Robust vascular development occurs during implantation and early placentation of normal pregnancies. Studies to define the extent and mechanisms by which defects in vascularity contribute to human implantation failure and early miscarriage need to be undertaken.
Placental growth factor (PGF, previously known as PlGF) is prominently expressed by trophoblasts in human placenta, whereas most nontrophoblast cells express low levels of PGF mRNA under normal physiological conditions. We have shown that hypoxia decreases PGF expression in the trophoblast, but little is known about transcriptional regulation of PGF gene expression. We sought to determine promoter regions of the human PGF gene that contribute to its restricted high constitutive expression in the trophoblast. Overlapping putative promoter regions of human PGF gene encompassing 2-1.5 kb were cloned into reporter vectors and co-transfected into trophoblast and nontrophoblast cell lines. Promoter activity generated by a 2-1.5-kb clone was significantly higher in trophoblasts than in nontrophoblasts. Selective deletion mutants showed that a clone encompassing the PGF (2-828/++34) region generated promoter activity similar to the 2-1.5-kb region in the trophoblast. However, deletion of another 131 bp from this subclone (2-698/++34) resulted in significantly less promoter activity in the trophoblast. The (2-828/2-698) region significantly enhanced activity of a minimal promoter construct in trophoblast but not in nontrophoblast cells, suggesting that this region contributes to regulating PGF transcription in the trophoblast. Site-directed mutagenesis of a glial cell missing 1 (GCM1) motif in the 131-bp region significantly decreased enhancer activity in the trophoblast. Furthermore, overexpression of GCM1 significantly increased PGF 2-1.5-kb promoter activity and PGF mRNA expression in trophoblast and nontrophoblast cells. Forced overexpression of GCM1 restored PGF expression in the hypoxic trophoblast. These data support a functional role for GCM1 contributing to constitutively high trophoblast PGF expression and is the first direct evidence of an oxygen-responsive, trophoblast-specific transcription factor contributing to the regulation of PGF expression.
Objective To characterize patients with systemic lupus erythematosus (SLE) affected by coronavirus disease 2019 (COVID‐19) and to analyze associations of comorbidities and medications on infection outcomes. Methods Patients with SLE and reverse transcriptase–polymerase chain reaction–confirmed COVID‐19 were identified through an established New York University lupus cohort, query of 2 hospital systems, and referrals from rheumatologists. Data were prospectively collected via a web‐based questionnaire and review of medical records. Data on baseline characteristics were obtained for all patients with COVID‐19 to analyze risk factors for hospitalization. Data were also collected on asymptomatic patients and those with COVID‐19–like symptoms who tested negative or were not tested. Statistical analyses were limited to confirmed COVID‐19–positive patients. Results A total of 226 SLE patients were included: 41 with confirmed COVID‐19, 19 who tested negative for COVID‐19, 42 with COVID‐19–like symptoms who did not get tested, and 124 who remained asymptomatic without testing. Of the SLE patients with confirmed COVID‐19, hospitalization was required in 24 (59%) and intensive care unit–level of care in 4, and 4 died. Hospitalized patients tended to be older, nonwhite, Hispanic, have higher body mas index (BMI), history of nephritis, and at least 1 comorbidity. An exploratory (due to limited sample size) logistic regression analysis identified race, presence of at least 1 comorbidity, and BMI as independent predictors of hospitalization. Conclusion In general, the variables predictive of hospitalization in our SLE patients were similar to those identified in the general population. Further studies are needed to understand additional risk factors for poor COVID‐19 outcomes in patients with SLE.
Our findings of common alterations in SZ, BD, and MDD support the presence of core neurobiological disruptions in these disorders and suggest that neural structural distinctions between these disorders may be less prominent than initially postulated, particularly between SZ and BD.
