bluuebunny/crossref_metadata_2025 huggingface dataset:
NATURALLY OCCURRING ENZYME ACTIVITY VARIATION IN DROSOPHILA MELANOGASTER. II. RELATIONSHIPS AMONG ENZYMES
Authors: Wilton A N , Laurie-Ahlberg C C , Emigh T H , Curtsinger J W
Published: January 2021

This report describes an investigation of the specificities of the genetic effects, caused by whole chromosome substitution, on the activities of 23 enzymes in Drosophila melanogaster. Two types of correlation estimates are examined, the product-moment correlation over the chromosome substitution line means and the corresponding correlation of line effects, which is a standardized covariance component estimate. The two types of correlations give very similar results. Although there is ample evidence for specific line effects on individual enzyme activities, there are extensive intercorrelations among many of the enzymes for both second- and third-chromosome substitution lines. The pattern of correlations with respect to the metabolic functions or other properties of the enzymes is difficult to visualize by inspection of the correlation matrix, so a multivariate graphical technique, the biplot (Gabriel 1971), was employed to obtain a two-dimensional view of relationships among the enzyme activities. The second and third chromosome lines show similar patterns. Four of the five mitochondrial enzymes form one highly intercorrelated group whereas another highly intercorrelated group contains several cytosolic enzymes. Within the cytosolic group, particularly high correlations are observed between enzymes that have glucose 6-phosphate as a substrate or product and between enzymes that are NADP-dependent. Although the pattern of intercorrelations is not clearly explicable in terms of metabolic relationships among the enzymes, there is some tendency for enzymes that catalyze sequential reactions or share a substrate or product to have correlated activity levels.
THE EXPERIMENTAL ASSESSMENT OF FITNESS IN DROSOPHILA. I. COMPARATIVE MEASURES OF COMPETITIVE REPRODUCTIVE SUCCESS
Authors: Haymer David S , Hartl Daniel L
Published: January 2021

Strains of D. melanogaster, representing a range of genetic diversity, were systematically subjected to each of several techniques that have been devised to assess total or net fitness. All of these techniques operationally define fitness in terms of reproductive success under competitive conditions. For the set of strains tested, an excellent correlation was obtained between the competitive indices produced by two single-generation intraspecific competitions, despite fundamental differences in the strains used as competitive standards. The results of two interspecific tests were also correlated, but the intraspecific vs. interspecific test result comparisons ranged from highly significant to nonsignificant correlations. For the fitness estimates, the overall variances produced by the intraspecific tests were greater than those obtained in the interspecific competitions. No significant correlations were found between the results of a long-term (multi-generation) competitive assessment of fitness and any of the single-generation tests. Therefore, although all of these tests refer to a net parameter called "fitness", they are clearly not all measuring the same thing. Differences in the competitive interactions operative in each technique are suggested to account for these results.
MEIOTIC CHROMOSOME BEHAVIOR INFLUENCED BY MUTATION-ALTERED DISJUNCTION IN DROSOPHILA MELANOGASTER FEMALES
Authors: O′Tousa Joseph
Published: January 2021

The effects of a female-specific meiotic mutation, altered disjunction (ald: 361), are described. Although ald females show normal levels of meiotic exchange, sex- and 4th-chromosome nondisjunction occurs at an elevated level. A large proportion of the nondisjunction events is the result of nonhomologous disjunction of the sex and 4th chromosomes. These nonhomologous disjunction events, and probably all nondisjunction events occurring in ald females, are the result of two anomalies in chromosome behavior: (1) X chromosomes derived from exchange tetrads undergo nonhomologous disjunction and (2) the 4th chromosomes nonhomologously disjoin from larger chromosomes. There is at best a marginal effect of ald on the meiotic behavior of chromosomes 2 or 3. The results suggest that the ald  + gene product acts to prevent the participation of exchange X chromosomes and all 4th chromosomes in nonhomologous disjunction events. The possible role of ald  + in current models of the disjunction process is considered.
VARIATION IN AMYLASE HAPLOTYPES AMONG CONGENIC LINES OF THE HOUSE MOUSE
Authors: Nielsen J Tonnes
Published: January 2021

Pancreatic amylase in the mouse displays considerable quantitative genetic variation. Agar gel electrophoresis reveals that homozygous animals have either one form of the enzyme, type A, or two forms, type AB. Only few animals have been found that contradict this statement, namely among Mus musculus castaneus from Thailand, which has a single-banded B type. Double-banded homozygous specimens of various origins have different relative proportions of the two isoenzymes. By measuring the A:B ratios in such animals, a number of distinct haplotypes or amylase complexes, determining ratios ranging from 61% A:39% B to 12% A:88% B, have been recognized. These complexes differ also with respect to the total amount of amylase produced. If the reference stock C3H/As is given the value 1, then other haplotypes have values ranging from 1.0 to 0.27. Nineteen amylase haplotypes have been established in congenic lines on a C3H/As background. Some of these lines contain at least four active pancreatic amylase structural genes and breeding experiments have demonstrated that the genetic elements regulating total amylase production and relative proportions of the isoenzymes are located within the amylase complex, cis-acting, and very closely linked to the structural genes.
DUMPY MUTATIONS FOLLOWING X-IRRADIATION OF DROSOPHILA MELANOGASTER MATURE SPERM IN OXYGEN OR IN NITROGEN
Authors: Miyamoto Tomio
Published: January 2021

