bluuebunny/crossref_metadata_2025 huggingface dataset:
The Mutual Inhibition between PLETHORAs and ARABIDOPSIS RESPONSE REGULATORs Controls Root Zonation
Authors: Shtin Margaryta , Polverari Laura , Svolacchia Noemi , Bertolotti Gaia , Unterholzner Simon J , Di Mambro Riccardo , Costantino Paolo , Dello Ioio Raffaele , Sabatini Sabrina
Published: January 2023

During organogenesis, a key step toward the development of a functional organ is the separation of cells into specific domains with different activities. Mutual inhibition of gene expression has been shown to be sufficient to establish and maintain these domains during organogenesis in several multicellular organisms. Here, we show that the mutual inhibition between the PLETHORA transcription factors (PLTs) and the ARABIDOPSIS RESPONSE REGULATORs (ARRs) transcription factors is sufficient to separate cell division and cell differentiation during root organogenesis. In particular, we show that ARR1 suppresses PLT activities and that PLTs suppress ARR1 and ARR12 by targeting their proteins for degradation via the KISS ME DEADLY 2 F-box protein. These findings reveal new important aspects of the complex process of root zonation and development.
Microstructure and Texture of a Spinel Corona Around a Basalt Hosted Corundum Xenocrystal
Authors: Schuster Roman , Tiede Lisa , Ageeva Olga , Griffiths Thomas A , Abart Rainer , Habler Gerlinde
Published: January 2023

The microstructural and textural characteristics of a spinel corona that formed around a faceted corundum xenocrystal by reaction with the hosting basaltic melt in the Siebengebirge volcanic field demonstrate that the crystallographic and shape preferred orientation of spinel is influenced by the orientation of the reaction interface with respect to the corundum crystal lattice. The spinel roughly shows the common topotactic orientation relationships with corundum, where one of the $\{111\}_{Spl}$ planes is parallel to the (0001)$_{Crn}$ plane, and three of the $\{110\}_{Spl}$ planes are parallel to the $\{10\overline {1}0\}_{Crn}$ planes. In detail, there are subtle but systematic deviations from this topotactic relationship due to small rotations about the c-axis and/or an a-axis of corundum. The former is observed when the corundum c-axis is closely parallel to the interface plane, while the latter require a corundum a-axis orientation perpendicular to the interface. In this case, the preferred sense of rotation depends on the sign of the a-axis direction, irrespective of the spinel growth direction being parallel or antiparallel to this axis. Additionally, the selection of either one or both of two spinel twin variants that equally fulfill the topotactic orientation relationship depends on the orientation of the corundum-spinel interface with respect to the lattices of both the corundum and the spinel. Finally, also the grain boundary character is controlled by the interface orientation and the corundum lattice. Despite the differences between corona segments, the nature of these textures are persistent along and across each segment. We emphasize that all these microstructural and textural features are ascribed to the period of spinel growth in magmatic environment. The extent to which prominent slip planes in spinel are aligned parallel with the corundum-spinel interface seems to be of crucial importance for the nature of the spinel texture and microstructure, indicating that the activity of dislocations pertaining to these slip systems ease the accommodation of lattice misfit across the corundum-spinel interface. By comparison with experimentally grown spinel layers, we infer predominantly interface reaction controlled growth of the studied spinel corona.
Zeaxanthin is required for eyespot formation and phototaxis inEuglena gracilis
Authors: Tamaki Shun , Ozasa Kazunari , Nomura Toshihisa , Ishikawa Marumi , Yamada Koji , Suzuki Kengo , Mochida Keiichi
Published: January 2023

The eyespot apparatus is an organelle that forms carotenoid-rich globules in diverse flagellated microalgae and functions in phototaxis. The euglenophytes have structurally and functionally distinct eyespot apparatuses from chlorophytes. β-Carotene is the most abundant pigment detected in chlorophytes’ eyespots, while xanthophylls such as zeaxanthin and diadinoxanthin have been suggested to function in euglenophytes’ eyespots. Here, we investigated the association between carotenoid composition and eyespot formation via pathway-scale mutagenesis using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated genome editing in the euglenophyte Euglena gracilis. Lycopene cyclase (lcy) mutants exhibited sole lycopene accumulation, defective red eyespots, and phototactic insensitivity. Conversely, β-carotene hydroxylase (cytochrome P450 97h1, cyp97h1) mutants accumulated β-carotene and its hydroxylated products β-cryptoxanthin and zeaxanthin and formed phototactic eyespot apparatuses, while cyp97h1 cyp97f2 double mutants were deficient in β-carotene hydroxylation and mostly lacked functional eyespots. Thus, zeaxanthin is required for the stable formation of functional eyespots in E. gracilis, highlighting evolutionary differences between euglenophytes and chlorophytes in the metabolic regulation of photoreactive organelle formation.
Apple SUMO E3 ligase MdSIZ1 regulates cuticular wax biosynthesis by SUMOylating transcription factor MdMYB30
Authors: Zhang Ya-Li , Tian Yi , Man Yao-Yang , Zhang Chun-Ling , Wang Yi , You Chun-Xiang , Li Yuan-Yuan
Published: January 2023

