bluuebunny/crossref_metadata_2025 huggingface dataset:
Kinetoplastid‐specific X2‐family kinesins interact with a kinesin‐like pleckstrin homology domain protein that localizes to the trypanosomal microtubule quartet
Authors: Benz Corinna , Müller Nora , Kaltenbrunner Sabine , Váchová Hana , Vancová Marie , Lukeš Julius , Varga Vladimír , Hashimi Hassan
Published: June 2022

Kinesins are motor proteins found in all eukaryotic lineages that move along microtubules to mediate cellular processes such as mitosis and intracellular transport. In trypanosomatids, the kinesin superfamily has undergone a prominent expansion, resulting in one of the most diverse kinesin repertoires that includes the two kinetoplastid‐restricted families X1 and X2. Here, we characterize in Trypanosoma brucei TbKifX2A, an orphaned X2 kinesin. TbKifX2A tightly interacts with TbPH1, a kinesin‐like protein with a likely inactive motor domain, a rarely reported occurrence. Both TbKifX2A and TbPH1 localize to the microtubule quartet (MtQ), a characteristic but poorly understood cytoskeletal structure that wraps around the flagellar pocket as it extends to the cell body anterior. The proximal proteome of TbPH1 revealed two other interacting proteins, the flagellar pocket protein FP45 and intriguingly another X2 kinesin, TbKifX2C. Simultaneous ablation of TbKifX2A/TbPH1 results in the depletion of FP45 and TbKifX2C and also an expansion of the flagellar pocket, among other morphological defects. TbKifX2A is the first motor protein to be localized to the MtQ. The observation that TbKifX2C also associates with the MtQ suggests that the X2 kinesin family may have co‐evolved with the MtQ, both kinetoplastid‐specific traits.
The activity of the RGA5 sensor NLR from rice requires binding of its integrated HMA domain to effectors but not HMA domain self‐interaction
Authors: Xi Yuxuan , Chalvon Véronique , Padilla André , Cesari Stella , Kroj Thomas
Published: June 2022

The rice nucleotide‐binding (NB) and leucine‐rich repeat (LRR) domain immune receptors (NLRs) RGA4 and RGA5 form a helper NLR/sensor NLR (hNLR/sNLR) pair that specifically recognizes the effectors AVR‐Pia and AVR1‐CO39 from the blast fungus Magnaporthe oryzae. While RGA4 contains only canonical NLR domains, RGA5 has an additional unconventional heavy metal‐associated (HMA) domain integrated after its LRR domain. This RGA5HMA domain binds the effectors and is crucial for their recognition. Investigation of the three‐dimensional structure of the AVR1‐CO39/RGA5HMA complex by X‐ray crystallography identified a candidate surface for effector binding in the HMA domain and showed that the HMA domain self‐interacts in the absence of effector through the same surface. Here, we investigated the relevance of this HMA homodimerization for RGA5 function and the role of the RGA5HMA effector‐binding and self‐interaction surface in effector recognition. By analysing structure‐informed point mutations in the RGA5HMA‐binding surface in protein interaction studies and in Nicotiana benthamiana cell death assays, we found that HMA self‐interaction does not contribute to RGA5 function. However, the effector‐binding surface of RGA5HMA identified by X‐ray crystallography is crucial for both in vitro and in vivo effector binding as well as effector recognition. These results support the current hypothesis that noncanonical integrated domains of NLRs act primarily as effector traps and deepen our understanding of the sNLRs' function within NLR pairs.
Autoimmunity to ion channels in neurological diseases–Autoimmunity to aquaporin water channels
Authors: Tanaka Keiko , Nagaishi Akiko , Matsui Makoto
Published: June 2022

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease in which the majority of patients have autoantibodies against the aquaporin‐4 (AQP4) water channel. In the central nervous system (CNS), AQP4 is expressed on the cell membrane of astrocytes, and anti‐AQP4 antibodies harm AQP4 expressing astrocytes, resulting in astrocytopathy. The majority of patients are female and have acute visual disturbances and transverse myelitis, as well as brainstem and other cerebral lesions. These symptoms are frequently severe and develop quickly, resulting in substantial impairment in daily life. Patients are treated with high‐dose methylprednisolone infusions, plasma exchange, and intravenous immunoglobulin administration during the acute stage. Based on the pathogenesis of NMOSD, various effective relapse‐preventing therapies have emerged in recent years. The majority of them have been proved to have a positive impact on the patients who have been treated. They increased the number of therapy options available, albeit long‐term efficacy and safety would need to be monitored for a longer period. Through its unique fluid transport function in the CNS, knowledge of the functions of AQP4 has grown in the field of not only inflammatory disorders like NMOSD, but also other neurodegenerative disorders like Alzheimer's disease.
Evening blue‐light exposure, maternal glucose, and infant birthweight
Authors: Izci Balserak Bilgay , Hermann Renata , Hernandez Teri L. , Buhimschi Catalin , Park Chung
Published: June 2022