A comparison was made of the oxygen enhancement pattern among the different kinds of dumpy mutations (olv, ov, ol, lv, o and v types), yellow mutations on the scute-8 chromosome, white, miniature and forked mutations, and the marker losses in the doubly marked Y chromosome [BS Y sc  8 (y  +)], all of which were induced by X rays in mature sperm of Drosophila melanogaster. The results indicate that (1) an essential difference does not exist in the oxygen enhancement pattern between the different kinds of dumpy mutations, except for the ov exceptions. For these exceptions, relatively high enhancement by oxygen is elucidated; (2) a similarity exists in the oxygen enhancement pattern among the different kinds of dumpy mutations (except for the ov exceptions), yellow, miniature and forked mutations, and BS and y  + marker losses; and (3) the oxygen enhancement pattern elucidated for the ov exceptions is similar to that for the white mutations. These findings suggest that the nature of the different kinds of dumpy mutations is not different from one another, except for the ov exceptions, and that except for these ov exceptions and the white mutations, there seems to be some kind of similarity in the nature of mutation among the different kinds of mutations studied.
GENETIC RECOMBINATION AT THE BUFF SPORE COLOR LOCUS IN SORDARIA BREVICOLLIS. II. ANALYSIS OF FLANKING MARKER BEHAVIOR IN CROSSES BETWEEN BUFF MUTANTS
Authors: Sang Helen , Whitehouse Harold L K
Published: January 2021

Aberrant asci containing one or more wild-type spores were selected from crosses between pairs of alleles of the buff locus in the presence of closely linked flanking markers. Data were obtained relating to the site of aberrant segregation and the position of any associated crossover giving recombination of flanking markers. Aberrant segregation at a proximal site within the buff gene may be associated with a crossover proximal to the site of aberrant segregation or, with equal frequency, with a crossover distal to the site of the second mutant present in the cross. Similarly, segregation at a distal site may be associated with a crossover distal to the site or, with lower frequency, with a crossover proximal to the site of the proximal mutant present in the cross. Crossovers between the alleles were rare. This evidence for the relationship between hybrid DNA and crossing over is discussed in terms of current models for the mechanism of recombination.
ACTIVITY OF PLASMID REPLICONS IN CAULOBACTER CRESCENTUS: RP4 AND ColE1
Authors: O'Neill Edward A , Berlinberg Craig , Bender Robert A
Published: January 2021

The RP4 replicon was detected as covalently-closed circular DNA in Caulobacter crescentus strains into which it had been transferred from Escherichia coli. RP4-mediated transfer of ColE1-associated markers into C. crescentus occurred, but only as the result of transposon-mediated events. Both transposition of a ColE1-associated marker onto RP4 and cointegration of ColE1 with RP4 were observed. Chimeric plasmids containing both a ColE1 and an RP4 origin of replication were stably maintained in C. crescentus, but similar plasmids lacking the RP4 origin of replication were not stably maintained in C. crescentus. Thus we show that the ColE1 replicon cannot be maintained in C. crescentus unless it is covalently linked to another replicon, such as RK2, that can be maintained.
RELATIONS BETWEEN FACTORS CONTROLLING CROSSING OVER AND MUTABILITY IN MALES OF DROSOPHILA ANANASSAE
Authors: Hinton Claude W
Published: January 2021

Several stocks, selected because they carried previously identified factors governing either crossing over in males or mutability, were examined to determine whether the effects of these factors are restricted to one or the other process. Neither of two dominant enhancers of male crossing over had detectable effects on Minute mutation frequencies among progenies of assayed F1 males. Genetically equivalent F1 males monitored for crossing over showed no unequivocal effect of either of three mutators (two dominant and one extrachromosomal) or of a suppressor of mutability. However, one combination of a dominant crossover enhancer with a dominant mutator showed synergistic increases in both crossover and Minute frequencies, and the possibility exists that a single extrachromosomally transmitted element suppresses both male crossing over and mutability. This suppressor element (or elements) had been previously diagnosed in the pc stock which, in this study, was discovered to have also a dominant enhancer of male crossing over and a dominant mutator occupying separable loci in the third chromosome. The pc enhancer of male crossing over differs from the dominant enhancer in another stock with respect to the regional distribution of crossovers, and the pc mutator is distinguished from another 3-linked mutator by its preferential induction of mutations at the Delta locus.
EVIDENCE FOR BALANCING SELECTION AT HLA
Authors: Hedrick Philip W , Thomson Glenys
Published: January 2021

HLA data from the A and B loci for 22 populations were compared with the neutrality expectations from Ewens' sampling theory. In 25 of 44 cases, there was significantly less homozygosity than expected. Although a number of factors can affect homozygosity in this manner, upon close examination only symmetrical balancing selection appears to be consistent with these data.
BALANCING SELECTION, INVERSION POLYMORPHISM AND ADAPTATION IN DDT-RESISTANT POPULATIONS OF DROSOPHILA MELANOGASTER
Authors: Barnes Phillip T
Published: January 2021

The modes of selection important in maintaining an inversion-allozyme polymorphism in two laboratory populations of Drosophila melanogaster were examined. The populations, 731R and J2, are highly resistant to DDT. The polymorphism involves the Standard and In(3R)P chromosomal arrangements in very strong linkage association with the AO  1 and AO  4 allozymes, respectively, of the aldehyde oxidase locus—The mean fertilities of the three karyotypes were not significantly different in 731R, but, in J2, In/In was significantly inferior to St/St and St/In. Egg-to-adult viability tests indicated very strong heterozygote advantage at all frequency combinations of the karyotypes in both populations when DDT was present. When DDT was excluded, the viabilities varied over the frequency combinations but were not inversely correlated with karyotype frequency, as predicted by balancing frequency-dependent selection. Discrete, multiple-generation experiments showed a rapid increase in heterozygote frequency to about 80% in both populations when DDT was present. Without DDT, 731R showed apparent directional selection favoring St, whereas J2 showed persistence of the polymorphism, although with extensive fluctuation.—Thus, the inversion-allozyme polymorphism is directly involved in the adaptation to a specific environmental component, DDT, and the selective advantage of the heterozygotes is the important balancing force. Balancing frequency-dependent selection was not observed, which suggests the hypothesis that this form of selection may not be involved in adaptation to novel environmental conditions.
GENETICS OF YEAST GLUCOKINASE
Authors: Maitra P K , Lobo Zita
Published: January 2021

