in composites are inevitable in today's composite industry due to its exceptional mechanical properties. The objective of this paper is to investigate the effect of stacking sequence of carbon, glass and Kevlar bidirectional (0°/90°) woven mat synthetic fibers reinforced in epoxy matrix composite with silicon carbide (SiC) nanoparticles as filler material on mechanical and visco‐elastic behavior of developed novel hybrid polymer matrix composites (HPMCs). Vacuum bag infusion method is adopted to manufacture the composite specimens by stacking carbon, glass and Kevlar fibers alternatively with six layers and six different stacking sequences and tested as per ASTM standards. Tensile, flexural, impact and hardness test is conducted to identify the composite specimen with maximum mechanical characteristics. The maximum tensile and flexural strength of 398.178 and 671.25 MPa respectively is seen for the composite with strong fibers such as carbon and glass stacked away from the neutral axis. Also, the scanning electron microscope (SEM) images of tensile and flexural failure specimen revealed the failure mechanisms of developed composite specimens. Moreover, the dynamic mechanical analysis (DMA) revealed the visco‐elastic behavior of developed composites with glass transition temperature (Tg) at 115°C. This study emphasizes the influence of stacking sequence on thermo‐mechanical properties of the developed HPMC specimens and explores its potential for diverse applications.
Parental migration status moderates the link between parent–child relationship and children's well‐being through psychological distress
Authors: Mordeno Imelu G. , Gallemit I Marie Joy S. , Bangcola Bea Fatima B. , Busaco Jinky Joy Jessica L. , Tuto Reignajean T. , Hall Brian J.
Published: July 2022

The effects of parental migration on the well‐being of left‐behind children (LBC) are varied. Several studies demonstrated that parental migration reduces children's psychological health but other research showed contradictory results. This study sought to clarify this issue by examining the mediating role of psychological distress and the moderating role of parental migration status in the association between the parent–child relationship and children's psychological distress. A total of 743 LBC and 688 non‐LBC self‐reported their parent–child relationship, psychological distress, and well‐being. Findings showed that psychological distress mediated the association between parent–child relationship and children's well‐being. This denotes that greater parent–child relationship results into lowered levels of psychological distress, and in turn, increases children's emotional, psychological, and social well‐being. Moreover, the link between parent–child relationship and psychological distress was found to be contingent to parental migration status. Specifically, the negative association between parent–child relationship and psychological distress was especially strong among LBC in contrast to non‐ LBC. This implies that children with higher quality relationships with their parents tend to exhibit decreased severity of psychological distress symptoms, especially in children whose parents are working overseas. These results underscore the dynamic role of parent–child relationship in the well‐being of LBC, and suggest ways to develop intervention programs that include cultivating skills in managing psychological distress and improving the emotional, psychological, and social well‐being of LBC.
Predicting residue‐specific qualities of individual protein models using residual neural networks and graph neural networks
Authors: Zhao Chenguang , Liu Tong , Wang Zheng
Published: July 2022

The estimation of protein model accuracy (EMA) or model quality assessment (QA) is important for protein structure prediction. An accurate EMA algorithm can guide the refinement of models or pick the best model or best parts of models from a pool of predicted tertiary structures. We developed two novel methods: MASS2 and LAW, for predicting residue‐specific or local qualities of individual models, which incorporate residual neural networks and graph neural networks, respectively. These two methods use similar features extracted from protein models but different architectures of neural networks to predict the local accuracies of single models. MASS2 and LAW participated in the QA category of CASP14, and according to our evaluations based on CASP14 official criteria, MASS2 and LAW are the best and second‐best methods based on the Z‐scores of ASE/100, AUC, and ULR‐1.F1. We also evaluated MASS2, LAW, and the residue‐specific predicted deviations (between model and native structure) generated by AlphaFold2 on CASP14 AlphaFold2 tertiary structure (TS) models. LAW achieved comparable or better performances compared to the predicted deviations generated by AlphaFold2 on AlphaFold2 TS models, even though LAW was not trained on any AlphaFold2 TS models. Specifically, LAW performed better on AUC and ULR scores, and AlphaFold2 performed better on ASE scores. This means that AlphaFold2 is better at predicting deviations, but LAW is better at classifying accurate and inaccurate residues and detecting unreliable local regions. MASS2 and LAW can be freely accessed from http://dna.cs.miami.edu/MASS2-CASP14/ and http://dna.cs.miami.edu/LAW-CASP14/, respectively.
Data‐driven maintenance planning and scheduling based on predicted railway track condition
Authors: Sedghi Mahdieh , Bergquist Bjarne , Vanhatalo Erik , Migdalas Athanasios
Published: July 2022

