bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence that sisterless-a and sisterless-b are two of several discrete "numerator elements" of the X/A sex determination signal in Drosophila that switch Sxl between two alternative stable expression states.
Authors: Cline T W
Published: January 2021

The primary signal for Drosophila sex determination is the number of X chromosomes relative to the number of sets of autosomes. The present report shows that the numerator of this X/A signal appears to be determined by the cumulative dose of a relatively limited number of discrete X-linked genetic elements, two of which are sisterless-a and sisterless-b. This discovery regarding the nature of the sex determination signal grew out of previous studies of both the likely X/A signal target (the feminizing switch gene, Sex-lethal) and two positive regulators of that target gene (sis-a and daughterless). Combinations of genetic perturbations in these three genes had been shown to have synergistic effects. A model proposed in part to account for these interactions generated a large variety of strong predictions for sex-specific synergistic interactions that would be diagnostic for X/A numerator elements and could distinguish them from other components of the sex determination system. All these predictions, as well as other predictions for X/A numerator elements, are shown here to be fulfilled. The most compelling observations involve sexually reciprocal viability effects of duplications of wild-type genes: combinations of sis-a+, sis-b+ and/or Sxl+ duplications are lethal to males but rescue females from the otherwise lethal effects of changes in other components of the sex determination machinery. The many interactions described here illustrate an important principle that may seem counter-intuitive: perturbations of the sex determination signal for Drosophila generally will not appear to affect adult sexual phenotype. This principle follows from the fact that Sxl is involved in dosage compensation as well as sex determination, and from important aspects of the nature and timing of Sxl's regulation both by the X/A signal and by Sxl's own products (positive autoregulation). These factors mask potential effects on adult sexual differentiation by causing the premature death of cells and/or individuals. The fact that the vast array of results presented here conform to this principle is strong evidence in favor of a "binary state" model for Sxl regulation by the X/A signal. This model is favored over an alternative "multiple state" hypothesis that was proposed by others in a different study of the X/A signal. In that same study it was concluded that region 3E8-4F11 of the X chromosome contained especially potent X/A numerator elements.(ABSTRACT TRUNCATED AT 400 WORDS)
Sequence, genomic distribution and DNA modification of a Mu1 element from non-mutator maize stocks.
Authors: Chandler V L , Talbert L E , Raymond F
Published: January 2021

The increased mutation rate of Mutator stocks of maize has been shown to be the result of transposition of Mu elements. One element, Mu1, is present in 10-60 copies in Mutator stocks and approximately 0-3 copies in non-Mutator stocks. The sequence, structure and genomic distribution of an intact Mu1 element cloned from the non-Mutator inbred line B37 has been determined. The sequence of this element, termed Mu1.4-B37, is identical to Mu1 and it is flanked by 9-bp direct repeats indicative of a target site duplication. Mu1.4-B37 is not in the same genomic location in all stocks, which further suggests that it transposed into its genomic location in B37. We previously reported that in genomic DNA this element is modified such that certain methylation-sensitive restriction enzymes will not cut sites within the element. This is similar to that observed for Mu elements in Mutator stocks that have lost activity. We report herein that the Mu1.4-B37 element loses its modification and becomes accessible to digestion when placed in an active Mutator stock by genetic crosses. This suggests that factors conditioning unmodified elements are dominant in the initial cross between Mutator and non-Mutator stocks. In F2 individuals that have subsequently lost Mutator activity the Mu1.4-B37 element again becomes modified as do most of the Mu elements in the stock. Thus, the modification state of the Mu1.4-B37 element and the other Mu1-like elements correlates with Mutator activity. We hypothesize that factor(s) within an active Mutator stock may inhibit the modification of Mu elements, and that this activity is missing in non-Mutator stocks and may become limiting in certain Mutator stocks resulting in DNA modification.
Dosage-dependent modifiers of position effect variegation in Drosophila and a mass action model that explains their effect.
Authors: Locke J , Kotarski M A , Tartof K D
Published: January 2021

Twelve dominant enhancers of position effect variegation, representing four loci on the second and third chromosomes of Drosophila melanogaster, have been induced by P-element mutagenesis. Instead of simple transposon insertions, seven of these mutations are cytologically visible duplications and three are deficiencies. The duplications define two distinct regions, each coinciding with a locus that also behaves as a dominant haplo-dependent suppressor of variegation. Conversely, two of the deficiencies overlap with a region that contains a haplo-dependent enhancer of variegation while duplications of this same region act to suppress variegation. The third deficiency defines another haplo-dependent enhancer. These data indicate that loci capable of modifying variegation do so in an antipodal fashion through changes in the wild-type gene copy number and may be divided into two reciprocally acting classes. Class I modifiers enhance variegation when duplicated or suppress variegation when deficient. Class II modifiers enhance when deficient but suppress when duplicated. From our data, and those of others, we propose that in Drosophila there are about 20 to 30 dominant loci that modify variegation. Most appear to be of the class I type whereas only two class II modifiers have been identified so far. From these observations we put forth a model, based on the law of mass action, for understanding how such suppressor-enhancer loci function. We propose that each class I modifier codes for a structural protein component of heterochromatin and their effects on variegation are a consequence of their dosage dependent influence on the extent of the assembly of heterochromatin at the chromosomal site of the position effect. It is further proposed that class II modifiers may inhibit the class I products directly, bind to hypothetical termination sites that define heterochromatin boundaries or promote euchromatin formation. Consistent with our mass action model we find that combining two enhancers together produce additive and not epistatic effects. Also, since different enhancers have different relative strengths on different variegating mutants, we suggest that heterochromatic domains are constructed by a combinatorial association of proteins. The mass action model proposed here is of general significance for any assembly driven reaction and has implications for understanding a wide variety of biological phenomena.(ABSTRACT TRUNCATED AT 400 WORDS)
Regulation of two nested proteins from gene 49 (recombination endonuclease VII) and of a lambda RexA-like protein of bacteriophage T4.
Authors: Barth K A , Powell D , Trupin M , Mosig G
Published: January 2021