Mutants of Saccharomyces cerevisiae lacking glucokinase (EC 2.7.1.2) have no discernible phenotypic difference from the wild-type strain; in a hexokinaseless background, however, they are unable to grow on any sugar except galactose. Reversion studies with glucokinase mutants indicate that the yeast S. cerevisiae has no other enzyme for phosphorylating glucose except the two hexokinases, P1 and P2, and glucokinase. Spontaneous revertants of hxk1 hxk2 glk1 strains collected on glucose regain any one of these three enzymes. The majority of glucokinase revertants synthesize species of enzyme activity that are kinetically or otherwise indistinguishable from the wild-type enzyme. In a few cases the reverted enzyme is very perceptibly altered in properties with a Km for glucose two orders of magnitude higher than that of the enzyme from the wild-type parent. These recessive, noncomplementing mutants, thus, define a single structural gene GLK1 of glucokinase. Yeast diploids lacking all of the three enzymes for glucose phosphorylation fail to sporulate. Heterozygosity of either of the hexokinase genes HXK1 or HXK2, but not GLK1, restores sporulation. The location of GLK1 on chromosome III was indicated by loss of this chromosome when hexokinaseless diploids heterozygous for glk1 were selected for resistance to 2-deoxyglucose; the homologue of chromosome III carrying GLK1, the mating-type allele and other nutritional markers on this chromosome was lost. Meiotic mapping of glucokinase executed with heterozygosity of one of the hexokinases indicated that the gene GLK1 defining the structure of glucokinase protein is located on the left arm of chromosome III 24 cM to the left of his4 in the order: leu2—his4—glk1.—Only two of 206 independent glucokinase mutants are nonsense ochre, both of which map at one end of the gene. In hxk1 only one of 130 isolates is a nonsense mutation, whereas in hxk2 none has been found among 220 independent mutants. These results raise the possibility that the protein products of these genes have some other essential function.—An earlier mapping result for hxk2 has been corrected. The new location is on the left arm of chromosome VII, 17 cM distal to ade5 in the order: lys5—ade5—hxk2.
ANALYSES OF THE AGE OF GENES AND THE FIRST ARRIVAL TIMES IN A FINITE POPULATION
Authors: Maruyama Takeo , Fuerst Paul A
Published: January 2021

The age of a mutant gene is studied using the infinite allele model in which every mutant is new and selectively neutral. Based on a time reversal theory of Markov processes, we develop a method of mathematical analysis that is considerably simpler for calculating the various statistics of the age than previous methods. Formulas for the mean and variance and for the distribution of age are presented together with some examples of relevance to cases in natural populations.—Theoretical studies of the first arrival time of an allele to a specified frequency, given an initially monomorphic condition of the locus, are presented. It is shown that, beginning with an allele that has frequency p = 1 or an allele with frequency p = 1/2N, there is an initial lag phase in which there is virtually no chance of an allele with a specified intermediate frequency appearing in the population. The distribution of the first arrival time is also presented. The distribution shows several characteristics that are not immediately obvious from a consideration of only the mean and variance of first arrival time. Especially noteworthy is the existence of a very long tail to the distribution. We have also studied the distribution of the age of an allele in the population. Again, the distribution of this measure is shown to be more informative for several questions than are the mean and variance alone.
Expanded Supercooling Capacity With No Cryoprotectant Accumulation Underlies Cold Tolerance of the European Grapevine Moth
Authors: Masoudmagham Ashraf , Izadi Hamzeh , Mohammadzadeh Mojgan
Published: January 2021

The European grapevine moth, Lobesia botrana (Denis et Schiffermuller), is a serious invasive pest that causes significant losses to the flowers and fruits of grapes in most of the world. This multivoltine pest passes the winter as the third-generation diapausing pupa. The current study was designed to compare nondiapausing (first and second generations) and diapausing pupae (third generation) and to investigate the relationship among cold tolerance, the supercooling point (SCP), and diapause development of the third-generation diapausing pupae. The lethal temperatures (LTs) for the three generations were determined using 24-h exposure at subzero temperatures. The mean SCP of the pupae was estimated at approx. −22.6°C, the lowest level of which (−23.7°C) was recorded in the well-developed diapausing pupae in February. The highest level of cold tolerance was also recorded in February. There were no significant differences among the temperatures required to kill 30, 50, and 90% of the pupae. The temperatures significantly decreased from October onward and reached the lowest levels in February during which the lowest SCP and the highest cold tolerance were observed in the diapausing pupae. No significant differences were found in the cryoprotectant levels, among the diapausing and nondiapausing pupae, and the diapause development. The highest activity of cAMP-dependent protein kinase (AMPK) was recorded in the late diapause in February. The findings suggested a relationship among SCP depression, cold tolerance enhancement, and diapause development. A bimodal cold-tolerance strategy (freeze-intolerant and freeze-tolerant) was found to be a feature of the pupae.
UGT76B1, a promiscuous hub of small molecule-based immune signaling, glucosylates N-hydroxypipecolic acid, and balances plant immunity
Authors: Bauer Sibylle , Mekonnen Dereje W , Hartmann Michael , Yildiz Ipek , Janowski Robert , Lange Birgit , Geist Birgit , Zeier Jürgen , Schäffner Anton R
Published: January 2021

