Institutional Support for the Career Advancement of Women Faculty in Science and Academic Medicine: Successes, Challenges, and Future Directions.

Institutional support is crucial for the successful career advancement of all faculty but in particular those who are women. Evolving from the past, in which gender disparities were prevalent in many institutions, recent decades have witnessed significant progress in supporting the career advancement of women faculty in science and academic medicine. However, continued advancement is necessary as previously unrecognized needs and new opportunities for improvement emerge. To identify the needs, opportunities, and potential challenges encountered by women faculty, the Women's Leadership Committee of the Arteriosclerosis, Thrombosis, and Vascular Biology Council developed an initiative termed GROWTH (Generating Resources and Opportunities for Women in Technology and Health). The committee designed a survey questionnaire and interviewed 19 leaders with roles and responsibilities in faculty development from a total of 12 institutions across various regions of the United States. The results were compiled, analyzed, and discussed. Based on our interviews and analyses, we present the current status of these representative institutions in supporting faculty development, highlighting efforts specific to women faculty. Through the experiences, insights, and vision of these leaders, we identified success stories, challenges, and future priorities. Our article provides a primer and a snapshot of institutional efforts to support the advancement of women faculty. Importantly, this article can serve as a reference and resource for academic entities seeking ideas to gauge their commitment level to women faculty and to implement new initiatives. Additionally, this article can provide guidance and strategies for women faculty as they seek support and resources from their current or prospective institutions when pursuing new career opportunities.

Small AAAs: Recommendations for Rodent Model Research for the Identification of Novel Therapeutics.

CLINICAL PROBLEM: Most abdominal aortic aneurysms (AAAs) are small with low rupture risk (<1%/y) when diagnosed but slowly expand to ≥55 mm and undergo surgical repair. Patients and clinicians require medications to limit AAA growth and rupture, but drugs effective in animal models have not translated to patients. RECOMMENDATIONS FOR INCREASING TRANSLATION FROM MOUSE MODELS: Use models that simulate human AAA tissue pathology, growth patterns, and rupture; focus on the clinically relevant outcomes of growth and rupture; design studies with the rigor required of human clinical trials; monitor AAA growth using reproducible ultrasound; and perform studies in both males and females. SUMMARY OF STRENGTHS AND WEAKNESSES OF MOUSE MODELS: The aortic adventitial elastase oral ß-aminopropionitrile model has many strengths including simulating human AAA pathology and modeling prolonged aneurysm growth. The Ang II (angiotensin II) model performed less well as it better simulates acute aortic syndrome than AAA. The elastase plus TGFß (transforming growth factor-ß) blocking antibody model displays a high rupture rate, making prolonged monitoring of AAA growth not feasible. The elastase perfusion and calcium chloride models both display limited AAA growth.

ß-Aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Mice.

BACKGROUND: ß-aminopropionitrile (BAPN) is a pharmacological inhibitor of LOX (lysyl oxidase) and LOXLs (LOX-like proteins). Administration of BAPN promotes aortopathies, although there is a paucity of data on experimental conditions to generate pathology. The objective of this study was to define experimental parameters and determine whether equivalent or variable aortopathies were generated throughout the aortic tree during BAPN administration in mice. METHODS: BAPN was administered in drinking water for a period ranging from 1 to 12 weeks. The impacts of BAPN were first assessed with regard to BAPN dose, and mouse strain, age, and sex. BAPN-induced aortic pathological characterization was conducted using histology and immunostaining. To investigate the mechanistic basis of regional heterogeneity, the ascending and descending thoracic aortas were harvested after 1 week of BAPN administration before the appearance of overt pathology. RESULTS: BAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta in young C57BL/6J or N mice. No apparent differences were found between male and female mice. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for α-SMA (α-smooth muscle actin). One week of BAPN administration compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the 2 aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. CONCLUSIONS: BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in mice.

Renal Proximal Tubule Cell-specific Megalin Deletion Does Not Affect Atherosclerosis But Induces Tubulointerstitial Nephritis in Mice Fed Western Diet.