A key function of SUMOylation is the coordinated modification of numerous proteins to optimize plant growth and resistance to environmental stress. Plant cuticular wax is deposited on the surface of primary plant organs to form a barrier that provides protection against changes in terrestrial environments. Many recent studies have examined cuticular wax biosynthetic pathways and regulation. However, whether SUMOylation is involved in the regulation of cuticle wax deposition at the posttranslational level remains unclear. Here, we demonstrate that a small ubiquitin-like modifier (SUMO) E3 ligase, SAP AND MIZ1 DOMAIN CONTAINING LIGASE1 (MdSIZ1), regulates wax accumulation and cuticle permeability in apple (Malus domestica Borkh), SUMO E2 CONJUGATING ENZYME 1(MdSCE1) physically interacts with MdMYB30, a transcription factor involved in the regulation of cuticle wax accumulation. MdSIZ1 mediates the SUMOylation and accumulation of MdMYB30 by inhibiting its degradation through the 26S proteasome pathway. Furthermore, MdMYB30 directly binds to the β-KETOACYL-COA SYNTHASE 1 (MdKCS1) promoter to activate its expression and promote wax biosynthesis. These findings indicate that the MdSIZ1–MdMYB30–MdKCS1 module positively regulates cuticular wax biosynthesis in apples. Overall, the findings of our study provide insights into the regulation pathways involved in cuticular wax biosynthesis.
Effective cell membrane tension is independent of polyacrylamide substrate stiffness
Authors: Kreysing Eva , Hugh Jeffrey Mc , Foster Sarah K , Andresen Kurt , Greenhalgh Ryan D , Pillai Eva K , Dimitracopoulos Andrea , Keyser Ulrich F , Franze Kristian
Published: January 2023

Most animal cells are surrounded by a cell membrane and an underlying actomyosin cortex. Both structures are linked, and they are under tension. In-plane membrane tension and cortical tension both influence many cellular processes, including cell migration, division, and endocytosis. However, while actomyosin tension is regulated by substrate stiffness, how membrane tension responds to mechanical substrate properties is currently poorly understood. Here, we probed the effective membrane tension of neurons and fibroblasts cultured on glass and polyacrylamide substrates of varying stiffness using optical tweezers. In contrast to actomyosin-based traction forces, both peak forces and steady-state tether forces of cells cultured on hydrogels were independent of substrate stiffness and did not change after blocking myosin II activity using blebbistatin, indicating that tether and traction forces are not directly linked. Peak forces in fibroblasts on hydrogels were about twice as high as those in neurons, indicating stronger membrane–cortex adhesion in fibroblasts. Steady-state tether forces were generally higher in cells cultured on hydrogels than on glass, which we explain by a mechanical model. Our results provide new insights into the complex regulation of effective membrane tension and pave the way for a deeper understanding of the biological processes it instructs.
A “grappling hook” interaction connects self-assembly and chaperone activity of Nucleophosmin 1
Authors: Saluri Mihkel , Leppert Axel , Gese Genis Valentin , Sahin Cagla , Lama Dilraj , Kaldmäe Margit , Chen Gefei , Elofsson Arne , Allison Timothy M , Arsenian-Henriksson Marie , Johansson Jan , Lane David P , Hällberg B Martin , Landreh Michael
Published: January 2023

How the self-assembly of partially disordered proteins generates functional compartments in the cytoplasm and particularly in the nucleus is poorly understood. Nucleophosmin 1 (NPM1) is an abundant nucleolar protein that forms large oligomers and undergoes liquid–liquid phase separation by binding RNA or ribosomal proteins. It provides the scaffold for ribosome assembly but also prevents protein aggregation as part of the cellular stress response. Here, we use aggregation assays and native mass spectrometry (MS) to examine the relationship between the self-assembly and chaperone activity of NPM1. We find that oligomerization of full-length NPM1 modulates its ability to retard amyloid formation in vitro. Machine learning-based structure prediction and cryo-electron microscopy reveal fuzzy interactions between the acidic disordered region and the C-terminal nucleotide-binding domain, which cross-link NPM1 pentamers into partially disordered oligomers. The addition of basic peptides results in a tighter association within the oligomers, reducing their capacity to prevent amyloid formation. Together, our findings show that NPM1 uses a “grappling hook” mechanism to form a network-like structure that traps aggregation-prone proteins. Nucleolar proteins and RNAs simultaneously modulate the association strength and chaperone activity, suggesting a mechanism by which nucleolar composition regulates the chaperone activity of NPM1.
Histone deacetylation regulates de novo shoot regeneration
Authors: Temman Haruka , Sakamoto Takuya , Ueda Minoru , Sugimoto Kaoru , Migihashi Masako , Yamamoto Kazunari , Tsujimoto-Inui Yayoi , Sato Hikaru , Shibuta Mio K , Nishino Norikazu , Nakamura Tomoe , Shimada Hiroaki , Taniguchi Yukimi Y , Takeda Seiji , Aida Mitsuhiro , Suzuki Takamasa , Seki Motoaki , Matsunaga Sachihiro
Published: January 2023

During de novo plant organ regeneration, auxin induction mediates the formation of a pluripotent cell mass called callus, which regenerates shoots upon cytokinin induction. However, molecular mechanisms underlying transdifferentiation remain unknown. Here, we showed that the loss of HDA19, a histone deacetylase (HDAC) family gene, suppresses shoot regeneration. Treatment with an HDAC inhibitor revealed that the activity of this gene is essential for shoot regeneration. Further, we identified target genes whose expression was regulated through HDA19-mediated histone deacetylation during shoot induction and found that ENHANCER OF SHOOT REGENERATION 1 and CUP-SHAPED COTYLEDON 2 play important roles in shoot apical meristem formation. Histones at the loci of these genes were hyperacetylated and markedly upregulated in hda19. Transient ESR1 or CUC2 overexpression impaired shoot regeneration, as observed in hda19. Therefore, HDA19 mediates direct histone deacetylation of CUC2 and ESR1 loci to prevent their overexpression at the early stages of shoot regeneration.
Effect of alanine versus serine at position 88 of human transthyretin mutants on the protein stability
Authors: Lee Kyung-Hoon , Kuczera Krzysztof
Published: January 2023