Phage T4 gene 49, encoding recombination endonuclease VII, specifies, by initiation from an AUG and an internal GUG codon, two in-frame overlapping peptides (of 18 and 12 kD). The gene is transcribed early and late, albeit from different promoters. The sequence predicts that in long early transcripts, initiated far upstream of the coding sequence, the Shine-Dalgarno sequence of the first ribosome binding site can be sequestered in a hairpin and/or cleaved. These processes might reduce initiation from the first AUG and facilitate initiation of the 12-kD peptide from the internal GUG. The potential of this hairpin to participate in Y structures or cruciforms suggests possible autoregulation. Shorter, more stable late transcripts initiated from a late promoter immediately upstream of the first ribosome binding site cannot form this hairpin. More efficient translation of the longer 18-kD gene 49 peptide from these late transcripts accounts for the strong dependence of endonuclease VII activity on late gene expression. An ORF downstream from gene 49 can be translated from a motA-dependent transcript that starts inside gene 49 as well as from the gene 49 transcripts. Its initiation codon overlaps the stop codon of gene 49, suggesting some coupling of translation. The deduced protein resembles, among others, the RexA protein of phage lambda. Possible implications for T4 recombination and for the interference of lambda lysogens with T4 gene 49 and rII mutants are discussed.
Phenotypic assortment in Tetrahymena thermophila: assortment kinetics of antibiotic-resistance markers, tsA, death, and the highly amplified rDNA locus.
Authors: Merriam E V , Bruns P J
Published: January 2021

Phenotypic assortment in Tetrahymena thermophila results from random distribution of alleles during amitotic division of the macronucleus. The rate of assortment is dependent on input ratio and the number of assorting units. The assortment of the antibiotic resistance markers Chx, Mpr and gal was determined and is consistent for each with the model of 45 assorting chromosomes. The gene tsA (previously ts-1) shows normal assortment, in contrast to previous reports. A mutation in the highly amplified ribosomal locus (rdnA2) assorts as if present at only 45 copies. Death of clones occurred at a rate consistent with assortment for a single gene.
Fine-structure genetics of ama-1, an essential gene encoding the amanitin-binding subunit of RNA polymerase II in Caenorhabditis elegans.
Authors: Bullerjahn A M , Riddle D L
Published: January 2021

A fine-structure genetic map has been constructed for ama-1 IV, an essential gene in Caenorhabditis elegans encoding the amanitin-binding subunit of RNA polymerase II. Sixteen EMS-induced recessive-lethal mutations have been positioned in the gene by determining their intragenic recombination frequencies with m118, a mutation that confers dominant resistance to alpha-amanitin. The 16 mutants, all isolated in the ama-1(m118) background, include 13 that are early larval lethals, and three that are mid-larval lethals, at 25 degrees. Six of the mutants exhibit temperature-dependence in the severity of their phenotype. Intragenic recombination between the lethal site and the parental resistance mutation was detected by means of resistance to amanitin. Recombinants were detected at frequencies as low as 2 X 10(-6). The segregation of the closely linked flanking markers, unc-17 and unc-5, revealed whether the lethal mutation was to the left or the right of m118. By adding the distances between the extreme left and right mutations, the ama-1 gene is estimated to be 0.011 map unit long, with m118 positioned 0.004 map unit from the left-most lethal mutation. To order the lethal mutations with respect to each other, viable heteroallelic strains were constructed using the free duplication, mDp1[unc-17(e113) dpy-13(+) ama-1(+)]. The heteroallelic strains were sensitive to amanitin, and recombination events between the lethal mutations were specifically selected by means of the dominant amanitin resistance encoded on the recombinant chromosome. The segregation of outside markers revealed the left-right order of the lethal mutations. The position of mutations within the gene is nonrandom. Functional domains of the ama-1 gene indicated by the various lethal phenotypes are discussed.
Genetic analysis of the heterochromatin of chromosome 3 in Drosophila melanogaster. I. Products of compound-autosome detachment.
Authors: Marchant G E , Holm D G
Published: January 2021