Timely planning and scheduling of railway infrastructure maintenance interventions are crucial for increased safety, improved availability, and reduced cost. We propose a data‐driven decision‐support framework integrating track condition predictions with tactical maintenance planning and operational scheduling. The framework acknowledges prediction uncertainties by using a Wiener process‐based prediction model at the tactical level. We also develop planning and scheduling algorithms at the operational level. One algorithm focuses on cost‐optimisation, and one algorithm considers the multi‐component characteristics of the railway track by grouping track segments near each other for one maintenance activity. The proposed framework's performance is evaluated using track geometry measurement data from a 34 km railway section in northern Sweden, focusing on the tamping maintenance action. We analyse maintenance costs and demonstrate potential efficiency increases by applying the decision‐support framework.
Regularity Theory for Non-autonomous Partial Differential Equations Without Uhlenbeck Structure
Authors: Hästö Peter , Ok Jihoon
Published: July 2022

We establish maximal local regularity results of weak solutions or local minimizers of $$\begin{aligned} \mathrm {div}A(x, Du)=0 \quad \text {and}\quad \min _u \int _\Omega F(x,Du)\,\mathrm{d}x, \end{aligned}$$

div
A

(
x
,
D
u
)

=
0

and

min
u

∫
Ω

F

(
x
,
D
u
)

d
x
,

providing new ellipticity and continuity assumptions on A or F with general (p, q)-growth. Optimal regularity theory for the above non-autonomous problems is a long-standing issue; the classical approach by Giaquinta and Giusti involves assuming that the nonlinearity F satisfies a structure condition. This means that the growth and ellipticity conditions depend on a given special function, such as $$t^p$$

t
p

, $$\varphi (t)$$

φ
(
t
)

, $$t^{p(x)}$$

t

p
(
x
)

, $$t^p+a(x)t^q$$

t
p

+
a

(
x
)

t
q

, and not only F but also the given function is assumed to satisfy suitable continuity conditions. Hence these regularity conditions depend on given special functions. In this paper we study the problem without recourse to, special function structure and without assuming Uhlenbeck structure. We introduce a new ellipticity condition using A or F only, which entails that the function is quasi-isotropic, i.e. it may depend on the direction, but only up to a multiplicative constant. Moreover, we formulate the continuity condition on A or F without specific structure and without direct restriction on the ratio $$\frac{q}{p}$$

q
p

of the parameters from the (p, q)-growth condition. We establish local $$C^{1,\alpha }$$

C

1
,
α

-regularity for some $$\alpha \in (0,1)$$

α
∈
(
0
,
1
)

and $$C^{\alpha }$$

C
α

-regularity for any $$\alpha \in (0,1)$$

α
∈
(
0
,
1
)

of weak solutions and local minimizers. Previously known, essentially optimal, regularity results are included as special cases.
RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in untreated EGFR-mutated metastatic non-small cell lung cancer: exposure–response relationship
Authors: Nakagawa Kazuhiko , Garon Edward B. , Gao Ling , Callies Sophie , Zimmermann Annamaria , Walgren Richard , Visseren-Grul Carla , Reck Martin
Published: July 2022

Purpose

In RELAY, ramucirumab plus erlotinib (RAM + ERL) improved progression-free survival (PFS) in patients with untreated, metastatic, EGFR-mutated, non-small cell lung cancer (NSCLC). Here, we present the exposure–response relationship of RAM from RELAY.

Methods

Patients received ERL (150 mg/day) with either RAM (10 mg/kg) or placebo (PBO + ERL) every 2 weeks (Q2W). A population pharmacokinetic model predicted RAM minimum concentration after first dose (Cmin,1), and at steady state (Cmin,ss), which were used to evaluate correlation between RAM exposure and efficacy and safety. The Kaplan–Meier method and Cox regression analyses were utilized to evaluate exposure–efficacy by Cmin,1 quartile. Exposure–safety was evaluated by assessing incidence rates for safety parameters by Cmin,ss quartile, with ordered categorical analysis used for ALT/AST only.