Maternal–fetal consequences of exposure to blue‐wavelength light are poorly understood. This study tested the hypothesis that evening blue‐light exposure is associated with maternal fasting glucose and infant birthweight. Forty‐one pregnant women (body mass index = 32.90 ± 6.35 kg/m2; 24–39 years old; 16 with gestational diabetes mellitus [GDM]) wore actigraphs for 7 days, underwent polysomnography, and completed study questionnaires during gestational week 30 ± 3.76. Infant birthweight (n = 41) and maternal fasting glucose (n = 30; range = 16–36 weeks) were recorded from the mothers’ medical charts. Blue‐light exposure was obtained from Actiwatch‐Spectrum recordings. Adjusted and unadjusted linear regression analyses were performed to determine sleep characteristics associated with maternal fasting glucose and infant‐birthweight. The mean fasting mid‐ to late‐gestation glucose was 95.73 ± 24.68 mg/dl and infant birthweight was 3271 ± 436 g. In unadjusted analysis, maternal fasting glucose was associated with blue‐light exposure (β = 3.82, p = 0.03). In the final model of multiple linear regression for fasting glucose, evening blue‐light exposure (β = 4.00, p = 0.01) remained significant after controlling for gestational weight gain, parity, sleep duration, and GDM. Similarly, blue‐light exposure was associated with infant birthweight (69.79, p = 0.006) in the unadjusted model, and remained significant (β = 70.38, p = 0.01) after adjusting for weight gain, wakefulness after sleep onset, gestational age at delivery, and GDM. Higher blue‐light exposure in pregnancy is associated with higher fasting glucose and infant birthweight. Reduced use of electronic devices before bedtime is a modifiable behavior.
Involvement of ferroptosis in Porphyromonas gingivalis lipopolysaccharide‐stimulated periodontitis in vitro and in vivo
Authors: Qiao Shuwei , Li Baosheng , Cai Qing , Li Zhen , Yin Zhaoyi , He Jie , Li Yuyang , Meng Weiyan
Published: June 2022

Objectives

Ferroptosis is associated with multiple inflammatory diseases. Periodontitis is an inflammatory disease mainly caused by oral opportunistic pathogens. However, the ferroptosis–periodontitis relationship has not been thoroughly described. We here analyzed whether ferroptosis is involved in periodontitis.

Materials and methods

Human gingival fibroblasts (HGFs) were stimulated with P. gingivalis‐LPS and ferrostatin‐1 (Fer‐1, a ferroptosis inhibitor), and changes in mitochondrial morphology, ferroptosis‐related factors, and inflammation levels were detected. After the rat experimental periodontitis model was established, changes in ferroptosis‐related factors and inflammation levels were re‐evaluated in the same manner.

Results

Porphyromonas gingivalis‐LPS‐induced mitochondrial shrinkage, an increase in mitochondrial membrane density, and upregulation of reactive oxygen species in HGFs. The expression of prostaglandin‐endoperoxide synthase 2, transferrin receptor 1, and malondialdehyde and inflammation levels were upregulated, whereas the expression of solute carrier family seven member 11, glutathione peroxidase 4, superoxide dismutase, and glutathione were downregulated. Fer‐1 attenuated these aforementioned changes and inflammation levels induced by P. gingivalis‐LPS. The in vivo experiment results were consistent with the in vitro experiment results.

Conclusions

Ferroptosis is involved in inflammatory processes in HGFs upon P. gingivalis‐LPS stimulation. Ferroptosis is observed in the gingival tissue of periodontitis rats.
Epidemiologic Correlation and Drug Resistance Analysis of Pathogenic Bacteria in Different Open Limb Injury External Conditions
Authors: Xie Bang‐lin , Guo Run‐sheng , Liang Wen , Yang Xiao‐wei , Xu Jia‐Qiang , Wan Li‐jun , Yao Wen‐ye , Yi Zhi , Hu Ni‐ya , Zhang Bin
Published: June 2022

Objective

To study the epidemiological correlation and drug resistance of external factors of infection caused by open injury of limbs to pathogens.

Methods

This experiment is a retrospective study. We took the geographical location and climate of Nanchang, Jiangxi Province, China as the background, analyzed 2017 strains of pathogens from 1589 patients with limb trauma infection in a University Affiliated Hospital from 2012 to 2017. Patients were divided into three groups according to the type of incision: I, In‐hospital infection of clean limb incision, II, In‐hospital infection with open injury, III, Community infection with open injury of the limb. Groups II and Groups III were divided into six subgroups according to the causes of trauma, including: accidents from non‐motor vehicles, machinery, cutting/piercing, pedestrian injuries, struck by/against, pedal cycles, and other injuries. We found eight common pathogens of orthopedic infection, which were mainly divided into Gram‐positive bacteria (G+, mainly including Staphylococcus) and Gram‐negative bacteria (G‐, mainly Enterobacteriaceae). The relationship between main pathogens and damage mechanism, apparent temperature and relative humidity was discussed in this study. SPSS v22.0 was used for statistical analysis of the data. Friedman's two‐way ANOVA was used to analyze the difference between the injury mechanism and incidence of pathogenic bacteria. Linear regression was used to determine the trend between the incidence of major pathogens and seasonal temperature and humidity. The level of significance was set as P < 0.05.

Results

There was no significant difference in the distribution of pathogens between Groups II and Groups III (P>0.05). The drug resistance of Groups III was significantly higher than that of Groups II and Groups I. G+ bacteria were resistant to cephalosporin, ceftriaxone and other cephalosporins and erythromycin and other macrolides. They were sensitive to vancomycin and linezolid. G‐ were resistant to the first‐ and the second‐generation cephalosporins, including cefotetan and cefazolin, and ampicillin and other penicillins, while they were sensitive to third‐generation cephalosporins, such as ceftazidime, as well as to levofloxacin and other quinolones, meropenem, and other beta‐lactamases. The correlation between the injury mechanism and infection of pathogenic bacteria was not significant. The monthly average apparent temperature and relative humidity were correlated with the infection rate of pathogenic bacteria.