The heterochromatin of the third chromosome is the largest uncharacterized region of the Drosophila melanogaster genome, and the last major block of D. melanogaster heterochromatin to be thoroughly analyzed. In the present study, this region was genetically dissected by generating and analyzing a series of attached, detached and reattached third chromosomes. Separate detachment experiments were conducted for all 12 possible combinations of four newly synthesized sister-strand compound-3L and three newly synthesized sister-strand compound-3R chromosomes. A total of 443 recessive lethal detachment products carrying putative heterochromatic deficiencies were tested for complementation in a several-stage complementation analysis. The results revealed the presence of seven separable vital regions in the heterochromatin of chromosome 3. Attempts to reattach deficiency-carrying detachment products established that six of these vital regions are on the left arm, but only one is on the right arm. An analysis of the types and frequencies of detachment-product deficiencies generated in each detachment experiment permitted the genetic characterization of the progenitor compounds. It was also possible to determine the proximal-distal orientation of the genes on each arm, and to identify possible breakpoints for each lethal detachment product produced. The results of this study suggest that vital genes in the heterochromatin of the third chromosome are not randomly distributed between, nor within, the heterochromatic blocks of the left and right arms.
The antimorphic nature of the Tc allele at the mouse T locus.
Authors: MacMurray A , Shin H S
Published: January 2021

The T locus on mouse chromosome 17 is haploid-insufficient: deletion/+ heterozygous mice have a short tail. One exceptional allele, Tc, produces a tailless phenotype in heterozygous mice. Thus, Tc has a more severe phenotype than that of a deletion allele, suggesting either that Tc is further deleted for a neighboring locus, resulting in the additional phenotype, or that Tc is a gain-of-function mutation. We have shown that Tc is not deleted for the D17Leh119 and D17RP17 loci flanking T, which are deleted in some T alleles. Thus, the severity of the Tc phenotype is not due to the deletion of an adjacent locus. We have also examined the genetic nature of the Tc allele by placing it in trans with a T-locus duplication, twLub2, which has previously been independently confirmed at the molecular level to have a duplication in the chromosomal region including the T locus. We have shown that Tc is partially complemented by twLub2, unlike a null allele (deletion) which was previously shown to be fully complemented by twLub2. These results indicate that Tc behaves genetically as an antimorph, exerting its effect by antagonizing the function of a wild-type allele at the T locus. The apparent correlation between the gene dosage at the T locus and the length of the body axis is discussed.
Single-cell ATAC-Seq reveals cell type-specific transcriptional regulation and unique chromatin accessibility in human spermatogenesis
Authors: Wu Xiaolong , Lu Mujun , Yun Damin , Gao Sheng , Chen Shitao , Hu Longfei , Wu Yunhao , Wang Xiaorong , Duan Enkui , Cheng C Yan , Sun Fei
Published: January 2021

During human spermatogenesis, germ cells undergo dynamic changes in chromatin organization/re-packaging and in transcriptomes. In order to better understand the underlying mechanism(s), scATAC-Seq of 5376 testicular cells from 3 normal men were performed. Data were analyzed in parallel with the scRNA-Seq data of human testicular cells. In all, 10 germ cell types associated with spermatogenesis and 6 testicular somatic cell types were identified, along with 142 024 peaks located in promoter, genebody and CpG Island. We had examined chromatin accessibility of all chromosomes, with chromosomes 19 and 17 emerged as the leading chromosomes that displayed high chromatin accessibility. In accessible chromatin regions, transcription factor-binding sites were identified and specific motifs with high frequencies at different spermatogenesis stages were detected, including CTCF, BORIS, NFY, DMRT6, EN1, ISL1 and GLI3. Two most remarkable observations were noted. First, TLE3 was specifically expressed in differentiating spermatogonia. Second, PFN4 was found to be involved in actin cytoskeletal organization during meiosis. More important, unique regions upstream of PFN4 and TLE3 were shown to display high accessibility, illustrating their significance in supporting human spermatogenesis.
The rise of digital constitutionalism in the European Union
Authors: De Gregorio Giovanni
Published: January 2021

In the last twenty years, the policy of the European Union in the field of digital technologies has shifted from a liberal economic perspective to a constitution-oriented approach. This change of heart has resulted primarily from the rise of the information society which has created not only new opportunities but also challenges to fundamental rights and democratic values. Even more importantly, this technological framework driven by liberal ideas has empowered transnational corporations operating in the digital environment to perform quasi-public functions on a global scale. This article analyzes the path and the reasons that have led the European Union to enter a new phase of modern constitutionalism (i.e. digital constitutionalism). The primary goal of this article is to describe the characteristics of this new constitutional phase opposing platform powers, and to outline the potential evolution of European digital constitutionalism in the global context.
Chest wall resection and reconstruction for primary and metastatic sarcomas: an 11-year retrospective cohort study
Authors: Prisciandaro Elena , Hustache-Castaing Romain , Michot Audrey , Jougon Jacques , Thumerel Matthieu
Published: January 2021

OBJECTIVES

Chest wall sarcomas are rare, aggressive malignancies, the management of which mainly revolves around surgery. Radical tumour excision with free margins represents the optimal treatment for loco-regional clinically resectable disease. The objective of this study was to review our 11-year experience with chest wall resection for primary and metastatic sarcomas, focusing on surgical techniques and strategies for reconstruction.

METHODS

Retrospective analysis of a comprehensive database of patients who underwent chest wall resection for primary or secondary sarcoma at our Institute from January 2009 to December 2019.