Results

Analyses included 216 patients treated with RAM + ERL and 225 patients treated with PBO + ERL. Adjusting for significant baseline covariates, no exposure–efficacy relationship was identified in RELAY: PFS hazard ratio (mean, 95% confidence intervals) for the Cmin,1 quartiles were 0.67 (0.45–0.99), 0.77 (0.53–1.12), 0.57 (0.38–0.84), and 0.50 (0.33–0.76). No apparent exposure–safety relationship was observed for selected safety endpoints, including Grade ≥ 3 hypertension, diarrhea, and dermatitis acneiform, and any grade hypertension, any grade and Grade ≥ 3 proteinuria, and any grade ALT/AST increased within liver failure/liver injury.

Conclusions

No association was observed between RAM exposure and response, suggesting that the RELAY regimen of RAM 10 mg/kg Q2W with ERL is an optimized, efficacious, and safe first-line treatment for patients with untreated, metastatic, EGFR-mutated NSCLC.

Trial registration: ClinicalTrials.gov, NCT02411448.
Persistent organic pollutants and mercury in a colony of Antarctic seabirds: higher concentrations in 1998, 2001, and 2003 compared to 2014 to 2016
Authors: Kuepper Nadja D. , Böhm Leonard , Braun Christina , Bustamante Paco , Düring Rolf-Alexander , Libertelli Marcela M. , Quillfeldt Petra
Published: July 2022

Over decades, persistent organic pollutants (POPs) and trace metals like mercury (Hg) have reached the remotest areas of the world such as Antarctica by atmospheric transport. Once deposited in polar areas, low temperatures, and limited solar radiation lead to long environmental residence times, allowing the toxic substances to accumulate in biota. We investigated the load of polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDTs) and metabolites (DDEs, DDDs) in embryos from failed eggs of the smallest seabird breeding in Antarctica, the Wilson's storm-petrel (Oceanites oceanicus) at King George Island (Isla 25 de Mayo). We compared samples of different developmental stages collected in 2001, 2003, and 2014 to 2016 to investigate changes in pollutant concentrations over time. We detected eight PCBs including the dioxin-like (dl) congeners PCB 105 and 118 (ΣPCBs: 59-3403 ng g−1ww) as well as 4,4’-DDE, and 4,4’-DDD (ΣDDX: 19-1035 ng g−1ww) in the embryos. Samples from the years 2001 and 2003 showed higher concentrations of PCBs than those from 2014 to 2016. Concentrations of DDX was similar in both time intervals. Furthermore, we determined Hg concentrations in egg membranes from 1998 to 2003, and 2014 to 2016. Similar to PCBs, Hg in egg membranes were higher in 1998 than in 2003, and higher in 2003 than in the years 2014 to 2016, suggesting a slow recovery of the pelagic Antarctic environment from the detected legacy pollutants. Embryos showed an increase in pollutant concentrations within the last third of their development. This finding indicates that contaminant concentrations may differ among developmental stages, and it should be taken into account in analyses on toxic impact during embryogenesis.
Winter wet–dry weather patterns driving atmospheric rivers and Santa Ana winds provide evidence for increasing wildfire hazard in California
Authors: Guirguis Kristen , Gershunov Alexander , Hatchett Benjamin , Shulgina Tamara , DeFlorio Michael J. , Subramanian Aneesh C. , Guzman-Morales Janin , Aguilera Rosana , Clemesha Rachel , Corringham Thomas W. , Delle Monache Luca , Reynolds David , Tardy Alex , Small Ivory , Ralph F. Martin
Published: July 2022