Conclusion

In open injury of extremities, apparent temperature and relative humidity is an important risk factor for infection by pathogenic bacteria and the drug resistance of pathogenic bacteria in out‐of‐hospital infection was lower than that of hospital infection.
Long‐term outcomes of a time to isolation – based strategy for cryoballoon ablation compared to radiofrequency ablation in patients with symptomatic paroxysmal atrial fibrillation
Authors: Wei Yue , Chen Lin , Cao Jiang , Liu Shaowen , Ling Tianyou , Huang Xinmiao , Zhou Genqing , Lin Changjian , Xie Yun , Bao Yangyang , Luo Qingzhi , Ye Jiawen , Zhang Ning , Jin Qi , Wu Liqun
Published: June 2022

Background

Cryoballoon ablation (CBA) is one of the most commonly used technologies designed for pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF), although the dosing of CBA remains controversial. We evaluated the long‐term efficacy and safety of a novel individualized strategy of CBA compared to radiofrequency ablation (RFA) for patients with PAF.

Methods

In this observational study, symptomatic patients with drug‐refractory paroxysmal AF were prospectively consented and enrolled in four centers, being assigned either to the CBA or RFA arm for ablation. In the CBA group, we used a time to isolation (TTI) – based dosing protocol. The primary endpoint was the recurrence of atrial arrhythmia >30 s following a 90‐day blanking period. The secondary endpoint was procedure‐related complications and procedure parameters.

Results

A total of 500 patients were recruited in either the CBA group (n = 247) or the RFA group (n = 253) between January 2017 and July 2018. After a median follow‐up of 778 days, the atrial tachyarrhythmia‐free survival was 71.7% in the CBA group and 67.0% in the RFA group. CBA and RFA displayed similar major or minor complication occurrence, while the former had a significantly shorter procedure duration (82.5 min vs. 141.1 min, p < .001) and left atrial dwell time (60.1 min vs. 109.9 min, p < .001) but longer fluoroscopy exposure (13.8 min vs. 8.1 min, p < .001).

Conclusion

Compared to RFA, our TTI‐based CBA dosing protocol showed comparable efficacy and safety, with a significantly reduced procedure duration in patients with PAF.
The earliest enzyme replacement for infantile‐onset Pompe disease in Japan
Authors: Tocan Vlad , Mushimoto Yuichi , Kojima‐Ishii Kanako , Matsuda Akane , Toda Naoko , Toyomura Daisuke , Hirata Yuichiro , Sanefuji Masafumi , Sawada Takaaki , Sakai Yasunari , Nakamura Kimitoshi , Ohga Shouichi
Published: June 2022

Background

Infantile‐onset Pompe disease (IOPD) is the most severe phenotype of a lysosomal storage disorder caused by acid alpha‐glucosidase (GAA) deficiency. An enzymatic newborn screening (NBS) program started regionally in Japan in 2013 for early enzyme replacement therapy (ERT). We report the ERT responses of the first NBS‐identified Japanese IOPD case and of another case diagnosed prior to NBS, to discuss the problems of promptly starting ERT in Japan.

Methods

Acid alpha‐glucosidase activity was measured by fluorometric assay in both patients. The diagnosis of IOPD was confirmed by next‐generation followed by Sanger‐method sequencing (patient 1) or direct sequencing of polymerase chain reaction (PCR)‐amplified products (patient 2) of the GAA gene.

Results

A female infant identified by NBS had a novel out‐of‐frame (p.F181Dfs*6) variant and a reported pathogenic (p.R600C) variant, along with two pseudodeficiency variants. Enzyme replacement therapy was started at age 58 days when the infant had increased serum levels of creatine kinase and slight myocardial hypertrophy. Clinical and biochemical markers improved promptly. She has been alive and well without delayed development at age 14 months. Patient 2, a Japanese male, received a diagnosis of IOPD at age 5 months before the NBS era. He had a homozygotic variant of GAA (p.R608X), later registered as a cross‐reactive immunological material (CRIM)‐negative genotype, and developed a high titer of anti‐rhGAA antibodies. The patient has survived myocardial hypertrophy with continuous respiratory support for 12 years of ERT.

Conclusions

Enzyme replacement therapy should not be delayed over the age of 2 months for reversible cardiac function, although CRIM‐negative cases may hamper turnaround time reduction.
Ventricular depolarization and repolarization variability in children with type 1 diabetes mellitus
Authors: Bezen Diğdem , Türkmenoğlu Yelda , İrdem Ahmet
Published: June 2022

Background

Arrhythmias can be seen as a sign of cardiac autonomic neuropathy in type 1 diabetes mellitus. We aimed to evaluate pulmonary artery pressure, ventricular depolarization and repolarization variability in children with type 1 diabetes mellitus.

Methods

We investigated 78 children with type 1 diabetes mellitus (mean age 11.6 ± 3.6 years) and 68 age‐gender matched healthy children as control group. All type 1 diabetes mellitus patients were divided into three subgroups according to glycated hemoglobin (HbA1c) levels and the duration of disease. Electrocardiogram and transthoracic echocardiograms were performed on both groups.

Results

In patients with type 1 diabetes mellitus, there was an elongation in P, Pd, PR, QTc, QTd, QTcd, JT, JTc, JTd, Tp‐Te and Tp‐Te/QT, Tp‐Te/QTc, Tp‐Te/JT, Tp‐Te/JTc ratios were higher (P < 0.05). In patients with type 1 diabetes mellitus, pulmonary artery pressure was higher than control group (P = 0.001). Prolongation of QTc, thickness of left ventricle end‐diastolic diameter and left ventricle posterior wall diameter were higher in the HbA1c ≥9% subgroup. When adjusted for age there was no significant correlation between left ventricle parameters and HbA1c.