Human transthyretin (TTR) is a homo-tetrameric plasma protein associated with a high percentage of β-sheet forming amyloid fibrils. It accumulates in tissues or extracellular matrices to cause amyloid diseases. Free energy simulations with thermodynamic integration based on all-atom molecular dynamics simulations have been carried out to analyze the effects of the His88 → Ala and Ser mutations on the stability of human TTR. The calculated free energy change differences (ΔΔG) caused by the His88 → Ala and His88 → Ser mutations are −1.84 ± 0.86 and 7.56 ± 0.55 kcal/mol, respectively, which are in excellent agreement with prior reported experimental values. The simulation results show that the H88A mutant is more stable than the wild type, whereas the H88S mutant is less stable than the wild type. The free energy component analysis shows that the contribution to the free energy change difference (ΔΔG) for the His88 → Ala and His88 → Ser mutations mainly arise from electrostatic and van der Waals interactions, respectively. The electrostatic term stabilizes the H88A mutant more than the wild type, but the van der Waals interaction destabilizes the H88S mutant relative to the wild type. Individual residue contributions to the free energy change show neighboring residues exert stabilizing and destabilizing influence on the mutants. The implications of the simulation results for understanding the stabilizing and destabilizing effect and its contribution to protein stability are discussed.
Effect of Variation in Early Rehabilitation on Hospital Readmission After Hip Fracture
Authors: Kumar Amit , Roy Indrakshi , Falvey Jason , Rudolph James L , Rivera-Hernandez Maricruz , Shaibi Stefany , Sood Pallavi , Childers Christine , Karmarkar Amol
Published: January 2023

Objective

Provision of early rehabilitation services during acute hospitalization after a hip fracture is vital for improving patient outcomes. The purpose of this study was to examine the association between the amount of rehabilitation services received during the acute care stay and hospital readmission in older patients after a hip fracture.

Methods

Medicare claims data (2016–2017) for older adults admitted to acute hospitals for a hip fracture (n = 131,127) were used. Hospital-based rehabilitation (physical therapy, occupational therapy, or both) was categorized into tertiles by minutes per day as low (median = 17.5), middle (median = 30.0), and high (median = 48.8). The study outcome was risk-adjusted 7-day and 30-day all-cause hospital readmission.

Results

The median hospital stay was 5 days (interquartile range [IQR] = 4–6 days). The median rehabilitation minutes per day was 30 (IQR = 21–42.5 minutes), with 17 (IQR = 12.6–20.6 minutes) in the low tertile, 30 (IQR = 12.6–20.6 minutes) in the middle tertile, and 48.8 (IQR = 42.8–60.0 minutes) in the high tertile. Compared with high therapy minutes groups, those in the low and middle tertiles had higher odds of a 30-day readmission (low tertile: odds ratio [OR] = 1.11, 95% CI = 1.06–1.17; middle tertile: OR = 1.07, 95% CI = 1.02–1.12). In addition, patients who received low rehabilitation volume had higher odds of a 7-day readmission (OR = 1.20; 95% CI = 1.10–1.30) compared with high volume.

Conclusion

Elderly patients with hip fractures who received less rehabilitation were at higher risk of readmission within 7 and 30 days.

Impact

These findings confirm the need to update clinical guidelines in the provision of early rehabilitation services to improve patient outcomes during acute hospital stays for individuals with hip fracture.

Lay summary

There is significant individual- and hospital-level variation in the amount of hospital-based rehabilitation delivered to older adults during hip fracture hospitalization. Higher intensity of hospital-based rehabilitation care was associated with a lower risk of hospital readmission within 7 and 30 days.
On why the COVID-19 pandemic has not changed the world
Authors: Maboloc Christopher Ryan
Published: January 2023

This paper reacts to the proposal of Virgilio Rivas with respect to the role of art as a response to the threat of meaning that was brought forth by the COVID-19 pandemic. It will be argued that the purported new normal in which changes in the ways of life of people had been expected never actually occurred post-pandemic as power and economic interests still dominate the global order. The pandemic, in this regard, was simply a short pause from the hegemonic relationship among nations in the global order. The paper maintains that, in the end, people must continue to pursue human decency.
Digital exclusion as a potential cause of inequalities in access to care: a survey in people with inflammatory rheumatic diseases
Authors: Hider Samantha , Muller Sara , Gray Lauren , Manning Fay , Brooks Mike , Heining Dominic , Menon Ajit , Packham Jonathan , Raghuvanshi Subhra , Roddy Edward , Ryan Sarah , Scott Ian , Paskins Zoe
Published: January 2023

Objectives

COVID-19 led to rapid uptake of digital health care. We sought to examine digital access, health and digital literacy, and impact on confidence and satisfaction with remote consultations in people with inflammatory rheumatic diseases (IRDs).

Methods

People with IRDs (n = 2024) were identified from their electronic health record and invited to participate in a cross-sectional survey, using short message service (SMS) and postal approaches. Data were collected on demographics, self-reported diagnosis, access to and use of internet-enabled devices, health and digital literacy, together with confidence and satisfaction with remote consultations. Ethical approval was obtained (Ref 21/PR/0867).

Results

Six hundred and thirty-nine (639) people completed the survey [mean (s.d.) age 64.5 (13.1) years, 384 (60.1%) female]. Two hundred and eighty-seven (44.9%) completed it online. One hundred and twenty-six (19.7%) people reported not having access to an internet-enabled device. Ninety-three (14.6%) reported never accessing the internet; this proportion was highest (23%) in people with RA. One hundred and seventeen (18%) reported limited health literacy. Even in those reporting internet use, digital literacy was only moderate. People with limited health or digital literacy or without internet access were less likely to report confidence or satisfaction with remote consultations.