Floods caused by atmospheric rivers and wildfires fanned by Santa Ana winds are common occurrences in California with devastating societal impacts. In this work, we show that winter weather variability in California, including the occurrence of extreme and impactful events, is linked to four atmospheric circulation regimes over the North Pacific Ocean previously named and identified as the “NP4 modes”. These modes come in and out of phase with each other during the season, resulting in distinct weather patterns that recur throughout the historical record. Some phase combinations favor atmospheric river landfalls and extreme daily or multi-day precipitation, while other phase combinations favor anomalously hot weather and drying Santa Ana wind conditions over Southern California. This historical perspective of atmospheric circulation and impacts over 70 years reveals that weather patterns are changing in a way that enhances wildfire hazard in California, while the frequency of weather patterns linked to historical floods is not diminishing. These changes highlight the rising hazards of cascading weather extremes in California’s present and future.
Monoamine oxidase A and organic cation transporter 3 coordinate intracellular β1AR signaling to calibrate cardiac contractile function
Authors: Wang Ying , Zhao Meimi , Xu Bing , Bahriz Sherif M. F. , Zhu Chaoqun , Jovanovic Aleksandra , Ni Haibo , Jacobi Ariel , Kaludercic Nina , Di Lisa Fabio , Hell Johannes W. , Shih Jean C. , Paolocci Nazareno , Xiang Yang K.
Published: July 2022

We have recently identified a pool of intracellular β1 adrenergic receptors (β1ARs) at the sarcoplasmic reticulum (SR) crucial for cardiac function. Here, we aim to characterize the integrative control of intracellular catecholamine for subcellular β1AR signaling and cardiac function. Using anchored Förster resonance energy transfer (FRET) biosensors and transgenic mice, we determined the regulation of compartmentalized β1AR-PKA signaling at the SR and plasma membrane (PM) microdomains by organic cation transporter 3 (OCT3) and monoamine oxidase A (MAO-A), two critical modulators of catecholamine uptake and homeostasis. Additionally, we examined local PKA substrate phosphorylation and excitation–contraction coupling in cardiomyocyte. Cardiac-specific deletion of MAO-A (MAO-A-CKO) elevates catecholamines and cAMP levels in the myocardium, baseline cardiac function, and adrenergic responses. Both MAO-A deletion and inhibitor (MAOi) selectively enhance the local β1AR-PKA activity at the SR but not PM, and augment phosphorylation of phospholamban, Ca2+ cycling, and myocyte contractile response. Overexpression of MAO-A suppresses the SR-β1AR-PKA activity and PKA phosphorylation. However, deletion or inhibition of OCT3 by corticosterone prevents the effects induced by MAOi and MAO-A deletion in cardiomyocytes. Deletion or inhibition of OCT3 also negates the effects of MAOi and MAO-A deficiency in cardiac function and adrenergic responses in vivo. Our data show that MAO-A and OCT3 act in concert to fine-tune the intracellular SR-β1AR-PKA signaling and cardiac fight-or-flight response. We reveal a drug contraindication between anti-inflammatory corticosterone and anti-depressant MAOi in modulating adrenergic regulation in the heart, providing novel perspectives of these drugs with cardiac implications.
X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition
Authors: Volpatti Jonathan R. , Ghahramani-Seno Mehdi M. , Mansat Mélanie , Sabha Nesrin , Sarikaya Ege , Goodman Sarah J. , Chater-Diehl Eric , Celik Alper , Pannia Emanuela , Froment Carine , Combes-Soia Lucie , Maani Nika , Yuki Kyoko E. , Chicanne Gaëtan , Uusküla-Reimand Liis , Monis Simon , Alvi Sana Akhtar , Genetti Casie A. , Payrastre Bernard , Beggs Alan H. , Bonnemann Carsten G. , Muntoni Francesco , Wilson Michael D. , Weksberg Rosanna , Viaud Julien , Dowling James J.
Published: July 2022

X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1. At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish and identified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype. These observations led us to interrogate the epigenome in Mtm1 knockout mice; we found increased DNA methylation, which is normalized with valproic acid, and likely mediated through aberrant 1-carbon metabolism. Finally, we made the unexpected observation that XLMTM patients share a distinct DNA methylation signature, suggesting that epigenetic alteration is a conserved disease feature amenable to therapeutic intervention.
Increased susceptibility to Chrysanthemum Yellows phytoplasma infection in Atcals7ko plants is accompanied by enhanced expression of carbohydrate transporters
Authors: Bernardini Chiara , Santi Simonetta , Mian Giovanni , Levy Amit , Buoso Sara , Suh Joon Hyuk , Wang Yu , Vincent Christopher , van Bel Aart J. E. , Musetti Rita
Published: July 2022

Main conclusion

Loss of CALS7 appears to confer increased susceptibility to phytoplasma infection in Arabidopsis, altering expression of genes involved in sugar metabolism and membrane transport.