Conclusions

Atrial conduction delay and impairment of ventricular repolarization were significantly high and there was a predisposition for the development of pulmonary artery hypertension in children with type 1 diabetes mellitus. Poor glycemic control was not a risk factor for propensity of left ventricle hypertrophy and left ventricle dysfunction.
Higher quality rather than superior quantity of oocytes determine the amount of fertilizable oocytes in two outbred Dummerstorf high‐fertility mouse lines
Authors: Calanni‐Pileri Michela , Weitzel Joachim M. , Langhammer Martina , Michaelis Marten
Published: June 2022

Dummerstorf fertility lines FL1 and FL2 represent two models of enhanced fertility characterized by the doubling of the litter size compared with an unselected control population (ctrl line, Dummerstorf FztDU). Both biodiverse FLs managed to reach this goal by increasing the ovulation rate per cycle, even showing decreased pregnancy rate and irregular oestrous cycle and metabolic hormone levels, compared with ctrl. The aim of the present study was to analyse oocytes in terms of quality and quantity by comparing the entire pool of oocytes per ovary, with those from the antral follicles within the same animal. We performed Brilliant Cresyl Blue staining as a non‐invasive marker of oocyte quality in combination with an analysis of additional morphological indicators, e.g. cytoplasm clarity, cumulus cell layers, nuclear anatomy, size and shape. We compared our fertility lines with the unselected control population and with another independent line selected from the same founder population, showing lower litter size (DU6P). Our results suggest that fertility lines show decreased number of oocytes per ovary compared with DU6P but increased number of high‐quality oocytes before ovulation. Hence, the raise in the ovulation rate and litter size of those super fertile mouse lines are not associated with an increased number of oocytes per ovary but rather with an increased number of higher quality fertilizable oocytes per cycle. In addition, the most conspicuous method to acquire oocytes with the highest quality in our lines is to assess their morphology, rather than their status after staining. All these discoveries together may be of fundamental importance for further studies in livestock farm animals showing some similar characteristics, e.g. irregular cycle or hormonal misbalances, to improve production while lowering costs, and in humans to increase the possibilities of successful pregnancies for couples undergoing in vitro fertilization (IVF).
Justifying a presumed standing for environmental NGOs: A legal assessment of Article 9(3) of the Aarhus Convention
Authors: Danthinne Audrey , Eliantonio Mariolina , Peeters Marjan
Published: June 2022

The Aarhus Convention is a well‐known cornerstone of environmental law on the European continent. Nevertheless, interpretative dilemmas have arisen, particularly in relation to access to justice for environmental nongovernmental organizations (ENGOs). More precisely, while the standing criterion in Article 9(2) of the Convention is formulated in a rather precise and generous way for ENGOs, the standing criterion in Article 9(3) has been deliberately kept vague and makes no reference to ENGOs. In the meantime, some courts, both at the national and European Union (EU) level, have linked the scope ratione personae of Article 9(2) to that of Article 9(3), thus recognizing a presumed and therefore generous standing for ENGOs under both provisions. Because the Aarhus Convention explicitly provides for such an advantageous presumption only under Article 9(2), this article seeks to assess whether these remarkable judicial interpretations nonetheless find a convincing basis in EU law or in the Aarhus Convention respectively.
Novel insights into the biological pathways involved in severe asthma
Authors: Perez‐Garcia Javier , Pino‐Yanes Maria
Published: June 2022

See related article
Coastal proximity and individual living standards: Econometric evidence from georeferenced household surveys in sub‐Saharan Africa
Authors: Wild Frederik , Stadelmann David
Published: June 2022

We investigate georeferenced household‐level data consisting of up to 128,609 individuals living in 11,261 localities across 17 coastal sub‐Saharan African countries over 20 years. We analyze the relevance of coastal proximity, measured by the geographic distance to harbors, as a predictor of individual economic living standards. Our setting allows us to account for country‐time fixed effects as well as individual‐specific controls. Results reveal that individuals living further away from the coast are significantly poorer, measured along an array of welfare indicators. Our findings are robust to the inclusion of other geographic covariates of development such as climate (e.g., temperature, precipitation) or terrain conditions (e.g., ruggedness, land suitability). We also explore mechanisms through which coastal proximity may matter for individual welfare and decompose the estimated effect of coastal proximity via formal mediation analysis. Our results highlight the role of human capital, urbanization, and infrastructural endowments in explaining within‐country differences in individual economic welfare.
Stressful life events: Typology of aggression and mistreatment in male perpetrators of gender‐based violence
Authors: Rivas‐Rivero Esther , Bonilla‐Algovia Enrique
Published: June 2022

The objective of this study was to analyze groups based on the stressful life events suffered and to know the relationship of these profiles with the type of abuse exercised against women in the couple. A sample of 118 heterosexual men who perpetrated gender‐based violence was used, with a mean age of 40.46 years (SD = 11.14). The results show that those who suffered a greater number of adverse experiences abused their partners more frequently and with a more aggravated character. In addition, knowing typologies based on previous stressful life events could favor specific interventions in the elimination of the normalization of violence as a maladaptive relational strategy. It is necessary to continue investigating the characteristics of men who exercise gender‐based violence, as well as to analyze previous exposure to violence in the family of origin due to the influence it exerts on subsequent abuse.
JrWRKY21 interacts with JrPTI5L to activate the expression of JrPR5L for resistance to Colletotrichum gloeosporioides in walnut
Authors: Zhou Rui , Dong Yuhui , Liu Xia , Feng Shan , Wang Changxi , Ma Xinmei , Liu Jianning , Liang Qiang , Bao Yan , Xu Shengyi , Lang Xinya , Gai Shasha , Yang Ke Qiang , Fang Hongcheng
Published: June 2022