Conclusion

Limited health and digital literacy, lack of digital access and low reported internet use were common, especially in older people with RA. People with limited health literacy or limited digital access reported lower confidence and satisfaction with remote consultations. Digital implementation roll-out needs to take account of people requiring extra support to enable them to access care digitally or risks exacerbating health inequalities.
From intent to impact—The decline of broader impacts throughout an NSF project life cycle
Authors: Woodson Thomas , Boutilier Sophia
Published: January 2023

It is important for funding agencies to evaluate if scientists accomplish their research goals. By comparing a representative sample of National Science Foundation abstracts and project outcome reports (PORs) from 2014 to 2017, this article investigates whether scientists attain the broader impacts they propose. We find that the number of broader impacts proposed in the abstracts is significantly higher than the number of broader impacts reported in the PORs. The trend is common across directorates and type of impact, except when impacts serve advantaged groups. Only the number of broader impacts for advantaged groups increases from the abstract to the POR. Despite the difference between proposed impact and reported impact, our study does not conclude that scientists are delinquent or disingenuous when they propose their research. Rather, we question the capacity of current frameworks to capture the quality of impacts and to weigh the relative importance of impacts that serve marginalized groups versus those that sustain the status quo.
A multidisciplinary lifestyle program for rheumatoid arthritis: the ‘Plants for Joints’ randomized controlled trial
Authors: Walrabenstein Wendy , Wagenaar Carlijn A , van der Leeden Marike , Turkstra Franktien , Twisk Jos W R , Boers Maarten , van Middendorp Henriët , Weijs Peter J M , van Schaardenburg Dirkjan
Published: January 2023

Objective

To determine the effect of a multidisciplinary lifestyle program in patients with RA with low–moderate disease activity.

Methods

In the ‘Plants for Joints’ (PFJ) parallel-arm, assessor-blind randomized controlled trial, patients with RA and 28-joint DAS (DAS28) ≥2.6 and ≤5.1 were randomized to the PFJ or control group. The PFJ group followed a 16-week lifestyle program based on a whole-food plant-based diet, physical activity and stress management. The control group received usual care. Medication was kept stable 3 months before and during the trial whenever possible. We hypothesized that PFJ would lower disease activity (DAS28). Secondary outcomes included anthropometric, metabolic and patient-reported measures. An intention-to-treat analysis with a linear mixed model adjusted for baseline values was used to analyse between-group differences.

Results

Of the 83 people randomized, 77 completed the study. Participants were 92% female with mean (s.d.) age of 55 (12) years, BMI of 26 (4) kg/m2 and mean DAS28 of 3.8 (0.7). After 16 weeks the PFJ group had a mean 0.9-point greater improvement of DAS28 vs the control group (95% CI 0.4, 1.3; P < 0.0001). The PFJ intervention led to greater decreases in body weight (difference –3.9 kg), fat mass (–2.8 kg), waist circumference (–3 cm), HbA1c (–1.3 mmol/mol) and low-density lipoprotein (–0.32 mmol/l), whereas patient-reported outcome measures, blood pressure, glucose and other lipids did not change.

Conclusion

The 16-week PFJ multidisciplinary lifestyle program substantially decreased disease activity and improved metabolic status in people with RA with low–moderate disease activity.

Trial Registration

International Clinical Trials Registry Platform; https://www.who.int/clinical-trials-registry-platform; NL7800.
Fetal–neonatal and maternal outcomes in women with Sjögren syndrome: a population-based registry linkage study
Authors: Chan Tien-Ming , Wu Chiao-En , Yu Han-Hua , Hsiao Chao-yang , Su Tse-Hsuan , Chen Chun-Bing , Chiou Meng-Jiung , Yu Kuang-Hui , Kuo Chang-Fu
Published: January 2023

Objective

To provide better preconceptional and prenatal counselling to patients with sjögren syndrome (SS).

Methods

In total, 2 100 143 pregnancies between 2004 and 2014 were identified in the Taiwan National Health Insurance database and birth registry. The maternal history of SS was ascertained, and data were compared between pregnant women with and without SS. We assessed the odds ratios and 95% CIs of fetal–neonatal and maternal outcomes.

Results

There were 449 pregnancies in women with SS and 2 099 694 pregnancies in women without SS. The risks of still birth [odds ratio (OR) = 2.14, 95% CI = 1.01, 4.55], low birth weight (<2500 g, OR = 2.53, 95% CI = 1.92, 3.33), small for gestational age (OR = 2.03, 95% CI = 1.57, 2.03) and fetal distress (OR = 1.72, 95% CI = 1.2, 2.45) as well as maternal risks of pulmonary oedema (OR = 11.64, 95% CI = 1.62, 83.48), shock (OR = 6.07, 95% CI = 1.51, 24.3) and respiratory distress (OR = 5.61, 95% CI = 1.39, 22.6) were higher in the SS group than in the non-SS group.

Conclusion

Women with SS have significant risks of adverse fetal–neonatal and maternal outcomes and must undergo prenatal counselling to understand the risks involved before conception.
Sulphated penta-galloyl glucopyranoside (SPGG) is glycosaminoglycan mimetic allosteric inhibitor of cathepsin G
Authors: Al-Horani Rami A , Afosah Daniel K , Kar Srabani , Aliter Kholoud F , Mottamal Madhusoodanan
Published: January 2023

Objective

Cathepsin G (CatG) is a cationic serine protease with wide substrate specificity. CatG is reported to play a role in several inflammatory pathologies. Thus, we aimed at identifying a potent and allosteric inhibitor of CatG to be used as a platform in further drug development opportunities.

