bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic interactions with stressful environments in depression and addiction
Authors: Burmeister Margit , Sen Srijan 
Published: April 2021

SUMMARYStress is the most important proximal precipitant of depression, yet most large genome-wide association studies (GWAS) do not include stress as a variable. Here, we review how gene × environment (G × E) interaction might impede the discovery of genetic factors, discuss two examples of G × E interaction in depression and addiction, studies incorporating high-stress environments, as well as upcoming waves of genome-wide environment interaction studies (GWEIS). We discuss recent studies which have shown that genetic distributions can be affected by social factors such as migrations and socioeconomic background. These distinctions are not just academic but have practical consequences. Owing to interaction with the environment, genetic predispositions to depression should not be viewed as unmodifiable destiny. Patients may genetically differ not just in their response to drugs, as in the now well-recognised field of pharmacogenetics, but also in how they react to stressful environments and how they are affected by behavioural therapies.
Investigating smoking and nicotine dependence among people with severe mental illness during the COVID-19 pandemic: analysis of linked data from a UK Closing the Gap cohort
Authors: Peckham Emily , Allgar Victoria , Crosland Suzanne , Heron Paul , Johnston Gordon , Newbronner Elizabeth , Ratschen Elena , Spanakis Panagiotis , Wadman Ruth , Walker Lauren , Gilbody Simon 
Published: April 2021

Summary
Smoking rates are higher for people who use mental health services, which contributes substantially to health inequalities. Smoking can lead to worse COVID-19 outcomes, yet it remains unclear whether smoking has changed for people who use mental health services. We examined smoking patterns in a large clinical cohort of people with severe mental illness, before and during the pandemic. We found high levels of nicotine dependence and heavier patterns of smoking. Although some people had reported quitting, it is likely that smoking inequalities have become further entrenched. Mental health services should seek to mitigate this modifiable risk and source of poor health.
Building External Control Arms From Patient-Level Electronic Health Record Data to Replicate the Randomized IMblaze370 Control Arm in Metastatic Colorectal Cancer
Authors: Schröder Carsten , Lawrance Marcus , Li Chen , Lenain Christelle , Mhatre Shivani K. , Fakih Marwan , Reyes-Rivera Irmarie , Bretscher Michael T. 
Published: April 2021

PURPOSE External control (EC) arms derived from electronic health records (EHRs) can provide appropriate comparison groups when randomized control arms are not feasible, but have not been explored for metastatic colorectal cancer (mCRC) trials. We constructed EC arms from two patient-level EHR-derived databases and evaluated them against the control arm from a phase III, randomized controlled mCRC trial. METHODS IMblaze370 evaluated atezolizumab with or without cobimetinib versus regorafenib in patients with mCRC. EC arms were constructed from the Flatiron Health (FH) EHR-derived de-identified database and the combined FH/Foundation Medicine Clinico-Genomic Database (CGDB). IMblaze370 eligibility criteria were applied to the EC cohorts. Propensity scores and standardized mortality ratio weighting were used to balance baseline characteristics between the IMblaze370 and EC arms; balance was assessed using standardized mean differences. Kaplan-Meier method estimated median overall survival (OS). Cox proportional hazards models estimated hazard ratios with bootstrapped 95% CIs to compare differences in OS between study arms. RESULTS The FH EC included 184 patients; the CGDB EC included 108 patients. Most characteristics were well-balanced (standardized mean difference < 0.1) between each EC arm and the IMblaze370 population. Median OS was similar between the IMblaze370 control arm (8.5 months [95% CI, 6.41 to 10.71]) and both EC arms: FH (8.5 months [6.93 to 9.92]) and CGDB (8.8 months [7.85 to 9.92]). OS comparisons between the IMblaze370 experimental arm and the FH EC (hazard ratio, 0.85 [0.64 to 1.14]) and CGDB EC (0.86 [0.65 to 1.18]) yielded similar results as the comparison with the IMblaze370 control arm (1.01 [0.75 to 1.37]). CONCLUSION EC arms constructed from the FH database and the CGDB closely replicated the control arm from IMblaze370. EHR-derived EC arms can provide meaningful comparators in mCRC trials when recruiting a randomized control arm is not feasible.
Advancing Breast Cancer Advocacy in Eastern Europe and Central Asia: Findings From Women’s Empowerment Cancer Advocacy Network (WE CAN) Summits
Authors: Antone Nicoleta , Kizub Darya , Gralow Julie , Zujewski Jo Anne , Dvaladze Allison 
Published: April 2021