Background: Pharmacological inhibition of megalin (also known as low-density lipoprotein receptor-related protein 2: LRP2) attenuates atherosclerosis in hypercholesterolemic mice. Since megalin is abundant in renal proximal tubule cells (PTCs), the purpose of this study was to determine whether PTC-specific deletion of megalin reduces hypercholesterolemia-induced atherosclerosis in mice. Methods: Female Lrp2 f/f mice were bred with male Ndrg1-Cre ERT2 +/0 mice to develop PTC-LRP2 +/+ and -/- littermates. To study atherosclerosis, all mice were to bred to an LDL receptor -/- background and fed a Western diet to induce atherosclerosis. Results: PTC-specific megalin deletion did not attenuate atherosclerosis in LDL receptor -/- mice in either sex. Serendipitously, we discovered that PTC-specific megalin deletion led to interstitial infiltration of CD68+ cells and tubular atrophy. The pathology was only evident in male PTC-LRP2 -/- mice fed the Western diet, but not in mice fed a normal laboratory diet. Renal pathologies were also observed in male PTC-LRP2 -/- mice in an LDL receptor +/+ background fed the same Western diet, demonstrating that the renal pathologies were dependent on diet and not hypercholesterolemia. By contrast, female PTC-LRP2 -/- mice had no apparent renal pathologies. In vivo multiphoton microscopy demonstrated that PTC-specific megalin deletion dramatically diminished albumin accumulation in PTCs within 10 days of Western diet feeding. RNA sequencing analyses demonstrated the upregulation of inflammation-related pathways in kidney. Conclusions: PTC-specific megalin deletion does not affect atherosclerosis, but leads to tubulointerstitial nephritis in mice fed Western diet, with severe pathologies in male mice.

Contrasting water-use strategies to climate warming in white birch and larch in a boreal permafrost region.

The effects of rising atmospheric CO2 concentrations (Ca) with climate warming on intrinsic water-use efficiency and radial growth in boreal forests are still poorly understood. We measured tree-ring cellulose δ13C, δ18O, and tree-ring width in Larix dahurica (larch) and Betula platyphylla (white birch), and analyzed their relationships with climate variables in a boreal permafrost region of northeast China over past 68 years covering a pre-warming period (1951-1984; base period) and a warm period (1985-2018; warm period). We found that white birch but not larch significantly increased their radial growth over the warm period. The increased intrinsic water-use efficiency in both species was mainly driven by elevated Ca but not climate warming. White birch but not larch showed significantly positive correlations between tree-ring δ13C, δ18O and summer maximum temperature as well as vapor pressure deficit in the warm period, suggesting a strong stomatal response in the broad-leaved birch to temperature changes. The climate warming-induced radial growth enhancement in white birch is primarily associated with a conservative water-use strategy. In contrast, larch exhibits a profligate water-use strategy. It implies an advantage for white birch over larch in the warming permafrost regions.

Global convergence in terrestrial gross primary production response to atmospheric vapor pressure deficit.

Atmospheric vapor pressure deficit (VPD) increases with climate warming and may limit plant growth. However, gross primary production (GPP) responses to VPD remain a mystery, offering a significant source of uncertainty in the estimation of global terrestrial ecosystems carbon dynamics. In this study, in-situ measurements, satellite-derived data, and Earth System Models (ESMs) simulations were analysed to show that the GPP of most ecosystems has a similar threshold in response to VPD: first increasing and then declining. When VPD exceeds these thresholds, atmospheric drought stress reduces soil moisture and stomatal conductance, thereby decreasing the productivity of terrestrial ecosystems. Current ESMs underscore CO2 fertilization effects but predict significant GPP decline in low-latitude ecosystems when VPD exceeds the thresholds. These results emphasize the impacts of climate warming on VPD and propose limitations to future ecosystems productivity caused by increased atmospheric water demand. Incorporating VPD, soil moisture, and canopy conductance interactions into ESMs enhances the prediction of terrestrial ecosystem responses to climate change.

Angiotensinogen as a Therapeutic Target for Cardiovascular and Metabolic Diseases.

AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of Agt in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating Agt-floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of Agt has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.

Cell-free supernatant of Lactococcus lactis IDCC 2301 exerts anti-inflammatory effects in LPS-induced macrophages via NF-κB and MAPK signaling pathways.