Methods

Chromogenic substrate hydrolysis assays were used to evaluate the inhibition potency and selectivity of SPGG towards CatG. Salt-dependent studies, Michaelis–Menten kinetics and SDS-PAGE were exploited to decipher the mechanism of CatG inhibition by SPGG. Molecular modelling was also used to identify a plausible binding site.

Key findings

SPGG displayed an inhibition potency of 57 nM against CatG, which was substantially selective over other proteases. SPGG protected fibronectin and laminin against CatG-mediated degradation. SPGG reduced VMAX of CatG hydrolysis of a chromogenic substrate without affecting KM, suggesting an allosteric mechanism. Resolution of energy contributions indicated that non-ionic interactions contribute ~91% of binding energy, suggesting a substantial possibility of specific recognition. Molecular modelling indicated that SPGG plausibly binds to an anion-binding sequence of 109SRRVRRNRN117.

Conclusion

We present the discovery of SPGG as the first small molecule, potent, allosteric glycosaminoglycan mimetic inhibitor of CatG. SPGG is expected to open a major route to clinically relevant allosteric CatG anti-inflammatory agents.
Polarized Support for Intimate Partner Violence Gun-Related Interventions
Authors: Groggel Anne
Published: January 2023

Social movements pushed to reconceptualize intimate partner violence (IPV) as a social problem deserving of intervention rather than a private family matter. However, little work has examined which interventions the public is likely to support. How and where do personal politics affect perceptions of and responses to a social problem? To address these questions, 739 participants read a victim’s narrative from a court case and indicated their concern for the victim and support for issuing a protection order, prohibiting the abuser from owning a gun, or the victim owning a gun to protect herself. Concern for the victim and support for issuing a protection order was widespread, regardless of political leaning, with minor variations driven by role-taking and attitudes towards IPV. Similarly, support for the victim receiving a protection order was high, with political ideology and political affiliation having no direct effects. While concern increased support for each intervention, it held less explanatory power for gun-related interventions. Instead, political ideology and affiliation shaped support for disarming the abuser or arming the victim. Support for these interventions seemed to filter through a political lens. Thus, one’s personal politics drive divergent intervention attitudes, even when concern for a social problem is shared.
Comparing the Therapeutic Mechanism and Immune Response of Human and Mouse Mesenchymal Stem Cells in Immunocompetent Mice With Acute Liver Failure
Authors: Wang Chang-Hung , Chen Che-Yi , Wang Kai-Hung , Kao An-Pei , Chen Yi-Jou , Lin Pei-Hsuan , Chen Michael , Wu Tung-Yun , Cheng Jing-Jy , Lee Kuan-Der , Chuang Kuo-Hsiang
Published: January 2023

Current mesenchymal stem cell (MSC) research is based on xenotransplantation of human MSCs (hMSCs) in immunodeficient mice and cannot comprehensively predict MSC repair mechanisms and immunomodulatory effects in damaged tissue. This study compared the therapeutic efficacy, mechanisms, and immune response of hMSCs and mouse MSCs (mMSCs) in immunocompetent mice with CCl4-induced acute liver failure. mMSCs maintained F4/80+ hepatic macrophage recruitment into the damaged liver region, increased IL-6-dependent hepatocyte proliferation, and reduced inflammatory TNF-α cytokine secretion. Moreover, mMSCs reduced α-SMA+ myofibroblast activation by lowering TGF-β1 accumulation in damaged liver tissue. In contrast, hMSCs lowered TNF-α and TGF-β1 by reducing the recruitment of F4/80+ hepatic macrophages, which lost the ability to remove debris and induce IL-6 liver regeneration. Finally, hMSCs, but not mMSCs, caused a significant antibody response in immunocompetent mice; therefore, hMSCs are unsuitable for long-term MSC studies. This comparative study provides reference information for further MSC studies of immunocompetent mice.
Effects of Aspergillus oryzae prebiotic on dietary energy and nutrient digestibility of growing pigs
Authors: Zhu Jinlong , Shurson Gerald C , Whitacre Lynsey , Ipharraguerre Ignacio R , Urriola Pedro E
Published: January 2023

The objective of this study was to determine the effects of Aspergillus oryzae prebiotic (AOP) on nutrient digestibility in growing pigs fed high-fiber diets. Eighteen growing barrows (initial body weight = 50.6 ± 4.9 kg) were surgically equipped with a T-cannula at the distal ileum. Corn and soybean meal-based diets were formulated with fiber from cereal grain byproducts corn (distillers dried grains with solubles, DDGS), rice (rice bran, RB), or wheat (wheat middlings, WM) to meet or exceed all nutrient requirements for 50 to 75 kg growing pigs. Three additional diets were formulated to contain 0.05% AOP supplemented at the expense of corn in the DDGS diet (DDGS + AOP), RB diet (RB + AOP), and WM diet (WM + AOP). All diets contained 0.5% of titanium dioxide as an indigestible marker. Pigs were allotted randomly to a triplicated 6 × 2 Youden square design with six diets and two successive periods. Ileal digesta and fecal samples were collected for 2 d after a 21-d adaptation period, and dry matter (DM), gross energy (GE), crude protein (CP), ether extract (EE), neutral detergent fiber (NDF), and ash were analyzed to calculate apparent ileal digestibility (AID) and apparent total tract digestibility (ATTD). Standardized ileal digestibility (SID) of amino acids (AA) was calculated by correcting AID with basal endogenous AA losses from the same set of pigs. Pigs fed the DDGS+AOP diet had greater (P < 0.05) AID of EE compared with those fed the DDGS diet. However, supplementation of AOP did not (P > 0.05) affect AID of GE, DM, CP, NDF, ash or SID of AA of any high-fiber diet. Supplementation of 0.05% AOP increased (P < 0.05) ATTD of DM, GE, CP, NDF, and ash in DDGS, RB, and WM diets. Diet digestible energy was 35 kcal/kg greater (P < 0.05) in pigs fed AOP supplemented diets compared with those fed diets without AOP. In conclusion, supplementation of AOP increased ATTD of nutrients and energy value in high-fiber diets containing DDGS, RB, or WM.
Individual theta-band cortical entrainment to speech in quiet predicts word-in-noise comprehension
Authors: Becker Robert , Hervais-Adelman Alexis
Published: January 2023