Glucosylation modulates the biological activity of small molecules and frequently leads to their inactivation. The Arabidopsis thaliana glucosyltransferase UGT76B1 is involved in conjugating the stress hormone salicylic acid (SA) as well as isoleucic acid (ILA). Here, we show that UGT76B1 also glucosylates N-hydroxypipecolic acid (NHP), which is synthesized by FLAVIN-DEPENDENT MONOOXYGENASE 1 (FMO1) and activates systemic acquired resistance (SAR). Upon pathogen attack, Arabidopsis leaves generate two distinct NHP hexose conjugates, NHP-O-β-glucoside and NHP glucose ester, whereupon only NHP-O-β-glucoside formation requires a functional SA pathway. The ugt76b1 mutants specifically fail to generate the NHP-O-β-glucoside, and recombinant UGT76B1 synthesizes NHP-O-β-glucoside in vitro in competition with SA and ILA. The loss of UGT76B1 elevates the endogenous levels of NHP, SA, and ILA and establishes a constitutive SAR-like immune status. Introgression of the fmo1 mutant lacking NHP biosynthesis into the ugt76b1 background abolishes this SAR-like resistance. Moreover, overexpression of UGT76B1 in Arabidopsis shifts the NHP and SA pools toward O-β-glucoside formation and abrogates pathogen-induced SAR. Our results further indicate that NHP-triggered immunity is SA-dependent and relies on UGT76B1 as a common metabolic hub. Thereby, UGT76B1-mediated glucosylation controls the levels of active NHP, SA, and ILA in concert to balance the plant immune status.
Neuromodulatory Effect of Transcranial Direct Current Stimulation on Resting-State EEG Activity in Internet Gaming Disorder: A Randomized, Double-Blind, Sham-Controlled Parallel Group Trial
Authors: Lee Ji-Yoon , Jang Joon Hwan , Choi A Ruem , Chung Sun Ju , Kim Bomi , Park Minkyung , Oh Sohee , Jung Myung Hun , Choi Jung-Seok
Published: January 2021

Transcranial direct current stimulation (tDCS) has been used as an adjunct therapy for psychiatric disorders; however, little is known about the underlying neurophysiological effects of tDCS in Internet gaming disorder (IGD). We investigated the effects of tDCS on cortical activity using resting-state electroencephalography (EEG) in patients with IGD. This randomized, double-blind, sham-controlled parallel group study of tDCS (ClinicalTrials.gov NCT03347643) included 31 IGD patients. Participants received 10 sessions (2 sessions per day for 5 consecutive days) of active repetitive tDCS (2 mA for 20 min per session) or sham stimulation. Anode/cathode electrodes were placed over the left and right dorsolateral prefrontal cortex, respectively. In total, 26 participants (active group n = 14; sham group n = 12) completed the trial. Resting-state EEG spectral activity (absolute power) and functional connectivity (coherence) were used to assess the effects of tDCS on cortical activity before stimulation and 1 month after the intervention. Active stimulation of tDCS suppressed increase of intra-hemispheric beta coherence after 1 month, which was observed in the sham group. The 1-month follow-up assessment revealed that absolute gamma power in the left parietal region was decreased in the active group relative to the sham group. Our findings suggest that repetitive tDCS stabilizes fast-wave activity in IGD.
Transcriptome Analysis Reveals the Symbiotic Mechanism of Ustilago esculenta-Induced Gall Formation of Zizania latifolia
Authors: Li Jie , Lu Zhiyuan , Yang Yang , Hou Jinfeng , Yuan Lingyun , Chen Guohu , Wang Chenggang , Jia Shaoke , Feng Xuming , Zhu Shidong
Published: January 2021

Zizania latifolia is a perennial aquatic vegetable, whose symbiosis with the fungus Ustilago esculenta (member of Basidiomycota, class Ustilaginaceae) results in the establishment of swollen gall formations. Here, we analyzed symbiotic relations of Z. latifolia and U. esculenta, using a triadimefon (TDF) treatment and transcriptome sequencing (RNA-seq). Specifically, accurately identify the whole growth cycle of Z. latifolia. Microstructure observations showed that the presence of U. esculenta could be clearly observed after gall formation but was absent after the TDF treatment. A total of 17,541 differentially expressed genes (DEGs) were identified, based on the transcriptome. According to gene ontology term and Kyoto Encyclopedia of Genes and Genomes pathway results, plant hormone signal transduction, and cell wall–loosening factors were all significantly enriched due to U. esculenta infecting Z. latifolia; relative expression levels of hormone-related genes were identified, of which downregulation of indole 3-acetic acid (IAA)-related DEGs was most pronounced in JB_D versus JB_B. The ultra–high performance liquid chromatography analysis revealed that IAA, zeatin+trans zeatin riboside, and gibberellin 3 were increased under U. esculenta infection. Based on our results, we proposed a hormone–cell wall loosening model to study the symbiotic mechanism of gall formation after U. esculenta infects Z. latifolia. Our study thus provides a new perspective for studying the physiological and molecular mechanisms of U. esculenta infection of Z. latifolia causing swollen gall formations as well as a theoretical basis for enhancing future yields of cultivated Z. latifolia.

