bluuebunny/crossref_metadata_2025 huggingface dataset:
Enoxaparin titrated by anti-Xa levels reduces venous thromboembolism in trauma patients
Authors: Gates Rebecca S. , Lollar Daniel I. , Collier Bryan R. , Smith Jacob , Faulks Emily R. , Gillen Jacob R.
Published: September 2021

BACKGROUND

Trauma is a major risk factor for the development of a venous thromboembolism (VTE). After observing higher than expected VTE rates within our center’s Trauma Quality Improvement Program data, we instituted a change in our VTE prophylaxis protocol, moving to enoxaparin dosing titrated by anti-Xa levels. We hypothesized that this intervention would lower our symptomatic VTE rates.

METHODS

Adult trauma patients at a single institution meeting National Trauma Data Standard criteria from April 2015 to September 2019 were examined with regards to VTE chemoprophylaxis regimen and VTE incidence. Two groups of patients were identified based on VTE protocol—those who received enoxaparin 30 mg twice daily without routine anti-Xa levels (“pre”) versus those who received enoxaparin 40 mg twice daily with dose titrated by serial anti-Xa levels (“post”). Univariate and multivariate analyses were performed to define statistically significant differences in VTE incidence between the two cohorts.

RESULTS

There were 1698 patients within the “pre” group and 1406 patients within the “post” group. The two groups were essentially the same in terms of demographics and risk factors for bleeding or thrombosis. There was a statistically significant reduction in VTE rate (p = 0.01) and deep vein thrombosis rate (p = 0.01) but no significant reduction in pulmonary embolism rate (p = 0.21) after implementation of the anti-Xa titration protocol. Risk-adjusted Trauma Quality Improvement Program data showed an improvement in rate of symptomatic pulmonary embolism from fifth decile to first decile.

CONCLUSION

A protocol titrating prophylactic enoxaparin dose based on anti-Xa levels reduced VTE rates. Implementation of this type of protocol requires diligence from the physician and pharmacist team. Further research will investigate the impact of protocol compliance and time to appropriate anti-Xa level on incidence of VTE.

LEVEL OF EVIDENCE

Therapeutic/care management, Level IV.
Fetal and neonatal outcomes following maternal aortic balloon occlusion for hemorrhage in pregnancy: A review of the literature
Authors: Theodorou Christina M. , Rinderknecht Tanya N. , Girda Eugenia , Galante Joseph M. , Russo Rachel M.
Published: September 2021

BACKGROUND

Hemorrhage is a leading cause of maternal death worldwide, with increased risk in women with abnormal placentation. Aortic balloon occlusion (ABO), including resuscitative endovascular balloon occlusion, has been used for obstetrical hemorrhage for 20 years, and is associated with decreased operative blood loss, fewer transfusions, and lower rates of hysterectomy. However, the effect of aortic occlusion on fetal/neonatal outcomes is not well known.

METHODS

A literature review on ABO for obstetrical or traumatic hemorrhage was performed. Cases were included if fetal/neonatal outcomes were reported. Data were collected on timing of balloon inflation (predelivery or postdelivery), fetal/neonatal mortality, and Apgar scores. Secondary maternal outcomes included blood loss, need for hysterectomy, ABO-related complications, and mortality.

RESULTS

Twenty-one reports of ABO in 825 cases of obstetrical hemorrhage were reviewed (nine case reports/series and twelve comparative studies). 13.5% (111/825) had aortic occlusion prior to delivery of the fetus. Comparative cohorts included 448 patients who underwent iliac artery balloon occlusion (n = 219) or no vascular balloon occlusion (n = 229). The most common neonatal outcome reported was Apgar scores, with no difference in fetal/neonatal outcomes between ABO and non-ABO patients in any study. One neonatal mortality occurred in the sole reported case of ABO use in a pregnant trauma patient at 24 weeks gestation. One maternal mortality occurred because of aortic dissection. Five comparative studies reported significantly decreased blood loss in ABO patients compared to non-ABO patients, and four studies reported significantly lower rates of hysterectomy in ABO patients. ABO-related complications were reported in 1.6% of patients (13/825).

CONCLUSION

Obstetrical hemorrhage is a devastating complication, and ABO may potentially decrease blood loss and reduce the hysterectomy rate without compromising fetal and neonatal outcomes. Further research is needed to determine the safety of predelivery aortic occlusion as this occurred in 14% of the cases.
Neuro-Behçe Disease Causing Nuclear/Fascicular Forth Nerve Palsy
Authors: Kisilevsky Eli , Margolin Edward A.
Published: September 2021

Neuro-Behçe disease (NBD) has a predilection for affecting the parenchyma of the upper brainstem; however, involvement of the fourth nerve nucleus or fascicle by NBD has not been previously described. We report a case of a young man with acute right fourth nerve palsy and history of Behçet disease with an enhancing lesion in the left caudal midbrain corresponding to the left trochlear nerve nucleus/fascicle. This is the first described case of NBD producing nuclear/fascicular fourth nerve palsy. It also demonstrates an important clinicoanatomical correlate of decussation of fourth nerve fibers to the opposite side after exiting the midbrain.
Loss of function mutation inELF4causes autoinflammatory and immunodeficiency disease in human
Authors: Sun Gan , Qiu Luyao , An Yunfei , Ding Yuan , Zhou Lina , Wu Junfeng , Tang Xuemei , Xia Huawei , Cao Lili , You Fuping , Zhao Xiaodong , Du Hongqiang
Published: September 2021