Speech elicits brain activity time-locked to its amplitude envelope. The resulting speech-brain synchrony (SBS) is thought to be crucial to speech parsing and comprehension. It has been shown that higher speech-brain coherence is associated with increased speech intelligibility. However, studies depending on the experimental manipulation of speech stimuli do not allow conclusion about the causality of the observed tracking. Here, we investigate whether individual differences in the intrinsic propensity to track the speech envelope when listening to speech-in-quiet is predictive of individual differences in speech-recognition-in-noise, in an independent task. We evaluated the cerebral tracking of speech in source-localized magnetoencephalography, at timescales corresponding to the phrases, words, syllables and phonemes. We found that individual differences in syllabic tracking in right superior temporal gyrus and in left middle temporal gyrus (MTG) were positively associated with recognition accuracy in an independent words-in-noise task. Furthermore, directed connectivity analysis showed that this relationship is partially mediated by top-down connectivity from premotor cortex—associated with speech processing and active sensing in the auditory domain—to left MTG. Thus, the extent of SBS—even during clear speech—reflects an active mechanism of the speech processing system that may confer resilience to noise.
Cryopreserved human precision-cut lung slices provide an immune competent pulmonary test system for “on-demand” use and long-term cultures
Authors: Patel Vivek S , Amin Khalid , Wahab Adam , Marimoutou Méry , Ukishima Lindsey , Alvarez Jose , Battle Kelley , Stucki Andreas O , Clippinger Amy J , Behrsing Holger P
Published: January 2023

Human precision-cut lung slices (hPCLS), considered a highly relevant ex vivo model of the lung, offer native architecture and cells of the lung tissue including respiratory parenchyma, small airways, and immune competent cells. However, the irregular availability of donor lungs has limited the accessibility of this system. As described here, thousands of hPCLS can be created from 1 lung, cryopreserved, and used “on demand” by applying slicing and cryopreservation methodology improvements. Fresh and cryopreserved (∼7 and ∼34 weeks; F&C) hPCLS from 1 donor lung were cultured for up to 29 days and evaluated for biomass, viability, tissue integrity, and inflammatory markers in response to lipopolysaccharide (LPS; 5 µg/ml) and Triton X-100 (TX100; 0.1%) challenge (24 h) at days 1, 8, 15, 22, and 29 following culture initiation. The F&C hPCLS retained biomass, viability, and tissue integrity throughout the 29 days and demonstrated immune responsiveness with up to ∼30-fold LPS-induced cytokine increases. Histologically, more than 70% of normal cytomorphological features were preserved in all groups through day 29. Similar retention of tissue viability and immune responsiveness post cryopreservation (4–6 weeks) and culture (up to 14 days) was observed in hPCLS from additional 3 donor lungs. Banking cryopreserved hPCLS from various donors (and disease states) provides a critical element in researching human-derived pulmonary tissue. The retention of viability and functional responsiveness (≥4 weeks) allows evaluation of long-term, complex endpoints reflecting key events in Adverse Outcome Pathways and positions hPCLS as a valuable human-relevant model for use in regulatory applications.
Arsenic causes distinct gene expression changes in macrophages polarizedin vitrowith either interferon-γ or interleukin-4
Authors: Makhani Kiran , Chiavatti Chris , Negro Silva Luis Fernando , Lemaire Maryse , Bolt Alicia M , De Jay Nicolas , Giles Braeden , Zengin Ayse Nazli , Kleinman Claudia L , Mann Koren K
Published: January 2023

Arsenic exposure is correlated with atherosclerosis in epidemiological studies and in animal models. We have previously shown that arsenic exposure enhanced the atherosclerotic plaque size, increased the plaque lipid content, and decreased the plaque smooth muscle cell and collagen contents in the apolipoprotein E knockout (apoE−/−) mice. However, the percentage of plaque-resident macrophages, the primary drivers of atherosclerosis remained unchanged. Therefore, we hypothesized that although arsenic does not change the quantity of macrophages, it alters the macrophage transcriptome towards a proatherogenic state. To test this hypothesis, we used bone marrow-derived macrophages, polarized them to either interferon-γ (IFN-ɣ) stimulated, proinflammatory or interleukin-4 (IL-4) stimulated, alternatively activated macrophages in the presence or absence of 0.67 µM (50 ppb) arsenic and performed RNA sequencing. Arsenic exposure altered the gene expression of the macrophages in a subtype-specific manner. Most differentially expressed genes (88%) were altered specifically in either IFN-ɣ- or IL-4-stimulated macrophages, whereas in the remaining 12% of genes that changed in both cell types, did so in opposite directions. In IL-4-stimulated macrophages, arsenic significantly downregulated the genes involved in cholesterol biosynthesis and the chemokines CCL17/CCL22, whereas in IFN-ɣ-stimulated macrophages, the genes associated with the liver X receptor (LXR) pathway were downregulated by arsenic. Using a bone marrow transplant experiment, we validated that the deletion of LXRα from the hematopoietic compartment rescued arsenic-enhanced atherosclerosis in the apoE−/− mouse model. Together, these data suggest that arsenic modulates subtype-specific transcriptomic changes in macrophages and further emphasize the need to define macrophage heterogeneity in atherosclerotic plaques in order to evaluate the proatherogenic role of arsenic.
Boron deficiency mediates plant–insect (Diaphorima citri) interaction by disturbing leaf volatile organic compounds and cell wall functions
Authors: Dong ZhiHao , Liu XiaoDong , Srivastava Anoop Kumar , Tan QiLing , Low Wei , Yan Xiang , Wu SongWei , Sun XueCheng , Hu ChengXiao
Published: January 2023