Walnut (Juglans regia L.) anthracnose, induced by Colletotrichum gloeosporioides, is a catastrophic disease impacting the walnut industry in China. Although WRKY transcription factors play a key role in plant immunity, the function of the WRKY gene family in walnut resistance to C. gloeosporioides is not clear. Here, through transcriptome sequencing and quantitative real‐time polymerase chain reaction (qRT‐PCR), we identified a differentially expressed gene, JrWRKY21, that was significantly upregulated upon C. gloeosporioides infection in walnut. JrWRKY21 positively regulated walnut resistance to C. gloeosporioides, as demonstrated by virus‐induced gene silencing and transient gene overexpression. Additionally, JrWRKY21 directly interacted with the transcriptional activator of the pathogenesis‐related (PR) gene JrPTI5L in vitro and in vivo, and could bind to the W‐box in the JrPTI5L promoter for transcriptional activation. Moreover, JrPTI5L could induce the expression of the PR gene JrPR5L through binding to the GCCGAC motif in the promoter. Our data support that JrWRKY21 can indirectly activate the expression of the JrPR5L gene via the WRKY21–PTI5L protein complex to promote resistance against C. gloeosporioides in walnut. The results will enhance our understanding of the mechanism behind walnut disease resistance and facilitate the genetic improvement of walnut by molecular breeding for anthracnose‐resistant varieties.
Assessing central and peripheral respiratory chemoreceptor interaction in humans
Authors: Milloy Kristin M. , White Matthew G. , Chicilo Janelle O. C. , Cummings Kevin J. , Pfoh Jamie R. , Day Trevor A.
Published: June 2022

New Findings

What is the central question of this study?

We investigated the interaction between central and peripheral respiratory chemoreceptors in healthy, awake human participants by using a background of step increases in steady‐state normoxic fraction of inspired carbon dioxide to alter central chemoreceptor activation and by using the transient hypoxia test to target the peripheral chemoreceptors.

What is the main finding and its importance?

Our data suggest that the interaction between central and peripheral respiratory chemoreceptors is additive in minute ventilation and respiratory rate, but hypo‐additive in tidal volume. Our study adds important new data in reconciling chemoreceptor interaction in awake healthy humans and is consistent with previous reports of simple addition in intact rodents and humans.

Arterial blood gas levels are maintained through respiratory chemoreflexes, mediated by central chemoreceptors in the CNS and peripheral chemoreceptors located in the carotid bodies. The interaction between central and peripheral chemoreceptors is controversial, and few studies have investigated this interaction in awake, healthy humans, owing, in part, to methodological challenges. We investigated the interaction between the central and peripheral chemoreceptors in healthy humans using a transient hypoxia test (three consecutive breaths of 100% N2; TT‐HVR), which targets the temporal domain and stimulus specificity of the peripheral chemoreceptors. The TT‐HVRs were superimposed upon three randomized background levels of steady‐state inspired fraction of normoxic CO2(; 0, 0.02 and 0.04). Chemostimuli [calculated oxygen saturation ()] and respiratory variable responses [respiratory rate (RR), inspired tidal volume (VTI) and ventilation ()] were averaged from all three TT‐HVR trials at each level. Responses were assessed as: (1) a change (∆) from baseline; and (2) indexed against . Aside from a significantly lower ∆VTI response in 0.04 (P = 0.01), the hypoxic rate responses (∆RR or ∆RR/; P = 0.46 and P = 0.81), hypoxic tidal volume response (; P = 0.08) and the hypoxic ventilatory responses ( and ; P = 0.09 and P = 0.31) were not significantly different across trials. Our data suggest simple addition between central and peripheral chemoreceptors in , which is mediated through simple addition in RR responses, but hypo‐addition in VTI responses. Our study adds important new data in reconciling chemoreceptor interaction in awake, healthy humans and is consistent with previous reports of simple addition in intact rodents and humans.
ParB proteins can bypass DNA-bound roadblocks via dimer-dimer recruitment
Authors: Tišma Miloš , Panoukidou Maria , Antar Hammam , Soh Young-Min , Barth Roman , Pradhan Biswajit , Barth Anders , van der Torre Jaco , Michieletto Davide , Gruber Stephan , Dekker Cees
Published: June 2022

The ParAB
S
system is essential for prokaryotic chromosome segregation. After loading at
parS
on the genome, ParB (partition protein B) proteins rapidly redistribute to distances of ~15 kilobases from the loading site. It has remained puzzling how this large-distance spreading can occur along DNA loaded with hundreds of proteins. Using in vitro single-molecule fluorescence imaging, we show that ParB from
Bacillus subtilis
can load onto DNA distantly of
parS
, as loaded ParB molecules themselves are found to be able to recruit additional ParB proteins from bulk. Notably, this recruitment can occur in cis but also in trans, where, at low tensions within the DNA, newly recruited ParB can bypass roadblocks as it gets loaded to spatially proximal but genomically distant DNA regions. The data are supported by molecular dynamics simulations, which show that cooperative ParB-ParB recruitment can enhance spreading.
ParS
-independent recruitment explains how ParB can cover substantial genomic distance during chromosome segregation, which is vital for the bacterial cell cycle.
The central clock suffices to drive the majority of circulatory metabolic rhythms
Authors: Petrus Paul , Smith Jacob G. , Koronowski Kevin B. , Chen Siwei , Sato Tomoki , Greco Carolina M. , Mortimer Thomas , Welz Patrick-Simon , Zinna Valentina M. , Shimaji Kohei , Cervantes Marlene , Punzo Daniela , Baldi Pierre , Muñoz-Cánoves Pura , Sassone-Corsi Paolo , Aznar Benitah Salvador
Published: June 2022