RESULTS

Out of 26 patients, 21 (81%) suffered from primary chest wall sarcoma, while 5 (19%) had recurring disease. The median number of resected ribs was 3. Sternal resection was performed in 6 cases (23%). Prosthetic thoracic reconstruction was deemed necessary in 24 cases (92%). Tumour recurrence was observed in 15 patients (58%). The median overall survival was 73.6 months. Primary and secondary tumours showed comparable survival (P = 0.49). At univariate analysis, disease recurrence and infiltrated margins on pathological specimens were associated with poorer survival (P = 0.014 and 0.022, respectively). In patients with primary sarcoma, the median progression-free survival was 13.3 months. Associated visceral resections were significantly associated to postoperative complications (P = 0.02).

CONCLUSIONS

Chest wall resection followed by prosthetic reconstruction is feasible in carefully selected patients and should be performed by experienced surgeons with the aim of achieving free resection margins, resulting in improved long-term outcomes.
Key sources of strength and resilience for persons receiving services for Hansen's disease (leprosy) in Porto Velho, Brazil: What can we learn for service development?
Authors: van't Noordende Anna T , Bakirtzief da Silva Pereira Zoica , Kuipers Pim
Published: January 2021

Background

Individuals affected by Hansen's disease (leprosy) often experience stigma and discrimination. Greater psychosocial resilience may enable people to deal with such discrimination. This study aimed to explore sources of strength and resilience for individuals affected by Hansen's disease in Brazil.

Methods

We used a cross-sectional study design with a qualitative approach. Semistructured focus groups were conducted. Analysis comprised thematic categorisation of transcripts.

Results

Thirty-one participants were included: 23 individuals affected by Hansen's disease and 8 healthcare providers. We found that while a few individuals affected were provided with formal psychological support in the early phases of their treatment, many noted the importance of providing such support at this time. Most participants described relationships with and social support from family members, friends and with others affected by Hansen's disease as their primary source of resilience. A key context for building resilience was through the peer-level sharing and engagement experienced in self-care and support groups. Participants also emphasised the importance of providing appropriate information about Hansen's disease and the importance of beliefs and spirituality.

Conclusions

Hansen's disease services should seek to build resilience in early treatment through counselling and during treatment and beyond by having people affected getting together. Across both settings supporting family and social relationships, providing accurate information and acknowledging spiritual beliefs are important.
CD47 promotes T-cell lymphoma metastasis by up-regulating AKAP13-mediated RhoA activation
Authors: Kitai Yuichi , Ishiura Marie , Saitoh Kodai , Matsumoto Naoki , Owashi Kimiya , Yamada Shunsuke , Muromoto Ryuta , Kashiwakura Jun-ichi , Oritani Kenji , Matsuda Tadashi
Published: January 2021

CD47, a 50 kDa transmembrane protein, facilitates integrin-mediated cell adhesion and inhibits cell engulfment by phagocytes. Since CD47 blocking promotes engulfment of cancer cells by macrophages, it is important to clarify the mechanism of CD47 signaling in order to develop treatments for diseases involving CD47-overexpressing cancer cells, including breast cancer and lymphoma. Here, we show that CD47 plays an essential role in T-cell lymphoma metastasis by up-regulating basal RhoA activity independent of its anti-phagocytic function. CD47 interacts with AKAP13, a RhoA-specific guanine nucleotide exchange factor (GEF), and facilitates AKAP13-mediated RhoA activation. Our study shows that CD47 has a novel function on the AKAP13-RhoA axis and suggests that CD47–AKAP13 interaction would be a novel target for T-cell lymphoma treatment.
The Return of National Self-Sufficiency? Excavating Autarkic Thought in a De-Globalizing Era
Authors: Helleiner Eric
Published: January 2021

As the global crisis triggered by the COVID-19 virus unfolded, The Economist magazine published a cover in May 2020 titled “Goodbye globalization: the dangerous lure of self-sufficiency.” The title summed up well the new political interest in the ideology of national economic self-sufficiency in the pandemic context. Unfortunately, contemporary textbooks in the field of international political economy (IPE) say little about this kind of “autarkic” thought. No survey of the history of autarkic thought exists even within specialist IPE literature or in the fields of intellectual history and the history of economic thought. Filling this gap in existing scholarship, this article highlights a rich history of autarkic thought that includes the ideas of famous thinkers such as Jean-Jacques Rousseau, Johann Fichte, Mohandas Gandhi, and John Maynard Keynes. Three core rationales for a high degree of national self-sufficiency have been advanced in the past: (1) insulation from foreign economic influence, (2) insulation from foreign political and/or cultural influence, and (3) the promotion of international peace. At the same time, considerable disagreements have existed among autarkists about some of these rationales and their relative importance, as well as about the precise meaning of national self-sufficiency. These disagreements stemmed not just from differences in their specific goals but also from the different conditions across time and space in which autarkic thought was developed. In addition to improving understanding of the autarkic ideological tradition, this article contributes to emerging scholarship attempting to overcome Western-centrism in IPE scholarship as well as literature exploring the new politics of de-globalization in the current era.
Measuring nuclear calcium and actin assembly in living cells
Authors: Safaralizade Mahira , Fuderer Ronja , Grosse Robert , Zhao Bing
Published: January 2021