Nutritional enhancement has been reported to effectively relieve infected symptoms of Huanglongbing, one of the most destructive diseases of citrus. However, few studies focused on the role of plant nutrition in citrus plant–vector (Asian citrus psyllid; Diaphorina citri Kuwayama) interactions, which is regarded as an important part to develop an effective management strategy.

Method

In the present study, a hydroponic culture was carried out to evaluate the effects of boron deficiency on psyllid feeding process to decode the molecular/biochemical basis of host–psyllid interaction.

Results

Boron deficiency was observed to play a major role in accelerating the release of volatile organic compounds, especially methyl salicylate, affecting the shikimic acid pathway through an elevated synthesis of shikimic acid, l-phenylalanine, 3-phenylpyruvic acid and salicylic acid. These changes made citrus leaf more attractive to psyllid adults. Meanwhile, boron deficiency evidently decreased the boron concentration of leaf cell wall fractions, thereby, weakened the structural stability by affecting pectin and cellulose formations. A significant decrease of cell wall mechanical strength was observed in boron-deficiency leaf, which could be the critical reasons to reduce piercing and to increase phloem ingestion during psyllid feeding.

Conclusion

Our study demonstrated that boron deficiency facilitated the feeding behavior of psyllid adults through elevated release of methyl salicylate, coupled with weakened mechanical properties of cell wall.
Spatiotemporal, physiological and transcriptomic dynamics of wild jujube seedlings under saline conditions
Authors: He Aobing , Ma Zhibo , Li Yunfei , Huang Chen , Yong Jean Wan Hong , Huang Jian
Published: January 2023

Soil salinity is a major constraint limiting jujube production in China. Wild jujube (Ziziphus jujuba var. spinosa (Bunge) Hu ex H. F. Chow) is widely used as the rootstock of jujube (Z. jujuba) to overcome the saline conditions. To understand the adaptive mechanism in wild jujube under saline conditions, we combined spatiotemporal and physiological assessments with transcriptomic analysis on wild jujube seedlings undergoing various salt treatments. These salt treatments showed dose and duration effects on biomass, photosynthesis, (K+) and (Na+) accumulation. Salt treatments induced higher levels of salicylic acid in roots and leaves, whereas foliar abscisic acid was also elevated after 8 days. The number of differential expression genes increased with higher doses and also longer exposure of NaCl treatments, with concomitant changes in the enriched Gene Ontology terms that were indicative of altered physiological activities. Gene co-expression network analysis identified the core gene sets associated with salt-induced changes in leaves, stems and roots, respectively. The nitrogen transporters, potassium transporters and a few transcription factors belonging to WRKY/MYB/bHLH families were clustered as the hub genes responding to salt treatments, which were related to elevated nitrogen and K+/Na+. Ectopic overexpression of two WRKY transcription factor genes (ZjWRKY6 and ZjWRKY65) conferred stronger salt-tolerance in Arabidopsis thaliana transformants by enhancing the activities of antioxidant enzymes, decreasing malondialdehyde accumulation and maintaining K+/Na+ homeostasis. This study provided evidence about the spatiotemporal, physiological and transcriptomic dynamics of wild jujube during salt stress and identified potential genes for further research to improve salt tolerance in jujube.
Leaf sodium homeostasis controlled by salt gland is associated with salt tolerance in mangrove plant Avicennia marina
Authors: Guo Zejun , Wei Ming-Yue , Zhong You-Hui , Wu Xuan , Chi Bing-Jie , Li Jing , Li Huan , Zhang Lu-Dan , Wang Xiu-Xiu , Zhu Xue-Yi , Zheng Hai-Lei
Published: January 2023

Avicennia marina, a mangrove plant growing in coastal wetland habitats, is frequently affected by tidal salinity. To understand its salinity tolerance, the seedlings of A. marina were treated with 0, 200, 400 and 600 mM NaCl. We found the whole-plant dry weight and photosynthetic parameters increased at 200 mM NaCl but decreased over 400 mM NaCl. The maximum quantum yield of primary photochemistry (Fv/Fm) significantly decreased at 600 mM NaCl. Transmission electron microscopy observations showed high salinity caused the reduction in starch grain size, swelling of the thylakoids and separation of the granal stacks, and even destruction of the envelope. In addition, the dense protoplasm and abundant mitochondria in the secretory and stalk cells, and abundant plasmodesmata between salt gland cells were observed in the salt glands of the adaxial epidermis. At all salinities, Na+ content was higher in leaves than in stems and roots; however, Na+ content increased in the roots while it remained at a constant level in the leaves over 400 mM NaCl treatment, due to salt secretion from the salt glands. As a result, salt crystals on the leaf adaxial surface increased with salinity. On the other hand, salt treatment increased Na+ and K+ efflux and decreased H+ efflux from the salt glands by the non-invasive micro-test technology, although Na+ efflux reached the maximum at 400 mM NaCl. Further real-time quantitative PCR analysis indicated that the expression of Na+/H+ antiporter (SOS1 and NHX1), H+-ATPase (AHA1 and VHA-c1) and K+ channel (AKT1, HAK5 and GORK) were up-regulated, and only the only Na+ inward transporter (HKT1) was down-regulated in the salt glands enriched adaxial epidermis of the leaves under 400 mM NaCl treatment. In conclusion, salinity below 200 mM NaCl was beneficial to the growth of A. marina, and below 400 mM, the salt glands could excrete Na+ effectively, thus improving its salt tolerance.
The longitudinal evaluation of COVID-19 in pediatric patients and the impact of delta variant
Authors: Arslan Asli , Sahbudak Bal Zumrut , Yildirim Arslan Sema , Bilen Nimet Melis , Guner Ozenen Gizem , Yazıcı Özkaya Pınar , Yurtseven Ali , Çiçek Candan , Durusoy İsabel Raika , Ozkinay Ferda , Kurugol Zafer
Published: January 2023