Monogenic autoinflammatory diseases (mAIDs) are a heterogeneous group of diseases affecting primarily innate immunity, with various specific genetic causes. Genetic diagnosis of mAIDs can assist in the patient’s management and therapy. However, a large number of sporadic and familial cases remain genetically uncharacterized. Here, we described a pediatric patient suffering from recurrent viral and bacterial respiratory infection, refractory oral ulcer and constipation, who was clinically diagnosed of inborn errors of immunity (IEI). In an effort to establish genetic diagnosis, no known causative genes were identified by whole-exome sequencing. However, manually going through bioinformatically predicted candidate genes, we suspected and prioritizedELF4(chrX:129205133 A>G, c.691T>C, p.W231R) as the genetic cause for our patient. We then evaluated the pathogenicity of this mutation by both various bioinformatic methods and preliminary but definitive experimental approach. Our data suggested that W231R mutant ELF4 is a “loss of function” mutation causing decreased protein stability and decreased trans-activation activity. Thus, we identified a novel mAID, which we termed “X-linked autoinflammatory and immunodeficiency disease associated with ELF4, X-AIDE”.
Comparison of adverse events between COVID-19 and Flu vaccines
Authors: Pradhan Prajwal Mani , Shen Zhoutian , Li Changye , Remucal Michael J.
Published: September 2021

BACKGROUND

Among the various driving factors for vaccine hesitancy, confidence in the safety associated with the vaccine constitutes as one of the key factors. This study aimed at comparing the adverse effects of COVID-19 vaccines with the Flu vaccines.

METHODS

The VAERS data from 01/01/2020 to 08/20/2021 were used. The MedDRA terms coded by VAERS were further aggregated by a clinician into clinically meaningful broader terms.

RESULTS

Various common adverse events between Flu and COVID-19 vaccines have been identified. Adverse events such as headache and fever were very common across all age groups. Among the common adverse events between Flu and COVID-19 vaccine, the relative risk along with 95% CI indicated that such common adverse events were more likely to be experienced by COVID-19 vaccine users than Flu vaccine users. Our study also quantified the proportion of rare adverse events such as Guillain Barre Syndrome and Gynecological changes in the VAERS database for COVID-19 vaccines.

CONCLUSIONS

Based on the available data and results, it appears that there were some common adverse events between Flu vaccines and COVID-19 vaccines. These identified common adverse events warrant further investigations based on the relative risk and 95% CI.
Assessment of community efforts to advance computational prediction of protein-protein interactions
Authors: Wang Xu-Wen , Madeddu Lorenzo , Spirohn Kerstin , Martini Leonardo , Fazzone Adriano , Becchetti Luca , Wytock Thomas P. , Kovács István A. , Balogh Olivér M. , Benczik Bettina , Pétervári Mátyás , Ágg Bence , Ferdinandy Péter , Vulliard Loan , Menche Jörg , Colonnese Stefania , Petti Manuela , Scarano Gaetano , Cuomo Francesca , Hao Tong , Laval Florent , Willems Luc , Twizere Jean-Claude , Calderwood Michael A. , Petrillo Enrico , Barabási Albert-László , Silverman Edwin K. , Loscalzo Joseph , Velardi Paola , Liu Yang-Yu
Published: September 2021