Life on Earth anticipates recurring 24-hour environmental cycles via genetically encoded molecular clocks active in all mammalian organs. Communication between these clocks controls circadian homeostasis. Intertissue communication is mediated, in part, by temporal coordination of metabolism. Here, we characterize the extent to which clocks in different organs control systemic metabolic rhythms, an area that remains largely unexplored. We analyzed the metabolome of serum from mice with tissue-specific expression of the clock gene
Bmal1
. Having functional hepatic and muscle clocks can only drive a minority (13%) of systemic metabolic rhythms. Conversely, limiting
Bmal1
expression to the central pacemaker in the brain restores rhythms to 57% of circulatory metabolites. Rhythmic feeding imposed on clockless mice resulted in a similar rescue, indicating that the central clock mainly regulates metabolic rhythms via behavior. These findings explicate the circadian communication between tissues and highlight the importance of the central clock in governing those signals.
Delivery of therapeutic carbon monoxide by gas-entrapping materials
Authors: Byrne James D. , Gallo David , Boyce Hannah , Becker Sarah L. , Kezar Kristi M. , Cotoia Alicia T. , Feig Vivian R. , Lopes Aaron , Csizmadia Eva , Longhi Maria Serena , Lee Jung Seung , Kim Hyunjoon , Wentworth Adam J. , Shankar Sidharth , Lee Ghee Rye , Bi Jianling , Witt Emily , Ishida Keiko , Hayward Alison , Kuosmanen Johannes L. P. , Jenkins Josh , Wainer Jacob , Aragon Aya , Wong Kaitlyn , Steiger Christoph , Jeck William R. , Bosch Dustin E. , Coleman Mitchell C. , Spitz Douglas R. , Tift Michael , Langer Robert , Otterbein Leo E. , Traverso Giovanni
Published: June 2022

Carbon monoxide (CO) has long been considered a toxic gas but is now a recognized bioactive gasotransmitter with potent immunomodulatory effects. Although inhaled CO is currently under investigation for use in patients with lung disease, this mode of administration can present clinical challenges. The capacity to deliver CO directly and safely to the gastrointestinal (GI) tract could transform the management of diseases affecting the GI mucosa such as inflammatory bowel disease or radiation injury. To address this unmet need, inspired by molecular gastronomy techniques, we have developed a family of gas-entrapping materials (GEMs) for delivery of CO to the GI tract. We show highly tunable and potent delivery of CO, achieving clinically relevant CO concentrations in vivo in rodent and swine models. To support the potential range of applications of foam GEMs, we evaluated the system in three distinct disease models. We show that a GEM containing CO dose-dependently reduced acetaminophen-induced hepatocellular injury, dampened colitis-associated inflammation and oxidative tissue injury, and mitigated radiation-induced gut epithelial damage in rodents. Collectively, foam GEMs have potential paradigm-shifting implications for the safe therapeutic use of CO across a range of indications.
MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy
Authors: Morelli Kathryn H. , Jin Wenhao , Shathe Shashank , Madrigal Assael A. , Jones Krysten L. , Schwartz Joshua L. , Bridges Tristan , Mueller Jasmine R. , Shankar Archana , Chaim Isaac A. , Day John W. , Yeo Gene W.
Published: June 2022

Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3′ untranslated region of the dystrophia myotonica-protein kinase (
DMPK
) gene. Despite its prominence as the most common adult-onset muscular dystrophy, patients with congenital to juvenile-onset forms of DM1 can present with debilitating neurocognitive symptoms along the autism spectrum, characteristic of possible in utero cortical defects. However, the molecular mechanism by which CTG MREs lead to these developmental central nervous system (CNS) manifestations is unknown. Here, we showed that CUG foci found early in the maturation of three-dimensional (3D) cortical organoids from DM1 patient–derived induced pluripotent stem cells (iPSCs) cause hyperphosphorylation of CUGBP Elav-like family member 2 (CELF2) protein. Integrative single-cell RNA sequencing and enhanced cross-linking and immunoprecipitation (eCLIP) analysis revealed that reduced CELF2 protein–RNA substrate interactions results in misregulation of genes critical for excitatory synaptic signaling in glutamatergic neurons, including key components of the methyl-CpG binding protein 2 (MECP2) pathway. Comparisons to MECP2
(y/−)
cortical organoids revealed convergent molecular and cellular defects such as glutamate toxicity and neuronal loss. Our findings provide evidence suggesting that early-onset DM1 might involve neurodevelopmental disorder-associated pathways and identify
N
-methyl-
d
-aspartic acid (NMDA) antagonists as potential treatment avenues for neuronal defects in DM1.
Metagenomes, Metagenome-Assembled Genomes, and Metatranscriptomes from Polychlorinated Biphenyl-Contaminated Sediment Microcosms
Authors: Ewald Jessica M. , Schnoor Jerald L. , Mattes Timothy E.
Published: June 2022

We present a comprehensive data set that describes an anaerobic microbial consortium native to polychlorinated biphenyl (PCB)-contaminated sediments. Obtained from sediment microcosms incubated for 200 days, the data set includes 4 metagenomes, 4 metatranscriptomes (in duplicate), and 62 metagenome-assembled genomes and captures microbial community interactions, structure, and function relevant to anaerobic PCB biodegradation.
Acinetobacter baumannii Sampled from Cattle and Pigs Represent Novel Clones
Authors: Mateo-Estrada Valeria , Vali Leila , Hamouda Ahmed , Evans Benjamin A. , Castillo-Ramírez Santiago
Published: June 2022