Callose deposition around sieve pores, under control of callose synthase 7 (CALS7), has been interpreted as a mechanical response to limit pathogen spread in phytoplasma-infected plants. Wild-type and Atcals7ko mutants were, therefore, employed to unveil the mode of involvement of CALS7 in the plant’s response to phytoplasma infection. The fresh weights of healthy and CY-(Chrysanthemum Yellows) phytoplasma-infected Arabidopsis wild type and mutant plants indicated two superimposed effects of the absence of CALS7: a partial impairment of photo-assimilate transport and a stimulated phytoplasma proliferation as illustrated by a significantly increased phytoplasma titre in Atcal7ko mutants. Further studies solely dealt with the effects of CALS7 absence on phytoplasma growth. Phytoplasma infection affected sieve-element substructure to a larger extent in mutants than in wild-type plants, which was also true for the levels of some free carbohydrates. Moreover, infection induced a similar upregulation of gene expression of enzymes involved in sucrose cleavage (AtSUS5, AtSUS6) and transmembrane transport (AtSWEET11) in mutants and wild-type plants, but an increased gene expression of carbohydrate transmembrane transporters (AtSWEET12, AtSTP13, AtSUC3) in infected mutants only. It remains still unclear how the absence of AtCALS7 leads to gene upregulation and how an increased intercellular mobility of carbohydrates and possibly effectors contributes to a higher susceptibility. It is also unclear if modified sieve-pore structures in mutants allow a better spread of phytoplasmas giving rise to higher titre.
Collision with Gondwana or with Baltica? Ordovician magmatic arc volcanism in the Marmarosh Massif (Eastern Carpathians, Ukraine)
Authors: Gawęda Aleksandra , Szopa Krzysztof , Golonka Jan , Chew David , Stepanyuk Leonid , Belskyy Volodymir , Waśkowska Anna , Siliauskas Laurynas , Drakou Foteini
Published: July 2022

The pre-Alpine Marmarosh Massif is a tectonically complex unit of the crystalline basement within the Eastern Outer Carpathians. In the eastern (Ukrainian) segment of this massif, two units have been identified—the Bilyi Potok Nappe and the Dilove Nappe. Petrological investigations coupled with zircon U–Pb dating were performed on metavolcanic rocks (porphyroids) and their phyllite host rocks, sampled from three locations within the Dilove Nappe. The geochemical characteristics of the meta-rhyodacite porphyroids revealed a volcanic arc affinity of the protolith, with U–Pb zircon ages of 452.8 ± 1.5 Ma and 461.5 ± 1.6 Ma and zircon saturation temperatures in the range of 823–892 °C. The phyllite host rocks (meta-tuff) yield a U–Pb zircon maximum estimate for the eruption age at 584.7 ± 2.9 Ma. Peak amphibolite-facies metamorphism (M1) was estimated at the pressure of 600–900 MPa with a temperature range of 560–600 °C. Retrogression (M2), possibly related to Alpine nappe stacking and shearing, is assumed to have taken place at 200–250 MPa and 384–222 °C. The volcanic arc is interpreted as an early Caledonian arc that was subsequently accreted to the margin of Baltica during the closure of the easternmost Tornquist Ocean rather than Cenerian (early Paleozoic) orogenic events on the margin of East Gondwana.
Proteomic comparison between physiological degeneration and needle puncture model of disc generation disease
Authors: He Shuangjun , Zhou Xinfeng , Yang Guotao , Zhou Zhangzhe , Zhang Yijian , Shao Xiaofeng , Liang Ting , Lv Nanning , Chen Jianhong , Qian Zhonglai
Published: July 2022

Background

The completeness of the intervertebral disc proteome is fundamental to the integrity and functionality of the intervertebral disc.

Methods

The 20 experimental rats were placed into two groups randomly, normal group (NG) and acupuncture pathological degeneration group-2 weeks (APDG-2w). The ten 24-month-old rats were grouped into physiological degeneration group (PDG). Magnetic resonance imaging, X-ray examination, histological staining (hematoxylin & eosin, safranin-O cartilage, and alcian blue staining), and immunohistochemical examination were carried out for assessing the degree of disc degradation. Intervertebral disc was collected, and protein composition was determined by LC- MS, followed by bioinformatic analysis including significance analysis, subcellular localization prediction, protein domain prediction, GO function and KEGG pathway analysis, and protein interaction network construction. LC-PRM was done for protein quantification.