[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law. 2021
The Root Lesion Nematode EffectorPpen10370Is Essential for Parasitism ofPratylenchus penetrans
Authors: Vieira Paulo , Vicente Cláudia S. L. , Branco Jordana , Buchan Gary , Mota Manuel , Nemchinov Lev G.
Published: January 2021

The root lesion nematode Pratylenchus penetrans is a migratory species that attacks a broad range of crops. Like other plant pathogens, P. penetrans deploys a battery of secreted protein effectors to manipulate plant hosts and induce disease. Although several candidate effectors of P. penetrans have been identified, detailed mechanisms of their functions and particularly their host targets remain largely unexplored. In this study, a repertoire of candidate genes encoding pioneer effectors of P. penetrans was amplified from mixed life stages of the nematode, and candidate effectors were cloned and subjected to transient expression in a heterologous host, Nicotiana benthamiana, using potato virus X–based gene vector. Among seven analyzed genes, the candidate effector designated as Ppen10370 triggered pleiotropic phenotypes substantially different from those produced by wild type infection. Transcriptome analysis of plants expressing Ppen10370 demonstrated that observed phenotypic changes were likely related to disruption of core biological processes in the plant due to effector-originated activities. Cross-species comparative analysis of Ppen10370 identified homolog gene sequences in five other Pratylenchus species, and their transcripts were found to be localized specifically in the nematode esophageal glands by in situ hybridization. RNA silencing of the Ppen10370 resulted in a significant reduction of nematode reproduction and development, demonstrating an important role of the esophageal gland effector for parasitism.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
The FgCYP51B Y123H Mutation Confers Reduced Sensitivity to Prochloraz and Is Important for Conidiation and Ascospore Development in Fusarium graminearum
Authors: Zhao Yanxiang , Chi Mengyu , Sun Hunlin , Qian Hengwei , Yang Jun , Huang Jinguang
Published: January 2021

Fusarium graminearum is one of the most important causal agents of Fusarium head blight disease and is controlled mainly by chemicals such as demethylation inhibitor (DMI) fungicides. FgCYP51B is one of the DMI targets in F. graminearum, and Tyrosine123 (Y123) is an important amino acid in F. graminearum CYP51B, located in one of predicted substrate binding pockets based on the binding mode between DMIs and CYP51B. Previous studies suggest that resistance to DMI fungicides is attributed primarily to point mutations in the CYP51 gene and that the Y123H mutation in F. verticillioides CYP51 confers prochloraz resistance in the laboratory. To investigate the function of FgCYP51B Y123 residue in the growth and development, pathogenicity, and DMI resistance, we generated and analyzed the FgCYP51B Y123H mutant. Results revealed that the Y123H mutation led to reduced conidial sporulation and affected ascospore development; moreover, the mutation conferred reduced sensitivity to prochloraz. Quantitative PCR and molecular docking were performed to investigate the resistance mechanism. Results indicated that Y123H mutation changed the target gene expression and decreased the binding affinity of FgCYP51 to prochloraz. These results will attract more attention to the potential DMI-resistant mutation of F. graminearum and increase our understanding of the DMI resistance mechanism.
Effect of deep neuromuscular blockade on serum cytokines and postoperative delirium in elderly patients undergoing total hip replacement
Authors: Oh Chung-Sik , Lim Ho Yung , Jeon Hong Jun , Kim Tae-Hoon , Park Hyun-Jun , Piao Liyun , Kim Seong-Hyop
Published: January 2021

BACKGROUND

Deep neuromuscular blockade (NMB) may reduce muscle injury and related inflammation. The inflammation is one of the pathophysiological processes of peri-operative complications.

OBJECTIVE

To compare the degree of inflammation and related postoperative complications including postoperative delirium (POD) and peri-operative bleeding according to the degree of NMB during general anaesthesia for total hip replacement.

DESIGN

A prospective, single-blind, randomised controlled trial.

SETTING

Tertiary, university hospital, single centre.

PATIENTS

Eighty-two patients undergoing total hip replacement surgery were included in the final analysis.

INTERVENTIONS

Moderate (Mod) and deep (Deep) NMB groups.

MAIN OUTCOME MEASURES

The changes in inflammatory cytokines were measured. The incidence of POD was evaluated by using confusion assessment method (CAM). The differences of postoperative bleeding and peri-operative oxygenation in both groups were also measured.

RESULTS

The NMB reversal duration was significantly longer in the Mod NMB group than in the Deep NMB group. Changes in interleukin-6 were significantly smaller in the Deep NMB group than in the Mod NMB group (P < 0.001). The incidence of POD was not significantly different between groups (34 versus 17% in Mod and Deep NMB groups, respectively; P = 0.129). The amount of postoperative bleeding until postoperative day 2 was significantly greater in the Mod NMB group than in the Deep NMB group (P = 0.027).

CONCLUSION

Our findings suggest that inflammation related to peri-operative complications could be associated with the depth of NMB during total hip replacement. However, the incidence of POD might not be associated to the depth of NMB.

TRIAL REGISTRATION

National Library of Medicine (NLM) at the National Institutes of Health (NIH) of United States. (Identifier: NCT02507609). Online address: http://clinicaltrials.gov
Pre-operative anaemia and myocardial injury after noncardiac surgery
Authors: Kwon Ji-Hye , Park Jungchan , Lee Seung-Hwa , Lee Jong Hwan , Min Jeong Jin , Kim Jihoon , Oh Ah Ran , Seo Wonho , Hyeon Cheol Won , Yang Kwangmo , Choi Jin-ho , Lee Sang-Chol , Kim Kyunga , Ahn Joonghyun , Gwon Hyeon-Cheol
Published: January 2021

BACKGROUND

Pre-operative anaemia is associated with adverse outcomes of noncardiac surgery, but its association with myocardial injury after noncardiac surgery (MINS) has not been fully investigated.