Nuclear calcium signalling has emerged as a critical mechanism regulating processes like chromatin organization and gene expression. Recently, we have shown that nuclear calcium elevation triggers rapid and transient actin filament assembly inside the nucleus. Here, we constructed and employed a nuclear-specific calcium sensor based upon the new generation of genetically encoded probes jGCaMP7f. By fusing a nuclear localization signal to jGCaMP7f, we achieved highly efficient nuclear-specific targeting. Comparing the jGCaMP7f-NLS probe with the previous GCaMP6f-NLS calcium sensor showed clearly that jGCaMP7f-NLS is more sensitive and reverses significantly quicker thereby reflecting rapid nuclear calcium transients in a closely physiological manner. We further confirm that nuclear calcium transients precede nuclear actin polymerization by several seconds. Our data show that calcium-triggered nuclear actin assembly in fibroblasts is independent of the actin nucleating Arp2/3 complex. Together, jGCaMP7f-NLS represents an easy to use, reliable and highly sensitive nuclear calcium sensor that allows to tightly interrogate real-time, spatiotemporal calcium signalling and calcium-elicited effects in the nucleus of living cells.
Influencing factors of end-of-dose failure in patients with cancer pain after oral oxycodone sustained-release tablets: a retrospective, case–control study
Authors: Huang Hang-Xing , Liu Ke-Ke , Zhang Lu , Huang Ya-Min , Liu Wen-Hui , Xiao Jian
Published: January 2021

Objective

Comparing the characteristics of end-of-dose failure patients and non-end-of-dose failure patients in the Chinese population and exploring the factors that may affect the occurrence of end-of-dose failure in cancer pain patients.

Methods

The outpatient with cancer pain from 2016 to 2019 were collected through hospital information system, and patients were included who met the following criteria: patients with the average numerical rating scale  ≥4 points within 3 days after taking the oxycodone sustained-release preparation, titrated to an effective therapeutic dose suitable for patients, had at least two clinical visits information of the patient with a minimum of ≥3 days between visits, the average numerical rating scale of the next visit after the treatment of occasional pain is ≥4, and were divided into end-of-dose failure group and non-end-of-dose failure group.

Results

Age (P < 0.05, odds ratio 0.933), diagnosis of nasopharyngeal carcinoma (P < 0.05, odds ratio 0.009), pain site is the head and neck (P < 0.05, odds ratio 0.005) and the abdomen (P < 0.01, odds ratio 0.021), and the metastatic site is the liver (P < 0.05, odds ratio 0.001) are related to the occurrence of end-of-dose failure.

Conclusions

Younger patients are more likely to develop end-of-dose failure. Patients diagnosed with nasopharyngeal cancer, with pain in the head and neck and abdomen, and with liver metastases have a lower incidence of end-of-dose failure.
DM3Loc: multi-label mRNA subcellular localization prediction and analysis based on multi-head self-attention mechanism
Authors: Wang Duolin , Zhang Zhaoyue , Jiang Yuexu , Mao Ziting , Wang Dong , Lin Hao , Xu Dong
Published: January 2021

Subcellular localization of messenger RNAs (mRNAs), as a prevalent mechanism, gives precise and efficient control for the translation process. There is mounting evidence for the important roles of this process in a variety of cellular events. Computational methods for mRNA subcellular localization prediction provide a useful approach for studying mRNA functions. However, few computational methods were designed for mRNA subcellular localization prediction and their performance have room for improvement. Especially, there is still no available tool to predict for mRNAs that have multiple localization annotations. In this paper, we propose a multi-head self-attention method, DM3Loc, for multi-label mRNA subcellular localization prediction. Evaluation results show that DM3Loc outperforms existing methods and tools in general. Furthermore, DM3Loc has the interpretation ability to analyze RNA-binding protein motifs and key signals on mRNAs for subcellular localization. Our analyses found hundreds of instances of mRNA isoform-specific subcellular localizations and many significantly enriched gene functions for mRNAs in different subcellular localizations.
Cortical perfusion as assessed with contrast-enhanced ultrasound is lower in patients with chronic kidney disease than in healthy subjects but increases under low salt conditions
Authors: Garessus Jonas , Brito Wendy , Loncle Nicolas , Vanelli Anna , Hendriks-Balk Marielle , Wuerzner Grégoire , Schneider Antoine , Burnier Michel , Pruijm Menno
Published: January 2021

Background

Disturbances in renal microcirculation play an important role in the pathophysiology of chronic kidney disease (CKD), but the lack of easy accessible techniques hampers our understanding of the regulation of the renal microcirculation in humans. We assessed whether contrast-enhanced ultrasound (CEUS) can identify differences in cortical perfusion and alterations induced by different dietary salt intakes in CKD patients and controls.

Methods

Participants underwent CEUS twice: once after 5 days of high-salt (HS) intake, and again after 5 days of low salt (LS) diet. Sonovue® (0.015 mL/kg/min) was perfused as contrast agent and four consecutive destruction–reperfusion sequences were analysed per visit. The primary outcome measure was the (change in) mean perfusion index (PI) of the renal cortex.