PURPOSE Breast cancer civil society organizations have emerged in Eastern Europe and Central Asia to raise awareness about cancer as a survivable disease and provide patient support. We explored the experiences and priorities of these organizations with the goal of making recommendations to advance cancer advocacy and improve cancer care. METHODS We conducted in-depth interviews and focus group discussions with representatives of civil society organizations attending the 7th Women’s Empowerment Cancer Advocacy Network Summit in Romania in 2015. Interviews were audiorecorded, transcribed, coded, and analyzed for key themes. Findings were discussed at the 8th Women’s Empowerment Cancer Advocacy Network Summit in Ukraine in 2017 to ensure accuracy. RESULTS We conducted nine in-depth interviews and three focus group discussions with a total of 36 participants. Survivor- and oncologist-led organizations played an important role in filling existing gaps in public health care systems through awareness raising, patient support, and advocacy to improve early detection and access to treatment. Barriers to these efforts included persistent stigma, mistrust of patients toward the public health care system, limited access to evidence-based guidelines, difficulty adapting existing best practices to their setting, and insufficient involvement of policymakers. Key facilitators of advocacy efforts included effective local and international partnerships with physicians, like-minded organizations, and policymakers to facilitate access to educational resources, improve breast cancer early detection and care, and catalyze meaningful policy change. CONCLUSION Our findings highlight the value of providing opportunities for advocates to connect and share experiences. To advance cancer advocacy and improve cancer care, the following needs were identified: dissemination of resource-adapted information for improving outcomes; needs assessments; improved program-monitoring practices; and fostering and promotion of collaboration between advocates, medical professionals, and local governments.
Efficacy of an Online Curriculum for Perioperative Goals of Care and Code Status Discussions: A Randomized Controlled Trial
Authors: Robertson Amy C. , Fowler Leslie C. , Kimball Thomas S. , Niconchuk Jonathan A. , Kreger Michael T. , Brovman Ethan Y. , Rickerson Elizabeth , Sadovnikoff Nicholas , Hepner David L. , McEvoy Matthew D. , Bader Angela M. , Urman Richard D. 
Published: April 2021

BACKGROUND:
Preoperative goals of care (GOC) and code status (CS) discussions are important in achieving an in-depth understanding of the patient’s care goals in the setting of a serious illness, enabling the clinician to ensure patient autonomy and shared decision making. Past studies have shown that anesthesiologists are not formally trained in leading these discussions and may lack the necessary skill set. We created an innovative online video curriculum designed to teach these skills. This curriculum was compared to a traditional method of learning from reading the medical literature.

METHODS:
In this bi-institutional randomized controlled trial at 2 major academic medical centers, 60 anesthesiology trainees were randomized to receive the educational content in 1 of 2 formats: (1) the novel video curriculum (video group) or (2) journal articles (reading group). Thirty residents were assigned to the experimental video curriculum group, and 30 were assigned to the reading group. The content incorporated into the 2 formats focused on general preoperative evaluation of patients and communication strategies pertaining to GOC and CS discussions. Residents in both groups underwent a pre- and postintervention objective structured clinical examination (OSCE) with standardized patients. Both OSCEs were scored using the same 24-point rubric. Score changes between the 2 OSCEs were examined using linear regression, and interrater reliability was assessed using weighted Cohen’s kappa.

RESULTS:
Residents receiving the video curriculum performed significantly better overall on the OSCE encounter, with a mean score of 4.19 compared to 3.79 in the reading group. The video curriculum group also demonstrated statistically significant increased scores on 8 of 24 rubric categories when compared to the reading group.