OBJECTIVE

The association between pre-operative anaemia and MINS.

DESIGN

A single-centre retrospective cohort study.

SETTING

Tertiary care referral centre.

PATIENTS

Patients with measured cardiac troponin (cTn) I levels after noncardiac surgery.

INTERVENTIONS

Patients were separated according to pre-operative anaemia (haemoglobin <13 g dl−1 in men and <12 g dl−1 in women). Anaemia was further stratified into mild and moderate-to-severe at a haemoglobin level threshold of 11 g dl−1.

MAIN OUTCOME MEASURES

The primary outcome was MINS, defined as a peak cTn I level more than 99th percentile of the upper reference limit within 30 postoperative days.

RESULTS

Data from a total of 35 170 patients were collected, including 22 062 (62.7%) patients in the normal group and 13 108 (37.3%) in the anaemia group. After propensity score matching, 11919 sets of patients were generated, and the incidence of MINS was significantly associated with anaemia [14.5 vs. 21.0%, odds ratio (OR) 1.57, 95% confidence interval (CI) 1.47 to 1.68, P < 0.001]. For the entire population, multivariable analysis showed a graded association between anaemia severity and MINS (OR 1.32, 95% CI 1.22 to 1.43, P < 0.001 for mild anaemia and OR 1.80, 95% CI 1.66 to 1.94, P < 0.001 for moderate-to-severe anaemia compared with the normal group) and a significantly higher incidence of MINS for moderate-to-severe anaemia than mild anaemia (18.6 vs. 28.6%, OR 1.37, 95% CI 1.25 to 1.50, P < 0.001). The estimated threshold for pre-operative haemoglobin associated with MINS was 12.2 g dl−1, with an area under the curve of 0.622.

CONCLUSIONS

Pre-operative anaemia was independently associated with MINS, suggesting that MINS may be related to the association between anaemia and postoperative mortality.

TRIAL REGISTRATION

SMC 2019-08-048
The short-term efficacy and safety of fractional CO2 laser therapy for vulvovaginal symptoms in menopause, breast cancer, and lichen sclerosus
Authors: Gardner Alyssa N. , Aschkenazi Sarit O.
Published: January 2021

Objective:

To review the short-term effects and safety of vulvovaginal fractional microablative CO2 laser therapy on atrophy symptoms using validated questionnaires pre- and posttreatment.

Methods:

This is a retrospective chart review from January, 2016 to December, 2019 on 139 women with vulvovaginal atrophy symptoms, who completed three treatments about 6 weeks apart. All were >18 years old and nonpregnant. As is the practice in our clinic for all women receiving treatment, they were surveyed prior to the 1st and 3rd treatments with validated questionnaires, Female Sexual Function Index (FSFI) and Vulvovaginal Symptoms Questionnaire (VSQ), as well as a visual analog scale (VAS). Paired t test was completed on the pre- and post FSFI and VAS scores. Pre- and postproportions of the VSQ were evaluated by the Fisher's exact test. Means were presented for each study variable. Multivariable regression analysis was completed on continuous and binomial variables for scores predictors.

Results:

Mean age was 62 years with a mean follow-up of 13.8 weeks. Concomitant topical estrogen was reported in 53% (n = 74). Breast cancer diagnosis was documented in 27% (n = 38), and lichen sclerosus in 22% (n = 31). All FSFI scores improved (pre: 12.7, post: 19.0, P < 0.001). The VSQ showed 18 of 21 questions significantly improved (P < 0.05). The VAS showed significant improvement in painful intercourse (pre: 6.6, post: 2.4, P < 0.001), and vulvar dryness (pre: 4.6, post: 1.5, P < 0.001). Posttreatments, 17 additional women became sexually active. No major adverse events were reported.

Conclusions:

Fractional CO2 laser may be effective and safe for the treatment vulvovaginal atrophy.

Video Summary:
http://links.lww.com/MENO/A700.
Review of Technical Advancements and Clinical Applications of Photon-counting Computed Tomography in Imaging of the Thorax
Authors: Farhadi Faraz , Rajagopal Jayasai R. , Nikpanah Moozhan , Sahbaee Pooyan , Malayeri Ashkan A. , Pritchard William F. , Samei Ehsan , Jones Elizabeth C. , Chen Marcus Y.
Published: January 2021

Photon-counting computed tomography (CT) is a developing technology that has the potential to address some limitations of CT imaging and bring about improvements and potentially new applications to this field. Photon-counting detectors have a fundamentally different detection mechanism from conventional CT energy-integrating detectors that can improve dose efficiency, spatial resolution, and energy-discrimination capabilities. In the past decade, promising human studies have been reported in the literature that have demonstrated benefits of this relatively new technology for various clinical applications. In this review, we provide a succinct description of the photon-counting detector technology and its detection mechanism in comparison with energy-integrating detectors in a manner understandable for clinicians and radiologists, introduce benefits and some of the existing challenges present in this technology, and provide an overview of the current status and potential clinical applications of this technology in imaging of the thorax by providing example images acquired with an investigational whole-body photon-counting CT scanner.
Predicting treatment toxicity in older adults with cancer
Authors: Menjak Ines B. , Giffoni de Mello Morais Mata Danilo , Chesney Tyler R. , Haase Kristen R.
Published: January 2021

Purpose of review

To provide an overview of the recent advancements in predicting toxicity associated with cancer treatment in older patients.