Results

Physiological degeneration and especially needle puncture decreased T2 signal intensity and intervertebral disc height. Results from hematoxylin & eosin, safranin-O, and alcian blue staining revealed that the annulus fibrosus apparently showed the wavy and collapsed fibrocartilage lamellas in APDG-2w and PDG groups. The contents of the nucleus pulposus were decreased in physiological degeneration group and APDG-2w group compared with NG. Results from immunohistochemical analysis suggested the degeneration of intervertebral disc and inflammation in APDG-2w and PDG groups. The protein composition and expression between needle puncture rat models and the physiological degeneration group showed significant difference.

Conclusions

Our studies produced point-reference datasets of normal rats, physiological degeneration rats, and needle puncture rat models, which is beneficial to subsequent pathological studies. There is differential expression of protein expression in degenerative discs with aging and acupuncture, which may be used as a potential discriminating index for different intervertebral degenerations.
Reuniting the Three Sisters: collaborative science with Native growers to improve soil and community health
Authors: Kapayou D. G. , Herrighty E. M. , Hill C. Gish , Camacho V. Cano , Nair A. , Winham D. M. , McDaniel M. D.
Published: July 2022

Before Euro-American settlement, many Native American nations intercropped maize (Zea mays), beans (Phaseolus vulgaris), and squash (Cucurbita pepo) in what is colloquially called the “Three Sisters.” Here we review the historic importance and consequences of rejuvenation of Three Sisters intercropping (3SI), outline a framework to engage Native growers in community science with positive feedbacks to university research, and present preliminary findings from ethnography and a randomized, replicated 3SI experiment. We developed mutually beneficial collaborative research agendas with four Midwestern US Native American nations. Ethnographic data highlighted a culturally based respect for 3SI as living beings, the importance it holds for all cultural facets of these Native nations, and the critical impact the practice has on environmental sustainability. One concern expressed by Native growers during ethnographic research was improving soil health—part of the rationale for establishing the 3SI agronomic experiment. To address this, we collaboratively designed a 3SI experiment. After 1 year, 3SI increased short-term soil respiration by 24%, decreased salt-extractable nitrate by 54%, had no effect on soil microbial biomass (but increased its carbon-to-nitrogen ratio by 32%) compared to the average of monoculture crops. The overarching purpose of this collaborative project is to develop a deeper understanding of 3SI, its cultural importance to Native communities, and how reinvigorating the practice—and intercropping in general—can make agroecosystems more sustainable for people and the environment.
Discrimination between softwood and hardwood based on hemicellulose content obtained with portable nuclear magnetic resonance
Authors: Stagno Valeria , Ricci Sara , Longo Sveva , Verticchio Elena , Frasca Francesca , Siani Anna Maria , Capuani Silvia
Published: July 2022

Wood is a hygroscopic material that can reach an equilibrium moisture content when ambient temperature and relative humidity are constant. Moisture affects all properties of wood, as well as its preservative treatment. The hygroscopic behavior of wood can be attributed to the hydroxyl groups of its constituents. Since hemicellulose shows the greatest water affinity, it can be considered the main responsible for the ingress of water into the wood mass. Below the fiber saturation point, wood moisture is only stored in the cell walls. Proton Nuclear Magnetic Resonance (NMR) is a relative method used for the evaluation of moisture content distribution in wood and NMR relaxation is an excellent tool to study the hygroscopic behavior of different woods below the fiber saturation point. This work aimed to test the hypothesis of discriminating among softwoods and hardwoods of different botanical species and identifying further sub-clusters of woods based on the NMR proton spin–spin (T2) and spin–lattice (T1) relaxation times of their cell wall water in the hygroscopic moisture range. Importantly, the study was performed using a portable low-cost NMR instrument with which it is possible to investigate wood samples of any size. The main result of this study was that at RH = 94% the relaxation time T2,2, associated with the cell wall bound water, can be used as a marker to discriminate among softwoods and hardwoods.

Graphical abstract