ParticipantsA total of 1,558 participants, including 782 patients with major depressive disorder (MDD) and 776 healthy controls (HCs), were recruited from 5 research centers in China (The Second Xiangya Hospital, ). The detailed inclusion and exclusion criteria for each center are listed below. CMU dataset:Four hundred thirty-one participants were recruited for participation in this study, including 155 patients with MDD and 276 HCs. All patients with MDD were recruited from the outpatient clinic at the Department of Psychiatry, First Affiliated Hospital of China Medical University and the Mental Health Center of Shenyang. Patients with MDD were diagnosed by two trained psychiatrists using the Structured Clinical Interview for DSM-IV Disorders. Participants with MDD met the DSM-IV diagnostic criteria for MDD but not for any other Axis I disorders. The severity of depression was rated using the 17-item HDRS (Williams, 1988) and the Clinical Global Impression of Severity Scale (Guy, 1976). The control group was recruited from the local community. HC participants did not have a current or lifetime history of Axis I disorders or a history of psychotic, mood, or other Axis I disorders in first-degree relatives as determined from the detailed family history. The participants were excluded for the following reasons: 1) a lifetime history of substance/alcohol abuse or dependence, 2) a concomitant major medical disorder, 3) any MRI contraindications, 4) a history of head trauma with loss of consciousness ≥5 minutes or any neurological disorder, and 5) suboptimal imaging data quality. The study was approved by the Institutional Review Board of China Medical University. Among these participants, 1 patient and 5 HCs were excluded because of duplicate data in the data transfer, 1 HC was excluded due to errors in raw DICOM data, 6 patients were excluded due to the use of different scanning parameters, 3 HCs were excluded due to abnormalities in anatomical brain images, 6 patients and 6 HCs were excluded for large head motion during the R-fMRI scan (exceeding 3 mm of translational movements or 3° of rotational movements), 13 patients and 8 HCs were excluded because the MRI scan did not cover the entire brain, 4 patients and 2 HCs were excluded due to a change in the diagnosis in follow-up interviews, 1 HC was excluded due to a lack of demographic information, and 1 HC was excluded because of his young age. Finally, data from the remaining 125 patients with MDD and 249 HCs were used in the present study. CSU dataset:Patients with MDD were recruited from inpatient or outpatient departments of the Psychiatry Hospital of Zhumadian, Henan Province, China. The diagnosis of MDD was confirmed by
Brain network alterations have increasingly been implicated in schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). However, little is known about the similarities and differences in functional brain networks among patients with SCZ, BD, and MDD. A total of 512 participants (121 with SCZ, 100 with BD, 108 with MDD, and 183 healthy controls, matched for age and sex) completed resting-state functional magnetic resonance imaging at a single site. Four global measures (the clustering coefficient, the characteristic shortest path length, the normalized clustering coefficient, and the normalized characteristic path length) were computed at a voxel level to quantify segregated and integrated configurations. Inter-regional functional associations were examined based on the Euclidean distance between regions. Distance strength maps were used to localize regions with altered distances based on functional connectivity. Patient groups exhibited shifts in their network architectures toward randomized configurations, with SCZ>BD>MDD in the degree of randomization. Patient groups displayed significantly decreased short-range connectivity and increased medium-/long-range connectivity. Decreases in short-range connectivity were similar across the SZ, BD, and MDD groups and were primarily distributed in the primary sensory and association cortices and the thalamus. Increases in medium-/long-range connectivity were differentially localized within the prefrontal cortices among the patient groups. We highlight shared and distinct connectivity features in functional brain networks among patients with SCZ, BD, and MDD, which expands our understanding of the common and distinct pathophysiological mechanisms and provides crucial insights into neuroimaging-based methods for the early diagnosis of and interventions for psychiatric disorders.
Objective-To determine the mechanism for differential effects of low oxygen tension on human PlGF gene transcription in trophoblast and nontrophoblast cells.Study Design-Human PlGF reporter clones and real time RT-PCR were used to compare the effects of hypoxia on gene transcription in human trophoblast and nontrophoblast cell lines. Overexpression of HIF-1α, inhibition of HIF-1 function and biochemical assessments of HIF-1 cofactor interactions were used to characterize hypoxia response mechanisms regulating PlGF transcription.Results-PlGF transcription is specifically inhibited by low oxygen tension in trophoblast but is induced in some nontrophoblast cells. Overexpression of HIF-1α in normoxic cells or inhibition of HIF-1 function in hypoxic cells did not significantly alter transcription patterns of the PlGF gene in either cell type.Conclusions-These results suggest that transcriptional repression of PlGF gene expression occurs in human trophoblast exposed to low oxygen tension but that PlGF transcription is stimulated in certain hypoxic nontrophoblast cells. However, regulation of PlGF transcription is not mediated by functional HIF-1 activity in either cell types.
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