CONCLUSIONS:
Our novel video curriculum led to significant increases in resident performance during simulated GOC discussions and modest increases during CS discussions. Further development and refinement of this curriculum are warranted.
Differential expression of a muscle actin gene in muscle cell lineages of ascidian embryos
Authors: Tomlinson Craig R. , Beach Rebecca L. , Jeffery William R. 
Published: April 2021

ABSTRACTSpecific probes were used to examine the accumulation of muscle actin mRNA during embryonic development of the ascidian Styela. Clones of a muscle actin gene were obtained from an adult mantle cDNA library. Four lines of evidence indicate that these clones correspond to a muscle actin gene. First, their coding regions share 11 of 14 diagnostic amino acid positions with mammalian smooth and skeletal muscle actins. Second, subclones that contain only the 3’ noncoding region of the gene select mRNA coding for muscle actin, while subclones that include the coding region of the gene select mRNA coding for muscle and nonmuscle actins. Third, a probe that contains only the 3’ noncoding region detects a single band, corresponding to a 2 kb transcript, while a probe that includes the coding region detects the 2 kb transcript and at least one other band, presumably a cytoplasmic actin transcript. Fourth, the 3’ noncoding region probe detects transcripts only in muscle cells and their precursors, while the coding region probe detects transcripts in muscle and nonmuscle cells. The muscle actin transcript is present at very low levels in eggs and early embryos, begins to accumulate between the early gastrula and tailbud stages, and by the tadpole stage attains a level about 25-fold higher than in the egg. In situ hybridization showed that embryonic muscle actin transcripts are restricted to the muscle cell lineages. These transcripts were initially observed in primary muscle lineage cells (descendants of the B4.1 blastomeres) at the early gastrula stage and continued to be present in these cells throughout embryonic development. In contrast, muscle actin transcripts did not appear in secondary muscle lineage cells (descendants of b4.2 and A4.1 blastomeres) until the mid-tailbud stage, and were not detected in mesenchyme cells, the presumptive adult muscle cell precursors, at any time during embryonic development. The results suggest that muscle actin gene expression is subject to spatial and temporal regulation in the muscle cell lineages.
Differential accumulation of oocyte nuclear proteins by embryonic nuclei ofXenopus
Authors: Dreyer Christine 
Published: April 2021

ABSTRACTOocyte nuclear proteins of Xenopus are distributed into the cytoplasm of the maturing egg after germinal vesicle breakdown. Later they are found in all cell nuclei of the embryo. At early stages of development, different nuclear proteins behave differently. A class of’early shifting’ antigens is accumulated by pronuclei and cleavage nuclei, whereas others appear to be excluded from the nuclei at early stages but are shifted into the nuclei at blastula or during and after gastrulation. Accumulation of ‘late-shifting’ nuclear antigens is a gradual process and occurs during a period characteristic of each protein. Multiple artificial pronuclei can be formed after injection of sperm nuclei, erythrocyte nuclei or pure λ-DNA into unfertilized eggs. The artificial pronuclei accumulate early-but not late-shifting proteins. Early-migrating proteins rapidly accumulate into the germinal vesicle after de novo synthesis in the oocyte, indicating that the efficiency of translocation into nuclei is an intrinsic property of each protein. Artificial extension of the length of the cell cycle before midblastula transition does not lead to accumulation of the late-shifting nuclear antigens investigated.Abbreviations: mAB: monoclonal antibody; GV: germinal vesicle; DAPI: 4’,6-diamidino-2-phenyl-indol-dihydro-chloride; FITC: fluoresceinisothiocyanate; TCA: trichloroacetic acid; MBS-H: modified Barth’s solution.
Abnormally high variability in the uncrossed retinofugal pathway of mice with albino mosaicism
Authors: Jeffery R. W. , Jeffery Glen , Cattanach B. M. 
Published: April 2021