Results

Forty healthy volunteers (mean age ± standard deviation 50 ± 8 years) and 18 CKD Stages 2–4 patients [aged 55 ± 11 years, estimated glomerular filtration rate (eGFR) 54 ± 28 mL/min/1.73 m2] were included and underwent CEUS without side effects. Under HS conditions, cortical PI was significantly lower in CKD patients [1618 ± 1352 versus 3176 ± 2278 arbitrary units (a.u) in controls, P = 0.034]. Under LS, renal PI increased in CKD patients (with +1098 to 2716 ± 1540 a.u., P = 0.048), whereas PI remained stable in controls. In the continuous analysis, PI correlated with eGFR (Spearman’s r = 0.54, P = 0.005) but not with age, sex, blood pressure or aldosterone levels.

Conclusions

CEUS identified important reductions in cortical micro-perfusion in patients with moderate CKD. Lowering salt intake increased perfusion in CKD patients, but not in controls, underlining the benefits of an LS diet in CKD patients. Whether a low PI is an early sign of kidney damage and predicts renal function decline needs further study.
Did the Black Death cause economic development by ‘inventing’ fertility restriction?
Authors: Edwards Jeremy , Ogilvie Sheilagh
Published: January 2021

The Black Death is claimed to have caused the European Marriage Pattern in England by raising pastoral wages and thus delaying female marriage. We show that this argument does not hold. There is no consensus that late female marriage emerged in rural England after the Black Death. Women wanting to do pastoral work in medieval England did not have to remain unmarried, so improved pastoral opportunities did not necessitate later marriage. Nor does the quantitative relationship between pastoralism and female marriage age in England provide support for this argument. Fertility restriction was not exogenously triggered by the Black Death.
ALMA view of the Galactic super star cluster RCW 38 at 270 au resolution
Authors: Torii Kazufumi , Tokuda Kazuki , Tachihara Kengo , Onishi Toshikazu , Fukui Yasuo
Published: January 2021

We report millimeter/submillimeter continuum and molecular line observations of the Galactic super star cluster RCW 38, obtained from the Atacama Large Millimeter/Submillimeter Array with a minimum angular resolution of ${0{^{\prime \prime }_{.}}17}\times {0{^{\prime \prime }_{.}}15}$ (≃ 289 au × 255 au). The C18O image reveals many massive condensations embedded within filamentary structures extending along the northwest–southeast direction in the center of cluster. The condensations have sizes of 0.01–0.02 pc, H2 column densities of 1023–1024 cm−2, and H2 masses of 10–130 M⊙. In addition, the 233 GHz continuum image reveals two dense, small millimeter-sources with radii of 460 and 200 au (Source A and Source B). Source A is embedded within the most massive C18O condensation, whereas no counterpart is seen for Source B. The masses of Source A and Source B are estimated as 13 and 3 M⊙ at the optically thin limit, respectively. The C18O emission shows a velocity gradient of 2 km s−1 at the central 2000 au of Source A, which could be interpreted as a Keplerian rotation with a central mass of a few M⊙ or infall motion of gas. Further, the ALMA 12CO data reveal that Source A and Source B are associated with molecular outflows exhibiting maximum velocities of ∼30–70 km s−1. The outflows have short dynamical timescales of <1000 yr and high-mass outflow rates of ∼10−4–10−3 M⊙ yr−1. These observational signatures suggest an early evolutionary phase of the massive star formation in Source A and Source B.
Sinking carbon, nitrogen, and pigment flux within and beneath the euphotic zone in the oligotrophic, open-ocean Gulf of Mexico
Authors: Stukel Michael R , Kelly Thomas B , Landry Michael R , Selph Karen E , Swalethorp Rasmus
Published: January 2021

During two cruises in the oligotrophic oceanic Gulf of Mexico, we deployed sediment traps at three depths: center of the euphotic zone (EZ) (60 m), base of the EZ (117–151 m), and in the twilight zone (231 m). Organic carbon export declined with depth from 6.4 to 4.6 to 2.4 mmol C m−2 d−1, suggesting that net particle production was concentrated in the upper EZ. Net primary production varied from 24 to 29 mmol C m−2 d−1, slightly more than half in the upper EZ. Export ratios varied from 11 to 25%. Trap measurements of chlorophyll and phaeopigments allowed us to quantify fluxes of fresh phytoplankton and herbivorous fecal pellets, respectively, which were both minor contributors to total flux, although their contributions varied with depth. Phytoplankton flux was more important from the upper to lower EZ; fecal pellets were more important at the EZ base and below. C:N elemental ratios and 13C and 15N isotope analyses indicated particle transformations within and beneath the EZ. 234Th-238U disequilibrium measurements varied, likely reflecting the mixing of water from multiple regions over the ~month-long time-scale of 234Th. Our results highlight the complexity of the biological carbon pump in oligotrophic regions.
Lead in Synergism With IFNγ Acts on Bone Marrow-Resident Macrophages to Increase the Quiescence of Hematopoietic Stem Cells
Authors: Zhao Yifan , Li Qian , Zhu Tingting , He Jinyi , Xue Peng , Zheng Weiwei , Yao Ye , Qu Weidong , Zhou Zhijun , Lu Rongzhu , Zhou Zhou , He Rui , He Miao , Zhang Yubin
Published: January 2021