Recent findings

Various screening tools and validated risk calculators have been shown to help predict toxicity from surgery and chemotherapy. Radiation therapy has been more challenging to select the appropriate tool to reliably predict patients at risk for toxicity and noncompliance. Ongoing work on electronic geriatric assessment tools is showing promise in making comprehensive assessment more feasible.

Selecting appropriate cancer therapy is particularly important in older patients, and validated tools have been developed to guide clinicians for surgery and chemotherapy; however, radiotherapy toxicity remains an area for further development, as does the uptake of existing tools into routine oncology practice.
Autism associatedSHANK3missense point mutations impact conformational fluctuations and protein turnover at synapses
Authors: Bucher Michael , Niebling Stephan , Han Yuhao , Molodenskiy Dmitry , Kreienkamp Hans-Jürgen , Svergun Dmitri , Kim Eunjoon , Kostyukova Alla S. , Kreutz Michael R. , Mikhaylova Marina
Published: January 2021

Members of the SH3- and ankyrin-rich repeat (SHANK) protein family are considered as master scaffolds of the post-synaptic density of glutamatergic synapses. Several missense mutations within the canonical SHANK3 isoform have been proposed as causative for the development of autism spectrum disorders (ASDs). However, there is a surprising paucity of data linking missense mutation-induced changes in protein structure and dynamics to the occurrence of ASD-related synaptic phenotypes. In this work, we focus on two ASD-associated point mutations, both located within the same domain of SHANK3. In a proof-of-principle study we demonstrate that both mutant proteins show indeed distinct changes in secondary and tertiary structure as well as higher conformational fluctuations. Local and surprisingly also distal structural disturbances of protein folding result in altered synaptic targeting and changes of protein turnover at synaptic sites.
Extracellular endosulfatase Sulf-2 harbours a chondroitin/dermatan sulfate chain that modulates its enzyme activity
Authors: Masri Rana El , Seffouh Amal , Roelants Caroline , Seffouh Ilham , Gout Evelyne , Pérard Julien , Dalonneau Fabien , Nishitsuji Kazuchika , Noborn Fredrik , Nikpour Mahnaz , Larson Göran , Crétinon Yoann , Uchimura Kenji , Daniel Régis , Lortat-Jacob Hugues , Filhol Odile , Vivès Romain R.
Published: January 2021

Sulfs represent a class of unconventional sulfatases, which differ from all other members of the sulfatase family by their structures, catalytic features and biological functions. Through their specific endosulfatase activity in extracellular milieu, Sulfs provide an original post-synthetic regulatory mechanism for heparan sulfate complex polysaccharides and have been involved in multiple physiopathological processes, including cancer. However, Sulfs remain poorly characterized enzymes, with major discrepancies regarding theirin vivofunctions. Here we show that human Sulf-2 (HSulf-2) features a unique polysaccharide post-translational modification. We identified a chondroitin/dermatan sulfate glycosaminoglycan (GAG) chain, attached to the enzyme substrate binding domain. We found that this GAG chain affects enzyme/substrate recognition and tunes HSulf-2 activityin vitroandin vivousing a mouse model of tumorigenesis and metastasis. In addition, we showed that mammalian hyaluronidase acted as a promoter of HSulf-2 activity by digesting its GAG chain. In conclusion, our results highlight HSulf-2 as a unique proteoglycan enzyme and its newly-identified GAG chain as a critical non-catalytic modulator of the enzyme activity. These findings contribute in clarifying the conflicting data on the activities of the Sulfs and introduce a new paradigm into the study of these enzymes.
Differential phase register of Hes1 oscillations with mitoses underlies cell-cycle heterogeneity in ER+ breast cancer cells
Authors: Sabherwal Nitin , Rowntree Andrew , Marinopoulou Elli , Pettini Tom , Hourihane Sean , Thomas Riba , Kursawe Jochen , Soto Ximena , Papalopulu Nancy
Published: January 2021

Here, we study the dynamical expression of endogenously labelled Hes1, a transcriptional repressor implicated in controlling cell proliferation, to understand how cell-cycle length heterogeneity is generated in ER+ breast cancer cells. We find that Hes1 shows oscillatory expression with approximately 25h periodicity and during each cell-cycle has a variable peak in G1, a trough around G1-S transition and a less variable second peak in G2/M. Compared to other subpopulations, the cell-cycle in CD44HighCD24Lowcancer stem cells is longest and most variable. Most cells divide around the peak of the Hes1 expression wave but preceding mitoses in slow dividing CD44HighCD24Lowcells appear phase-shifted, resulting in a late-onset Hes1 peak in G1. The position, duration and shape of this peak, rather than the Hes1 expression levels, are good predictors of cell-cycle length. Diminishing Hes1 oscillations by enforcing sustained expression slows down the cell-cycle, impairs proliferation, abolishes the dynamic expression of p21, and increases the percentage of CD44HighCD24Lowcells. Reciprocally, blocking the cell-cycle causes an elongation of Hes1 periodicity, suggesting a bidirectional interaction of the Hes1 oscillator and the cell-cycle. We propose that Hes1 oscillations are functionally important for the efficient progression of the cell-cycle and that the position of mitosis in relation to the Hes1 wave underlies cell-cycle length heterogeneity in cancer cell subpopulations.