ABSTRACT
Female mice showing albino mosaicism due to an X-autosome translocation [Is(In7;X)Ct] have been studied in order to investigate the relationship between the distribution of melanin and the formation, early in development, of the abnormally small uncrossed retinofugal pathway characteristically found in all albino mammals. Earlier evidence indicates that cells normally bearing melanin play a role in producing the abnormality. In the mosaic mice, the albino gene is expressed in only about half of the cells due to random X-inactivation apd the patches of normal and albino cells are extremely small relative to total retinal size (&lt;l/50). We argued that if all the cells that would normally bear melanin play a role in producing the albino abnormality then the mosaic mice would have a pathway abnormality, about half the size of that in the albino mice. If, however, only a small patch of these cells plays a role, as has been proposed in earlier studies, then one would expect the size of the uncrossed pathway to be highly variable in the mosaic mice.
The size of the uncrossed pathway was assessed by placing horseradish peroxidase in the region of the optic tract and lateral geniculate nucleus unilaterally and then counting the number of retrogradely labelled retinal ganglion cells on the same side. The mosaic mice showed a highly variable uncrossed pathway. In some of the mosaic mice, it was the same size as in the albinos and, in others, it was the same size as in normally pigmented mice. Surprisingly, in a small number of mosaic mice, the uncrossed pathway was larger than normal. Whether this relatively rare occurrence of a supernormal uncrossed pathway is due to the higher gene dosage or to the translocation itself remains an open question.
Nuclear cytoplasmic interactions following nuclear transplantation in mouse embryos
Authors: Howlett Sarah K. , Barton Sheila C. , Surani M. Azim 
Published: April 2021

ABSTRACTWe have investigated the development of reconstituted embryos in which enucleated 1- or 2-cell embryos received various advanced nuclei. Enucleated 1-cells developed to the blastocyst stage only when an early 2cell donor nucleus was transferred but very rarely if the donor nucleus was derived from a late 2-cell, early 4-cell or mid 8-cell embryo. Although an 8-cell nucleus could only support development of an enucleated zygote to the 2-cell stage, it did express the hsp 68/70 × 103Mr proteins that are characteristic of the first embryonic gene activity. These polypeptides were absent in enucleated zygotes that did not receive a donor nucleus. Moreover, an 8-cell nucleus transferred to an enucleated late 2-cell blastomere could also support preimplantation development provided that the nuclear: cytoplasmic ratio was maintained as in intact 2-cell blastomeres. 8-cell nuclei transferred to zygotes that retained at least one pronucleus were able to support development to the blastocyst stage provided that the pronucleus was both fully transcriptionally active and present beyond the late 1-cell stage. This study suggests an active and continued helper role of the resident pronucleus for the participation by an 8-cell nucleus in reconstituted eggs.
Hypothesis: a Y-chromosomal gene causes gonadoblastoma in dysgenetic gonads
Authors: Page David C. 
Published: April 2021

ABSTRACT
The role of the human Y chromosome in the etiology of gonadoblastoma, a gonadal neoplasm, is considered and a two-part model is presented. According to this hypothesis: (1) There is a gene on the Y chromosome that strongly predisposes dysgenetic gonads to develop gonadoblastomas (Page, 1986) and (2) this postulated GBY gene (GonadoBlastoma locus on Y chromosome) has some physiological function in normal males. GBY may, for example, function in or prior to spermatogenesis in normal testes.
Y-DNA hybridization analysis of individuals with gonadoblastoma and partial deletions of the Y chromosome should be of use in testing this proposal. To date, such studies suggest that GBY maps to the region that includes deletion intervals 4B to 7, i.e. it is located near the centromere or on the long arm of the Y chromosome.
Studies of Sl/Sl
d↔ + / + mouse aggregation chimaeras : II. Effect of the steel locus on spermatogenesis
Authors: Nakayama Hiroki , Kuroda Hideya , Onoue Hitoshi , Fujita Jun , Nishimune Yoshitake , Matsumoto Keishi , Nagano Toshio , Suzuki Fumie , Kitamura Yukihiko 
Published: April 2021