Lead (Pb) is a highly toxic heavy metal that broadly exists in our living environment. Although Pb has been shown to influence the development of immune cells, to date, the impact of Pb on hematopoietic stem cells (HSCs) in the bone marrow (BM) remains unknown. As people are ubiquitously exposed to Pb and HSC are essential for human health, understanding the impact of Pb on HSC is significant for public health. In this study, we found that wild-type B6 mice treated with 1250 ppm Pb, but not 125 ppm Pb via drinking water for 8 weeks had increased quiescence of HSC in the BM. Functional analyses demonstrated that wild-type mice treated with 1250 ppm Pb had increased potential for HSC to repopulate the immune system and engraft to the niche in the BM under a competitive chimeric microenvironment of lethally irradiated recipients. Moreover, we found that Pb-increased quiescence of HSC critically relied on a synergetic action of Pb and interferon γ (IFNγ) on BM-resident macrophages (BM-MΦ), but not a direct action of Pb on HSC. Specifically, in steady state, BM-MΦ promoted HSC proliferation; and upon Pb treatment, IFNγ was induced in the BM, and thereafter Pb in synergism with IFNγ acted on BM-MΦ to cause BM-MΦ to become suppressive for HSC proliferation, thus leading to increased quiescence of HSC. Our study suggests that Pb increased the quiescence of HSC via a synergetic action of Pb and IFNγ on BM-MΦ, which was previously unrecognized toxicity of Pb.
Predicting the Physical and Mental Health Status of Individuals With Chronic Musculoskeletal Pain From a Biopsychosocial Perspective
Authors: Martínez-Borba Verónica , Ripoll-Server Paula , Yakobov Esther , Suso-Ribera Carlos
Published: January 2021

Objectives:

Chronic pain is theoretically conceptualized from a biopsychosocial perspective. However, research into chronic pain still tends to focus on isolated, biological, psychological, or social variables. Simultaneous examination of these variables in the prediction of outcomes is important because communalities between predictors exist. Examination of unique contributions might help guide research and interventions in a more effective way.

Methods:

The participants were 114 individuals with chronic pain (mean age=58.81, SD=11.85; 58.8% women and 41.2% men) who responded to demographics (age and sex), pain characteristics (duration and sensory qualities), psychological (catastrophizing and perceived injustice), and social (marital adjustment) measures. Multivariate analyses were conducted to investigate their unique contributions to pain-related health variables pain severity, pain interference, disability, anxiety, and depressive symptoms.

Results:

Bivariate analyses evidenced significant associations between pain sensory qualities, catastrophizing, perceived injustice, and all health variables. In multivariate analyses, pain sensory qualities were associated with pain severity (β=0.10; 95% confidence interval [CI]=0.05, 0.14; t=4.28, P<0.001), while perceived injustice was associated with pain interference (β=0.08; 95% CI=0.03, 0.12; t=3.59, P<0.001), disability (β=0.25; 95% CI=0.08, 0.42; t=2.92, P=0.004), anxiety (β=0.18; 95% CI=0.08, 0.27; t=3.65, P<0.001), and depressive symptoms (β=0.14; 95% CI=0.05, 0.23; t=2.92, P=0.004). Age, sex, pain duration, and marital adjustment were not associated with health variables either in bivariate or in multivariate analyses (all P>0.010).

Discussion:

As expected, communalities between biopsychosocial variables exist, which resulted in a reduced number of unique contributions in multivariate analyses. Perceived injustice emerged as a unique contributor to variables, which points to this psychological construct as a potentially important therapeutic target in multidisciplinary treatment of pain.
High Rate of Pain Sensitization in Musculoskeletal Shoulder Diseases
Authors: Previtali Davide , Bordoni Vittorio , Filardo Giuseppe , Marchettini Paolo , Guerra Enrico , Candrian Christian
Published: January 2021

Background:

Pain sensitization, defined as an increased responsiveness of nociceptive neurons to normal input, is detected in several musculoskeletal diseases, but there are no systematic reviews or meta-analyses about pain sensitization in shoulder pain.

Objectives:

The aim of the study was to document pain sensitization rate and its impact in patients with shoulder pain.

Materials and Methods:

PubMed, Cochrane Library, and Web of Science were searched on January 8, 2020. Level I-IV studies, evaluating pain sensitization in musculoskeletal shoulder disorders through validated methods (questionnaires/algometry) were included. The primary outcome was pain sensitization rate. Secondary outcomes were the pain sensitivity level measured as pressure pain threshold, temporal summation, conditioned pain modulation, and suprathreshold heat pain response. Associated demographic and psychosocial factors were evaluated.

Results:

The rate of abnormal pressure pain threshold in patients with shoulder pain varied from 29% to 77%. Questionnaires detected pain sensitization in 11% to 24% of patients. This meta-analysis showed no difference in pressure pain threshold and central pain modulation but documented a significant difference in terms of suprathreshold heat pain response, indicating a hypersensitivity state in patients with shoulder pain versus asymptomatic controls. The only factor that was constantly found to correlate with higher sensitivity was a lower postoperative outcome.