This study investigated the anti-inflammatory effects of cell-free supernatant of Lactococcus lactis IDCC 2301 on lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Expression of inflammatory mediators and cytokines, and the production of nitric oxide (NO) and prostaglandin E2 (PGE2) were qualitatively analysed. The expression of signal transductors in inflammatory cascades was quantified by western blot. Treatment with cell-free supernatant of L. lactis IDCC 2301 significantly decreased the mRNA expression levels of tumour necrosis factor (TNF-α) and interleukins including IL-1ß and IL-6. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) were also remarkably reduced in LPS-induced macrophages after the treatment. Furthermore, L. lactis IDCC 2301 reduced the levels of both dephosphorylated and phosphorylated forms of nuclear factor-kappa B (NF-κB), IκB-α, extracellular signal-regulated kinases (ERK), c-Jun amino-terminal kinases (JNK), and p38 in LPS-induced RAW 264.7 cells. Therefore, L. lactis IDCC 2301 shows anti-inflammatory activity by suppressing the NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways.

Diagnosis of osteochondral lesions of the talus on Dual-layer spectral detector CT arthrography: clinical feasibility of virtual noncontrast images.

AIM: To compare the image quality of virtual noncontrast (VNC) and true noncontrast (TNC) CT images and to evaluate the clinical feasibility of VNC CT images for assessing osteochondral lesions of the talus (OLTs). MATERIALS AND METHODS: Forty-five OLT patients who underwent ankle CT arthrography (CTA) using dual-layer spectral detector CT were enrolled. Reconstruction of VNC and three-dimensional volume rendering images was performed. Afterward, image noise, the signal-to-noise ratio (SNR), and the contrast-to-noise ratio (CNR) were measured. For the subjective evaluation, two board-certified musculoskeletal radiologists [R2-1] assessed spatial resolution, overall image quality, and lesion conspicuity. The accuracy rate for OLT grading was determined in 23 patients who underwent arthroscopic surgery. RESULTS: While VNC images showed significantly less noise than TNC images, TNC images showed better SNRs and CNRs (p<.01). In the subjective analysis, TNC images showed better overall image quality (p<.001). For the 3D volume rendering images, VNC images scored significantly higher for lesion conspicuity (p<.001). The accuracy rates of CTA and CTA with VNC images for OLT grading were 79.2% and 83.3%, respectively. Regarding confidence level, when CTA and VNC images were evaluated together, the confidence level was significantly higher than that when only CTA images were evaluated (p<.001). CONCLUSION: VNC imaging can provide better confidence level of OLT grading and evaluation of the integrity of the subchondral bone plate when combined with conventional CTA without additional radiation dose to the patient. In addition, VNC images-based 3D volume rendering reconstruction would be helpful for preoperative planning in OLT patients.

Gut microbiome predicts cognitive function and depressive symptoms in late life.

Depression in older adults with cognitive impairment increases progression to dementia. Microbiota is associated with current mood and cognition, but the extent to which it predicts future symptoms is unknown. In this work, we identified microbial features that reflect current and predict future cognitive and depressive symptoms. Clinical assessments and stool samples were collected from 268 participants with varying cognitive and depressive symptoms. Seventy participants underwent 2-year follow-up. Microbial community diversity, structure, and composition were assessed using high-resolution 16 S rRNA marker gene sequencing. We implemented linear regression to characterize the relationship between microbiome composition, current cognitive impairment, and depressive symptoms. We leveraged elastic net regression to discover features that reflect current or future cognitive function and depressive symptoms. Greater microbial community diversity associated with lower current cognition in the whole sample, and greater depression in participants not on antidepressants. Poor current cognitive function associated with lower relative abundance of Bifidobacterium, while greater GABA degradation associated with greater current depression severity. Future cognitive decline associated with lower cognitive function, lower relative abundance of Intestinibacter, lower glutamate degradation, and higher baseline histamine synthesis. Future increase in depressive symptoms associated with higher baseline depression and anxiety, lower cognitive function, diabetes, lower relative abundance of Bacteroidota, and lower glutamate degradation. Our results suggest cognitive dysfunction and depression are unique states with an overall biological effect detectable through gut microbiota. The microbiome may present a noninvasive readout and prognostic tool for cognitive and psychiatric states.

[Progress in application of aspirin desensitization and maintenance therapy in aspirin-exacerbated respiratory disease].

Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome characterized by chronic rhinosinusitis with nasal polyps, asthma and the development of significant airway symptoms following the ingestion of aspirin and other nonsteroid anti-inflammatory drugs (NSAIDs). At present, aspirin challenge is the gold standard for diagnosis. Aspirin desensitization and aspirin therapy after desensitization (ATAD) is one of the classical therapies. This paper described the application of aspirin desensitization and ATAD in AERD and provided the reference for the comprehensive treatment of AERD.

Impacts of snow cover seasonality on spring land surface phenology of forests in Changbai mountains of Northeast China.

Snow cover phenology (SCP) strongly affects forest spring phenology (the start of growing season, SOS), but the underlying mechanism of the relationship varies. In this study, we aimed to analyze the relationship between forest SOS and SCP, and investigate the mechanisms about how changes of SCP affect forest SOS. To do so, we extracted forest SOS and SCP from multiple remote sensing datasets and analyzed the spatio-temporal patterns of both in Changbai Mountains (2001-2020). We assessed the relationships between SCP and forest SOS using partial least squares regression analysis and investigated the potential mechanism of SCP changes affecting on forest SOS using path analysis. We found earlier forest SOS (-0.5 days/year), prolonged snow cover duration (SCD, 0.43 day/year), and earlier snow cover end day (SCED, -0.1 days/year) in the region. The results indicated that SCD showed negative influence while SCED showed positive influence on forest SOS in most of the region. Results revealed that the influence of SCP on forest SOS was mainly through altering spring temperature and the dominant path of SCP influencing forest SOS followed hydrothermal gradients. Our study reveals new insights into the influence of changing SCP on forest SOS, which provides the theoretical basis for including SCP in the phenological models.

Private land management is more important than public land in sustaining oaks in temperate forests in the eastern U.S.

Preserving the abundance and stocking of oaks (Quercus spp.) has become increasingly challenging in temperate hardwood forests of the eastern US in recent decades due to a remarkable shift in dominance to mesophytic species (e.g., red maple Acer rubrum). Studies have shown that efforts to sustain oaks while restraining maples yield limited success. Given that a significant portion of forestlands in the eastern U.S. are privately owned, it is critical to assess whether current forest management on cross-ownership forests can achieve those objectives. However, such assessments are rare. In this study, we employed a landscape modeling approach to investigate the long-term outcomes (i.e., 150-year forest composition and structure) of business-as-usual management and alternative management in a large, temperate hardwood forest landscape in Ohio, US. The business-as-usual management continues the current existing management practices, whereas the alternative management increases the pace and scale of forest management on both private and public lands to favor oaks. We compared the basal area and relative dominance for oaks (including Q. alba, Q. coccinea, Q. prinus, Q. rubra, and Q. velutina) and maples (including A. rubrum, A. saccharinum, and A. saccharum). Our results demonstrate that the implementation of business-as-usual management practices on both private and public lands may not effectively ensure the long-term sustainability of oak populations, but instead promote the proliferation of maple species over time. By contrast, alternative management on both private and public lands can effectively sustain oaks across a range of diameter classes while mitigating the growth of large, dominant maples. Our study emphasizes the influential role of private lands in driving oak-maple dynamics at the regional scale, as they can generate significant regional effects even when public lands continue with their business-as-usual management practices. Starting conditions based on landownership are crucial considerations for understanding these dynamics over time.

[Application value of questionnaires in the screening obstructive sleep apnea syndrome in pregnancy across trimesters].