Over the last decades, huge amounts of information have been obtained for clinical isolates of
A. baumannii
and the clones they belong to. In contrast, very little is known about the genomic identity and the genomic basis for virulence and resistance of animal isolates.
Past eruptions of a newly discovered active, shallow, silicic submarine volcano near Tokyo Bay, Japan
Authors: McIntosh Iona M. , Tani Kenichiro , Nichols Alexander R.L. , Chang Qing , Kimura Jun-Ichi
Published: June 2022

Oomurodashi is a newly discovered active, shallow, silicic submarine volcano only 60 km from Tokyo Bay. We reveal its past eruptive activity, and potential future hazards, by examining volatile contents of its subaerial and submarine pumice and lava deposits. These novel data for shallow silicic submarine eruption products were obtained using new Fourier transform infrared spectroscopy (FTIR) analytical techniques for vesicular and hydrated glasses. All matrix glasses have H2O species data consistent with low-temperature hydration following eruption. We therefore used unaltered OH data to investigate past eruptions. Geochemistry confirmed that Oomurodashi was the source of a ca. 13.5 ka subaerial tephra deposit on nearby inhabited islands. We infer from pumice OH contents and tephra characteristics that this deposit was formed by explosive submarine phreatomagmatic activity that produced the shallow crater in the submarine edifice. OH contents of in-place submarine lavas are lower than expected for their current water depth; comparison with past sea level implies that these lavas erupted at ca. 7–10 ka and ca. 14 ka when sea level was lower. Oomurodashi has also erupted submarine pumice with different densities, quench depths, and dispersal histories; however, any pumice sufficiently buoyant to produce floating pumice rafts will have been lost from the local geological record, so pumice rafts remain a potential future hazard.
Brexit’s Implications for the Transatlantic Relationship
Authors: Prikhodko O. V.
Published: June 2022

Since the Second World War, the United Kingdom has served as a transatlantic bridge between the United States and Europe and as a conduit of the US influence in European affairs. Since joining the EU, Britain has been one of the main contributors to the European Union’s foreign, security, and defense policies. The withdrawal of the United Kingdom from the EU in 2020 marked a milestone in European politics. The UK’s decision to leave the European Union has raised questions concerning probable implications of Brexit for the transatlantic relationship and the European balance of power. Brexit entails multifaceted changes in Britain’s global posture, in particular, new nuances in its dealings with the United States and European partners. These shifts embrace a wide range of political, defense, security, and economic issues. They have stirred up debates on the British strategy’s tilt towards the Indo–Pacific and Britain’s future cooperation with its American ally and the EU. Having considered developments in the Washington–London–Brussels relations in the wake of the Brexit referendum, this article figures out trends in the interactions of these key players that reflect their visions of a post-Brexit reality.
The Effect of Collectivization on the Fate of Russia in the 20th Century
Authors: Kondrashin Viktor
Published: June 2022

This article discusses the phenomenon of collectivization and concludes that it is the most important event in the history of Russia in the twentieth century, which radically changed its agrarian system and had a huge impact on the subsequent development of the country. It is pointed out that collectivization cannot be understood without comprehending the entire historical path of Russian modernization. This article analyzes the Bukharin alternative to Stalinist collectivization, characterizes the historical significance of the creation of the collective farm system in the Soviet Union, and considers its impact on the economy and the mentality of the Soviet peasantry.
Agriculturist V.G. Venzher in the Search of Reforming the Soviet Union
Authors: Nikulin Alexander
Published: June 2022

On the anniversary of the centenary of the formation of the Soviet Union, we naturally remember the name and ideas of one of the most brilliant Soviet agricultural economists, who made a huge practical and theoretical contribution to attempts to reform not only Soviet agriculture but also Soviet society as a whole. Vladimir Grigoryevich Venzher (1899–1990) was an agriculturist and economist, who primarily became widely known for his correspondence with Stalin in the early 1950s about the possibilities of reforms in the collective farm system of the Soviet Union.

At the same time, the fact that his personality was much broader and deeper than his professional incarnation as an agrarian economist. Venzher, of course, was also an original and deep social thinker, partly Marxist and partly populist-cooperative, who repeatedly proposed to the Soviet leadership and then in relation to the Kosygin and Gorbachev reforms a number of comprehensive alternative reforms aimed at shaping the sustainable development of the Soviet Union and Russia based primarily on the required agrarian reforms.1 To prove and develop this statement, this article examines several key fragments of the political economy and social and philosophical heritage of Venzher in the 1960s–1980s, his letters to the Central Committee of the CPSU, and some of his scientific monographs, which have not yet attracted much attention from researchers.
Incomplete recovery in patients with minor head injury directly discharged home from the emergency department: a prospective cohort follow-up study
Authors: Coffeng Sophie Maria , Jacobs Bram , Kim Laura Jane , ter Maaten Jan Cornelis , van der Naalt Joukje
Published: June 2022

Objectives

To determine the frequency of post-traumatic complaints and recovery rate of non-hospitalised patients with minor head injury (MHI) and their relationship with demographic and injury characteristics. We also evaluated the differences between patient groups in this least severe category of brain and head injury.

Design

Prospective cohort follow-up study.

Setting

Patients admitted to the emergency department (ED) of a tertiary hospital in the Netherlands.

Participants

242 patients with MHI (n=100 with head injury only and n=142 with mild traumatic brain injury (mTBI)) discharged home directly after evaluation at the ED.