Abstract
Mutant mice of Sl/Sld genotype are deficient in melanocytes, erythrocytes, mast cells and germ cells. Deficiency of melanocytes, erythrocytes and mast cells is not attributable to an intrinsic defect in their precursor cells but to a defect in the tissue environment that is necessary for migration, proliferation and/or differentiation. We investigated the mechanism of germ cell deficiency in male Sl/Sld mice by producing aggregation chimaeras from Sl/Sld and +/ + embryos. Chimaeric mice with apparent white stripes were obtained. Two of four such chimaeras were fertile and the phenotypes of resulting progenies showed that some Sl/Sld germ cells had differentiated into functioning sperms in the testis of the chimaeras. In cross sections of the testes of chimaeras, both differentiated and nondifferentiated tubules were observed. However, the proportions of type A spermato-gonia to Sertoli cells in both types of tubules were comparable to the values observed in differentiated tubules of normal +/+ mice. We reconstructed the whole length of four tubules from serial sections. Differentiated and nondifferentiated segments alternated in a single tubule. The shortest differentiated segment contained about 180 Sertoli cells and the shortest nondifferentiated segment about 150 Sertoli cells. These results suggest that Sertoli cells of either Sl/Sld or +/ + genotype make discrete patches and that differentiation of type A spermatogonia does not occur in patches of Sl/Sld Sertoli cells.
Developmental patterning of carbohydrate antigens during early embryogenesis of the chick: expression of antigens of the poly-N-acetyllactosamine series
Authors: Thorpe Susan J. , Bellairs Ruth , Feizi Ten 
Published: April 2021

Abstract
This report describes a striking temporal and spatial patterning of specific carbohydrate sequences in the developing chick embryo. By using oligosaccharide sequence-specific monoclonal antibodies as immuno-histochemical reagents in conjunction with neuraminidase, it was possible to visualize the occurrence, as well as the changes in distribution, of oligosaccharides of the poly-N-acetyllactosamine series. These were (a) long-chain unbranched sequences reactive with anti-i Den, (b) long-chain branched sequences reactive with anti-I Step and (c) short-chain branched sequences reactive with anti-I Ma and (d) their sialylated forms. The salient observations with serial sections of embryos from the unincubated to the 17th stage were as follows.
A pronounced anteroposterior patterning appeared during neuroectodermal development, such that the long-chain unbranched and long-chain branched sequences, which were abundant on the ectoderm of the earlier stages, were replaced by shortchain branched sialo-oligosaccharides in the developing brain and anterior neural tube. A striking anteroposterior and mediolatera) patterning developed in the subectodermal extracellular spaces. The long-chain linear and short-chain non-sialylated sequences demarcated regions favourable for migration of the lateral plate mesoderm. A distinction was made between the dorsal and ventral routes of the trunk neural crest in that the extracellular matrix of the dorsal route only was associated with long-chain linear and short-chain sialylated branched sequences. A circumscribed perinotochordal distribution of the short-chain sialylated branched sequences was observed in the region of the future centra of the vertebrae. An abundance of long-chain linear and long-chain sialylated branched structures was detected in primordial germ cells which permitted their identification during migration.
These observations suggest that oligosaccharides of the poly-N-acetyllactosamine series may have roles as short-range, region-specific information factors during morphogenetic events that take place in the developing embryo, and they open the way to the search for recognition proteins (e.g. endogenous lectins) specific for each of these oligosaccharide structures.
The distribution of tenascin coincides with pathways of neural crest cell migration
Authors: Mackie E. J. , Tucker R. P. , Halfter W. , Chiquet-Ehrismann R. , Epperlein H. H. 
Published: April 2021

Abstract
The distribution of the extracellular matrix (ECM) glycoprotein, tenascin, has been compared with that of fibronectin in neural crest migration pathways of Xenopus laevis, quail and rat embryos. In all species studied, the distribution of tenascin, examined by immunohistochemistry, was more closely correlated with pathways of migration than that of fibronectin, which is known to be important for neural crest migration. In Xenopus laevis embryos, anti-tenascin stained the dorsal fin matrix and ECM along the ventral route of migration, but not the ECM found laterally between the ectoderm and somites where neural crest cells do not migrate. In quail embryos, the appearance of tenascin in neural crest pathways was well correlated with the anterior-to-posterior wave of migration. The distribution of tenascin within somites was compared with that of the neural crest marker, HNK-1, in quail embryos. In the dorsal halves of quail somites which contained migrating neural crest cells, the predominant tenascin staining was in the anterior halves of the somites, codistributed with the migrating cells. In rat embryos, tenascin was detectable in the somites only in the anterior halves. Tenascin was not detectable in the matrix of cultured quail neural crest cells, but was in the matrix surrounding somite and notochord cells in vitro. Neural crest cells cultured on a substratum of tenascin did not spread and were rounded. We propose that tenascin is an important factor controlling neural crest morphogenesis, perhaps by modifying the interaction of neural crest cells with fibronectin.