Objective: To evaluate the clinical utility value of questionnaires of Berlin, STOP, STOP-Bang (SBQ), Epworth Sleepiness Scale (ESS) in screening obstructive sleep apnea syndrome (OSAS) in pregnant women of different trimesters. Methods: Consecutive pregnant women at high risk for OSAS were enrolled from January, 2021 to April, 2022 at the obstetric clinic of Peking University People's Hospital. They completed questionnaires of Berlin, STOP, SBQ, ESS and also underwent an overnight polysomnography (PSG). To evaluate the accuracy of questionnaires of Berlin, STOP, SBQ, ESS, sensitivity, specificity, positive predictive values, negative predictive values and the area under the receiver operating characteristics (ROC) curve of these questionnaires in pregnancy across trimesters (Pregnancy 1-15 weeks was the first stage, pregnancy 16-27 weeks was the second stage, and pregnancy 28-40 weeks was the third stage) were calculated. Results: A total of 100 pregnant women [(34.5±4.3) years old (26-46 years old)] were included in this study, including 20, 35 and 45 pregnant women in the first, second and third trimester of pregnancy, respectively. Based on PSG results, 45 (45%) of 100 pregnant women were diagnosed with OSAS. The overall predictive values of the four questionnaires were not good, area under[AUC(95%CI)] the ROC curve ESS, Berlin questionnaire STOP and SBQ were 0.54(0.43, 0.66), 0.59 (0.47, 0.70), 0.62(0.51, 0.73) and 0.61 (0.49, 0.72), respectively, sensitivity was 35.6%, 65.9%, 48.9%, 28.9%, specificity was 71.7%, 52.5%, 73.6%, 92.5%. When categorized according to trimesters, the predicted values of the four questionnaires increased in the first trimester, the AUC (95%CI) of STOP questionnaire was 0.81 (0.61, 1.00), sensitivity was 75.0%, specificity was 87.5%. Conclusion: The overall predictive power of the four screening questionnaires is limited in pregnant women. But predictive value of STOP questionnaire is acceptable in the first trimester.

Association of NOTCH3 With Elastic Fiber Dispersion in the Infrarenal Abdominal Aorta of Cynomolgus Monkeys.

BACKGROUND: The regional heterogeneity of vascular components and transcriptomes is an important determinant of aortic biology. This notion has been explored in multiple mouse studies. In the present study, we examined the regional heterogeneity of aortas in nonhuman primates. METHODS: Aortic samples were harvested from the ascending, descending thoracic, suprarenal, and infrarenal regions of young control monkeys and adult monkeys with high fructose consumption for 3 years. The regional heterogeneity of aortic structure and transcriptomes was examined by histological and bulk RNA sequencing analyses, respectively. RESULTS: Immunostaining of CD31 and αSMA (alpha-smooth muscle actin) revealed that endothelial and smooth muscle cells were distributed homogeneously across the aortic regions. In contrast, elastic fibers were less abundant and dispersed in the infrarenal aorta compared with other regions and associated with collagen deposition. Bulk RNA sequencing identified a distinct transcriptome related to the Notch signaling pathway in the infrarenal aorta with significantly increased NOTCH3 mRNA compared with other regions. Immunostaining revealed that NOTCH3 protein was increased in the media of the infrarenal aorta. The abundance of medial NOTCH3 was positively correlated with the dispersion of elastic fibers. Adult cynomolgus monkeys with high fructose consumption displayed vascular wall remodeling, such as smooth muscle cell loss and elastic fiber disruption, predominantly in the infrarenal region. The correlation between NOTCH3 and elastic fiber dispersion was enhanced in these monkeys. CONCLUSIONS: Aortas of young cynomolgus monkeys display regional heterogeneity of their transcriptome and the structure of elastin and collagens. Elastic fibers in the infrarenal aorta are dispersed along with upregulation of medial NOTCH3.

ß-aminopropionitrile Induces Distinct Pathologies in the Ascending and Descending Thoracic Aortic Regions of Young Mice.

This study characterized ß-aminopropionitrile (BAPN)-induced aortopathies in young mice. The effects of BAPN were first determined with regard to BAPN dose and mouse strain, age, and sex. BAPN-induced aortic rupture predominantly occurred or originated in the descending thoracic aorta. For mice surviving 12 weeks of BAPN administration, profound dilatation was consistently observed in the ascending region, while there were more heterogeneous changes in the descending thoracic region. Pathological features were distinct between the ascending and descending thoracic regions. Aortic pathology in the ascending region was characterized by luminal dilatation and elastic fiber disruption throughout the media. The descending thoracic region frequently had dissections with false lumen formation, macrophage infiltration, collagen deposition, and remodeling of the wall surrounding the false lumen. Cells surrounding the false lumen were predominantly positive for α-smooth muscle actin. To investigate the molecular basis of the regional heterogeneity, ascending and descending thoracic aortas were harvested after one week of BAPN administration prior to the appearance of overt pathology. BAPN compromised contractile properties in both regions equivalently, and RNA sequencing did not show obvious differences between the two aortic regions in smooth muscle cell markers, cell proliferation markers, and extracellular components. In conclusion, BAPN-induced pathologies show distinct, heterogeneous features within and between ascending and descending aortic regions in young mice.