Background

Pediatric patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displayed milder symptoms than adults. However, they play an important role in case numbers and virus transmission. Therefore, we aimed to determine the epidemiological features of all pediatric patients infected with SARS-CoV-2 and put forth case numbers longitudinally throughout the delta variant dominant period.

Methods

A retrospective study was conducted at a university hospital and included patients between 0 and18 years old with a SARS-CoV-2 polymerase chain reaction (PCR) positive result, including inpatients and outpatients. Epidemiological and clinical features were recorded from electronic files, and telephone visits were performed between March 2020 and December 2021.

Results

During the study period, 3175 coronavirus disease 2019 (COVID-19) pediatric patients were admitted to our hospital with a mean age of 10.61 ± 4.6 years. Of the 1815 patients who could be interviewed, 85.7% reported at least one symptom. Before the delta variant period, 0–4 years aged children were more commonly infected, while school-aged children and adolescents were more common, and the rate of pediatric cases to all COVID-19 cases increased to 35.8% after the delta variant became dominant. Symptomatic cases were significantly higher before the delta variant (87.8% vs. 84.06%, p = 0.016). The hospitalization rate was higher before the delta variant (p < 0.001), whereas PICU admission showed no statistical difference.

Conclusions

The frequency of school-aged children and adolescents raised with the impact of both school openings and the delta variant, and the rate of pediatric cases increased in total COVID-19 patient numbers.
Decomplexation proteomic analysis and purity assessment of a biologic for snakebite envenoming: Philippine Cobra Antivenom
Authors: Palasuberniam Praneetha , Tan Kae Yi , Chan Yi Wei , Blanco Francis Bonn , Tan Choo Hock
Published: January 2023

Background

Philippine Cobra Antivenom (PCAV) is the only snake antivenom manufactured in the Philippines. It is used clinically to treat envenoming caused by the Philippine Spitting Cobra (Naja philippinensis). While PCAV is effective pharmacologically, it is crucial to ensure the safety profile of this biologic that is derived from animal plasma.

Methods

This study examined the composition purity of PCAV through a decomplexation proteomic approach, applying size-exclusion chromatography (SEC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and tandem mass spectrometry liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results

SDS-PAGE and SEC showed that the major protein in PCAV (constituting ∼80% of total proteins) is approximately 110 kDa, consistent with the F(ab’)2 molecule. This protein is reducible into two subunits suggestive of the light and heavy chains of immunoglobulin G. LC-MS/MS further identified the proteins as equine immunoglobulins, representing the key therapeutic ingredient of this biologic product. However, protein impurities, including fibrinogens, alpha-2-macroglobulins, albumin, transferrin, fibronectin and plasminogen, were detected at ∼20% of the total antivenom proteins, unveiling a concern for hypersensitivity reactions.

Conclusions

Together, the findings show that PCAV contains a favorable content of F(ab’)2 for neutralization, while the antibody purification process awaits improvement to minimize the presence of protein impurities.
A prospective study of snakebite in a tertiary care hospital in south-western Nepal
Authors: Pandey Deb Prasad , Shrestha Bhola Ram , Acharya Krishna Prasad , Shah Khagendra Jang , Thapa-Magar Chhabilal , Dhakal Ishwari Prasad , Mohamed Fahim , Isbister Geoffrey K
Published: January 2023

Background

Snakebite is a neglected public health issue in Nepal. We aimed to characterize patients with snake envenoming admitted to hospital in south-western Nepal.

Methods

This was a prospective cohort study of 476 snakebite patients admitted to Bheri Hospital from May to December 2017. Data were collected on patient demographics, bite circumstances, snake type, treatment-seeking behavior, clinical effects, complications and treatment.

Results

There were 139/476 (29%) patients with clinical features of envenomation and 10 deaths (8%), of which six were prehospital deaths; 325/476 (68%) patients used non-recommended prehospital first aid, including 278 (58%) who applied a tourniquet and 43 (9%) consulting traditional healers. Median time to hospital arrival was 1.5 (IQR: 0.8–4) h. Also, 127 envenomated patients (91%) developed neurotoxicity and 12 (9%) hemotoxicity, while 124 patients (89%) received antivenom, with a median dose of 10 (4–30) vials. Three patients developed anaphylaxis following antivenom administration; 111 of 139 (80%) cases were admitted to the ICU and 48 (35%) were intubated. Median length of hospital stay for all cases was 0.5 (IQR: 0.5–1.2) d, but it was 2.2 (IQR: 1.5–3.8) d for envenomated cases.

Conclusions

The majority of snakebite patients used non-recommended first aid or attended traditional healers. Almost one-third of patients developed systemic envenomation and required antivenom. The case fatality rate was high, but many died prior to arriving in hospital.