Discussion:

Pain sensitization has a high rate among patients with musculoskeletal shoulder pain, regardless of the specific etiology, and this may lead to worse clinical outcome after treatment of the primary disease. The best way to assess pain sensitization still needs to be identified as the assessment methods results in used high variability in the documented pain sensitization rate.
Local transversal aortic strain is impaired in ascending aorta dilatation
Authors: Cesareo Marco , Sabia Luca , Leone Dario , Avenatti Eleonora , Astarita Anna , Mingrone Giulia , Airale Lorenzo , Veglio Franco , Vallelonga Fabrizio , Milan Alberto
Published: January 2021

Background:

Ascending aorta dilatation is found in 13% of hypertensive patients. Little is known about elastic properties of ascending aorta in such patients. Echo-based transverse aortic strain analysis can describe mechanical properties of ascending aorta but has never been applied to patients with ascending aorta dilatation.

Aim:

To assess mechanical properties of ascending aorta by transverse aortic strain analysis (as β2-stiffness index) in hypertensive patients with ascending aorta dilatation and association between mechanical properties of ascending aorta and cardiovascular damage.

Methods:

A total of 100 hypertensive outpatients underwent transthoracic echocardiography and assessment of pulse wave velocity (PWV). Strain analysis of ascending aorta was performed with echocardiographic speckle-tracking software. Patients were divided in three groups based on ascending aorta diameter: less than 40, 40–45, and at least 45 mm.

Results:

Beta-SI increased exponentially with ascending aorta dimensions (P < 0.001). Patients with ascending aorta dilatation had Beta-SI significantly higher than those with normal ascending aorta diameter. A greater proportion of patient with impaired (i.e., elevated) Beta-SI was present in groups with larger ascending aorta (18.2 vs. 48.4 vs. 80%, respectively, P < 0.05). On multivariate logistic regression only impaired Beta-SI predicted ascending aorta dilatation (P < 0.001). Beta-SI was related to cardiovascular damage in terms of left ventricular (LV) mass (LV mass indexed to BSA, P = 0.030) and PWV (P = 0.028). Patients with high Beta-SI had greater LV mass indexed to BSA (117 ± 47 vs. 94 ± 24 g/m2; P = 0.010) and PWV (10.20 ± 2.99 vs. 8.63 ± 1.88 m/s; P = 0.013).

Conclusion:

Ascending aorta dilatation is associated with increased local aortic stiffness in hypertensive patients. Strain analysis adds functional information to the mere morphological evaluation of aortic diameter and could be a useful tool to better define cardiovascular risk in this population.
Management of Hepatitis‐B Virus Infection in Immunocompromised Children
Authors: Calvo Pier Luigi , Pinon Michele , Dell'Olio Dominic , Carpino Andrea , Biasin Eleonora , Pizzol Antonio , Catalano Silvia , Peruzzi Licia , Rigazio Caterina , Cisarò Fabio , Opramolla Anna , Asaftei Sebastian Dorin , Quarello Paola , Fagioli Franca
Published: January 2021

Objectives:

The aims of the study was to expand the pediatric experience on hepatitis‐B virus (HBV) reactivation, a known complication in patients with hematologic malignancies or on immunosuppression.

Methods:

Retrospective appraisal of HBV therapy/prophylaxis in immunocompromised children, studied from April 2006 to March 2020.

Results:

Eighteen HBV‐positive patients, 5 girls, median age 11.1 (4.1‐‐17.9) years were included. Seventeen of 18 were immunosuppressed at HBV‐infection diagnosis. Seventeen were at high risk of reactivation, 1 at moderate risk. Five of 18 had acute hepatitis B as first infection or reactivation, 6 had HBeAg‐positive infection, 1 an HBeAg‐negative infection and 6 HBsAg‐negative infection. Median follow‐up was 2.7 (0.7‐‐12.5) years. No HBV‐related mortality was observed. Prophylaxis had to be repeated in 1. Lamivudine was used in 6/12 viremic patients and HBV‐DNA negativization obtained in 2/6 (33%). Tenofovir‐DF was used in 2/12 and entecavir in 4/12: 100% attained HBV‐DNA negativization. Therapy had to be switched from tenofovir‐DF to entecavir in 1 patient because of renal impairment. Virological breakthroughs were observed in 1 lamivudine‐treated patient, leading to a hepatitis flare; 1 patient on entecavir had a hepatitis flare at immunoreconstitution. Mortality was 33% in the HBsAg‐positive group. Seven prophylactic treatments were administered to 6 patients with HBsAg‐negative infection: tenofovir‐DF in 2 HBV‐DNA‐positive, lamivudine in 5 HBV‐DNA‐negative, without reverse HBsAg seroconversion, morbidity or mortality.

Conclusions:

There is a residual risk of acute hepatitis B in immunocompromised children, mortality rate was substantial, potentially related to the delays in commencing chemotherapy caused by liver dysfunction. Tenofovir‐DF or entecavir are the drugs of choice for HBV treatment in immunocompromised children.
Pediatric Mesothelioma With ALK Fusions
Authors: Argani Pedram , Lian Derrick W.Q. , Agaimy Abbas , Metzler Markus , Wobker Sara E. , Matoso Andres , Epstein Jonathan I. , Sung Yun-Shao , Zhang Lei , Antonescu Cristina R.
Published: January 2021

Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In 1 case, cytogenetic analysis showed the presence of a t(2;15)(p23;q22) and fluorescence in situ hybridization confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by fluorescence in situ hybridization. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion-positive mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.