Significance statement

Tumours exhibit heterogeneities that are not due to mutations, including Cancer Stem Cells with different potencies. We show that the cancer stem cell state predisposed to dormancyin vivohas a highly variable and long cell-cycle. Using single-cell live-imaging for the transcriptional repressor Hes1 (a key molecule in cancer), we show a new type of circadian-like oscillatory expression of Hes1 in all cells in the population. The most potent cancer stem cells tend to divide around the trough of the Hes1 oscillatory wave, a feature predictive of a long cell-cycle. A novel concept proposed here is that the position of cell division with respect to the Hes1 wave is predictive of its prospective cell-cycle length and cancer cellular sub-state.
Reduced miR-184-3p expression occurring in Type 2 diabetic pancreatic islets protects β-cells from lipotoxic and proinflammatory apoptosis via a CRTC1-dependent mechanism
Authors: Grieco Giuseppina E. , Brusco Noemi , Nigi Laura , Formichi Caterina , Fignani Daniela , Licata Giada , Marselli Lorella , Marchetti Piero , Salvini Laura , Tinti Laura , Po Agnese , Ferretti Elisabetta , Sebastiani Guido , Dotta Francesco
Published: January 2021

Loss of functional β-cell mass in Type 2 diabetes (T2D) involves molecular mechanisms including β-cell apoptosis, dysfunction, and/or dedifferentiation. MicroRNA miR-184-3p has been demonstrated to be involved in multiple β-cell functions including insulin secretion, proliferation and survival. However, downstream targets and upstream regulators of miR-184-3p have not yet been fully elucidated. Here, we showed that levels of miR-184-3p are reduced in human T2D pancreatic islets and that its reduction protected β-cells from lipotoxic- and inflammatory-induced apoptosis. Interestingly, CREB-Transcriptional Coactivator-1 (CRTC1) is a direct target of miR-184-3p and indeed its expression is upregulated in human T2D pancreatic islets. The downregulation of miR-184-3p in β-cells induced the upregulation of CRTC1 both at mRNA and protein level. Of note, miR-184-3p protection effect was dependent on CRTC1, since its silencing in human β-cells abrogates the protective mechanism exerted by miR-184-3p inhibition. Additionally, we found that the β-cell specific transcription factor NKX6.1, whose DNA binding sites were predicted to be present in human and mouse MIR184 gene promoter sequence, was reduced in T2D human pancreatic islets, in line with miR-184-3p downregulation, and was positively correlated with microRNA expression. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression.

In conclusion, we found that miR-184-3p expression is controlled by the β-cell specific transcription factor NKX6.1 and that miR-184-3p reduction protects β-cells from apoptosis through the upregulation of its target gene CRTC1.
The geometry of the representation of decision variable and stimulus difficulty in the parietal cortex
Authors: Okazawa Gouki , Hatch Christina E. , Mancoo Allan , Machens Christian K. , Kiani Roozbeh
Published: January 2021

Lateral intraparietal (LIP) neurons represent formation of perceptual decisions involving eye movements. In circuit models for these decisions, neural ensembles that encode actions compete to form decisions. Consequently, decision variables (DVs) are represented as partially potentiated action plans, where ensembles increase their average responses for stronger evidence supporting their preferred actions. As another consequence, DV representation and readout are implemented similarly for decisions with identical competing actions, irrespective of input and task context differences. Here, we challenge those core principles using a novel face-discrimination task, where LIP firing rates decrease with supporting evidence, contrary to conventional motion-discrimination tasks. These opposite response patterns arise from similar mechanisms in which decisions form along curved population-response manifolds misaligned with action representations. These manifolds rotate in state space based on task context, necessitating distinct readouts. We show similar manifolds in lateral and medial prefrontal cortices, suggesting a ubiquitous representational geometry across decision-making circuits.
ERK signaling licenses SKN-1A/NRF1 for proteasome production and proteasomal stress resistance
Authors: Zhang Peng , Qu Hai-Yan , Wu Ziyun , Na Huimin , Hourihan John , Zhang Fang , Zhu Feimei , Isik Meltem , Walhout Albertha J.M. , Feng Yu-Xiong , Blackwell T. Keith
Published: January 2021

The ubiquitin-proteasome system is vital for cell growth and homeostasis, but for most cancers proteasomal inhibition has not been effective as a therapy. Normal and cancer cells adapt to proteasomal stress through an evolutionarily conserved recovery response, in which the transcription factor NRF1 upregulates proteasome subunit genes. Starting with aC. elegansscreen to identify regulators of the recovery response, here we show that this response depends upon phosphorylation of NRF1 on a single residue by the growth factor-activated kinase ERK1/2. Inhibition of this phosphorylation impairs NRF1 nuclear localization and proteasome gene activation, sensitizesC. elegansand cancer cells to proteasomal stress, and synergizes with proteasome inhibition to retard human melanoma growthin vivoin a mouse model. The evolutionarily conserved ERK1/2-NRF1 axis couples proteasome production to growth signaling, and represents a promising new strategy for expanding the range and efficacy of proteasomal inhibition therapy in cancer.
N-[2-(3,4-Dimethoxyphenyl)-2-(phenylsulfanyl)ethyl]-2-(2-fluorophenyl)acetamide
Authors: Ovalle Marco A. , Romero José A. , Aguirre Gerardo
Published: January 2021

The title compound, C24H24FNO3S, is an intermediate in the synthesis of fluorine containing isoquinoline alkaloids, which crystallizes in the triclinic space group P\overline{1} with one molecule in the asymmetric unit. The structure presents a racemic mixture of enantiomers. The C—S—C—C torsion angle between the benzene ring system and the sulfonyl benzene ring is −178.5 (1)°. In the crystal, N—H...O hydrogen bonds between neighbouring molecules form chains of molecules along the a-axis direction.