Outcome measures

The primary outcome measure was incomplete recovery at 3 months measured by the Glasgow Outcome Scale-Extended score <8. Secondary outcome measures were number of post-traumatic complaints assessed 2 weeks and 3 months postinjury by a standardised questionnaire. Also the number of patients that visited their general practitioner because of persistent complaints was determined.

Results

Three months postinjury 48% of patients reported more than one post-traumatic complaint. Half (51%) of patients showed incomplete recovery. Incomplete recovery was associated with headache directly postinjury (OR 3.27, 95% CI 1.28 to 8.34), age (OR 1.02, 95% CI 1.00 to 1.05) and the number of post-traumatic complaints (OR 1.24, 95% CI 1.09 to 1.40) and depression (OR 6.31, 95% CI 1.24 to 32.00) 2 weeks postinjury. Incomplete recovery was comparable between the head injury only and mTBI group (55% vs 50%, 95% CI −12.5 to −23.0). In total 36 MHI patients (28%) visited their general practitioner because of complaints related to their head injury.

Conclusion

Half of the non-hospitalised patients with MHI experienced incomplete recovery after 3 months without differences between head injury only and mTBI patients. Therefore, early identification of patients at risk for incomplete recovery must be started at the ED to provide appropriate aftercare to avoid long-term post-traumatic complaints.
Identifying key signs of motor neurone disease in primary care: a nested case–control study using the QResearch database
Authors: Mei Xue W , Burchardt Judith , Ranger Tom A , McDermott Christopher J , Radunovic Aleksandar , Coupland Carol , Hippisley-Cox Julia
Published: June 2022

Objective

To confirm the symptoms and signs for motor neuron disease (MND) in the Red Flag tool; to quantify the extent to which the key symptoms and signs are associated with MND; and to identify additional factors which may be helpful within the primary care setting in recognition of possible MND and triggering timely referral to neurology specialists.

Design

A nested case–control study.

Setting

1292 UK general practices contributing to the QResearch primary care database, linked to hospital and mortality data.

Participants

Baseline cohort included 16.8 million individuals aged 18 years and over without a diagnosis of MND at study entry and with more than 3 years of digitalised information available. The nested case–control data set comprised of 6437 cases of MND diagnosed between January 1998 and December 2019, matched by year of birth, gender, general practice and calendar year to 62 003 controls.

Main outcome measures

Clinically recognised symptoms and signs of MND prior to diagnosis and symptoms and factors which are relevant in primary care setting.

Results

This study identified 17 signs and symptoms that were independently associated with MND diagnosis in a multivariable analysis. Of these, seven were new to the Red Flag tool: ataxia, dysphasia, weight loss, wheeze, hoarseness of voice, urinary incontinence and constipation. Among those from the Red Flag tool, dysarthria had the strongest association with subsequent MND (adjusted OR (aOR): 43.2 (95% CI 36.0 to 52.0)) followed by muscle fasciculations (aOR: 40.2 (95% CI 25.6 to 63.1)) and muscle wasting (aOR: 31.0 (95% CI 19.5 to 49.4)). Additionally, the associations between MND diagnosis and family history, dropped foot, focal weakness and sialorrhoea remained robust after controlling for confounders. Patients who reported symptoms indicative of damage to the lower brainstem and its connections were diagnosed sooner than those who presented with respiratory or cognitive signs.

Conclusion

This is the first study that has identified, confirmed and quantified the association of key symptoms and signs with MND diagnosis. In addition to known factors, the study has identified the following new factors to be independently associated with MND prior to diagnosis: ataxia, dysphasia, wheeze and hoarseness of voice. These findings may be used to improve risk stratification and earlier detection of MND in primary care.
FutureMS cohort profile: a Scottish multicentre inception cohort study of relapsing-remitting multiple sclerosis
Authors: Kearns Patrick K A , Martin Sarah J , Chang Jessie , Meijboom Rozanna , York Elizabeth N , Chen Yingdi , Weaver Christine , Stenson Amy , Hafezi Katarzyna , Thomson Stacey , Freyer Elizabeth , Murphy Lee , Harroud Adil , Foley Peter , Hunt David , McLeod Margaret , O'Riordan Jonathon , Carod-Artal F J , MacDougall Niall J J , Baranzini Sergio E , Waldman Adam D , Connick Peter , Chandran Siddharthan
Published: June 2022

Purpose

Multiple sclerosis (MS) is an immune-mediated, neuroinflammatory disease of the central nervous system and in industrialised countries is the most common cause of progressive neurological disability in working age persons. While treatable, there is substantial interindividual heterogeneity in disease activity and response to treatment. Currently, the ability to predict at diagnosis who will have a benign, intermediate or aggressive disease course is very limited. There is, therefore, a need for integrated predictive tools to inform individualised treatment decision making.

Participants

Established with the aim of addressing this need for individualised predictive tools, FutureMS is a nationally representative, prospective observational cohort study of 440 adults with a new diagnosis of relapsing-remitting MS living in Scotland at the time of diagnosis between May 2016 and March 2019.

Findings to date

The study aims to explore the pathobiology and determinants of disease heterogeneity in MS and combines detailed clinical phenotyping with imaging, genetic and biomarker metrics of disease activity and progression. Recruitment, baseline assessment and follow-up at year 1 is complete. Here, we describe the cohort design and present a profile of the participants at baseline and 1 year of follow-up.

Future plans

A third follow-up wave for the cohort has recently begun at 5 years after first visit and a further wave of follow-up is funded for year 10. Longer-term follow-up is anticipated thereafter.