Comprehensive insights from the human protein-protein interaction (PPI) network, known as the human interactome, can provide important insights into the molecular mechanisms of complex biological processes and diseases. Despite the remarkable experimental efforts undertaken to date to determine the structure of the human interactome, many PPIs remain unmapped. Computational approaches, especially network-based methods, can facilitate the identification of new PPIs. Many such approaches have been proposed. However, a systematic evaluation of existing network-based methods in predicting PPIs is still lacking. Here, we report community efforts initiated by the International Network Medicine Consortium to benchmark the ability of 24 representative network-based methods to predict PPIs across five different interactomes, including a synthetic interactome generated by the duplication-mutation-complementation model, and the interactomes of four different organisms:A. thaliana,C. elegans,S. cerevisiae, andH. sapiens. We selected the top-seven methods through a computational validation on the human interactome. We next experimentally validated their top-500 predicted PPIs (in total 3,276 predicted PPIs) using the yeast two-hybrid assay, finding 1,177 new human PPIs (involving 633 proteins). Our results indicate that task-tailored similarity-based methods, which leverage the underlying network characteristics of PPIs, show superior performance over other general link prediction methods. Through experimental validation, we confirmed that the top-ranking methods show promising performance externally. For example, from the top 500 PPIs predicted by an advanced similarity-base method [MPS(B&T)], 430 were successfully tested by Y2H with 376 testing positive, yielding a precision of 87.4%. These results establish advanced similarity-based methods as powerful tools for the prediction of human PPIs.
Pre-clinical Research of Human Amnion-derived Mesenchymal Stem Cells and its First Clinical Treatment for a Severe Uremic Calciphylaxis Patient
Authors: Qin Lianju , Zhang Jing , Xiao Yujie , Liu Kang , Cui Yugui , Xu Fangyan , Ren Wenkai , Yuan Yanggang , Jiang Chunyan , Ning Song , Zeng Ming , Yang Guang , Qian Hanyang , Bian Anning , Li Fan , Ye Xiaoxue , Tang Shaowen , Dai Juncheng , Guo Jing , Wang Qiang , Sun Bin , Ge Yifei , Ouyang Chun , Xu Xueqiang , Wang Jing , Huang Yaoyu , Cui Hongqing , Zhou Jing , Wang Meilian , Su Zhonglan , Lu Yan , Wu Di , Zhang Zhihong , Shi Jingping , Liu Wei , Dong Li , Pan Yinbing , Zhao Baiqiao , Cui Ying , Gao Xueyan , Gao Zhanhui , Ma Xiang , Chen Aiqin , Wang Jie , Cao Meng , Cui Qian , Chen Li , Chen Feng , Yu Youjia , Ji Qiang , Zhang Zhiwei , Gu Mufeng , Zhuang Xiaojun , Lv Xiaolin , Wang Hui , Pan Yanyan , Wang Ling , Xu Xianrong , Zhao Jing , Wang Xiuqin , Liu Cuiping , Liang Ningxia , Xing Changying , Liu Jiayin , Wang Ningning
Published: September 2021

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. We reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers and mummified legs. Because of her rapid progression and refractory to conventional therapy, human amnion-derived mesenchymal stem cells (hAMSCs) treatment was approved. Establishment and release inspection of hAMSCs, efficacy and safety assessment including cytokines secretory ability, immunocompetence, tumorigenicity and genetics analysisin vitrowere introduced. We further performed acute and long-term hAMSC toxity evaluations in C57BL/6 mice/rats, abnormal immune response tests in C57BL/6 mice and tumorigenic tests in the neonatal NU nude mice. After pre-clinical research, she was treated by hAMSCs with intravenous and local intramuscular injection and external supernatants application to her ulcers. When followed up to 15 months, her blood-based markers of bone and mineral metabolism were improved, with regeneration of skin soft tissue and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1 month treatment showed vascular regeneration with mature non-calcified vessels within dermis and 20 months later re-epithelialization restored the integrity of damaged site. No infusion or local treatment related adverse events occurred. To the best of our knowledge, this is the first evidence for the clinical use of hAMSCs. These findings suggest hAMSCs warrant further investigation as a potential regenerative treatment for uremic calciphylaxis with effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multi-differentiation, re-epithelialization and restorage of integrity.
The impact of heating, ventilation, and air conditioning design features on the transmission of viruses, including the 2019 novel coronavirus: a systematic review of filtration
Authors: Thornton Gail M. , Fleck Brian A. , Kroeker Emily , Dandnayak Dhyey , Fleck Natalie , Zhong Lexuan , Hartling Lisa
Published: September 2021

Historically, viruses have demonstrated airborne transmission. Emerging evidence suggests the novel coronavirus (SARS-CoV-2) that causes COVID-19 may also spread by airborne transmission. This is more likely in indoor environments, particularly with poor ventilation. In the context of potential airborne transmission, a vital mitigation strategy for the built environment is heating, ventilation, and air conditioning (HVAC) systems. HVAC features could modify virus transmission potential. A systematic review following international standards was conducted to comprehensively identify and synthesize research examining the effectiveness of filters within HVAC systems in reducing virus transmission. Twenty-three relevant studies showed that: filtration was associated with decreased transmission; filters removed viruses from the air; increasing filter efficiency (efficiency of particle removal) was associated with decreased transmission, decreased infection risk, and increased viral filtration efficiency (efficiency of virus removal); increasing filter efficiency above MERV 13 was associated with limited benefit in further reduction of virus concentration and infection risk; and filters with the same efficiency rating from different companies showed variable performance. Increasing filter efficiency may mitigate virus transmission; however, improvement may be limited above MERV 13. Adapting HVAC systems to mitigate virus transmission requires a multi-factorial approach and filtration is one factor offering demonstrated potential for decreased transmission.

Practical Implications

In order for filtration to be an effective means of virus removal and transmission control, proper installation is required. As well, professionals should be aware of the fact that similarly rated filters from different companies may offer different virus reduction results. While increasing filtration efficiency (i.e., increasing MERV rating or moving from MERV to HEPA) is associated with virus mitigation, there appears to be diminishing returns for filters rated MERV 13 or higher. Although costs increase with filtration efficiency, filtration costs are lower than the cost of ventilation options with the equivalent reduction in transmission.
White matter hyperintensities may be an early marker for age-related cognitive decline
Authors: Morrison Cassandra , Dadar Mahsa , Villeneuve Sylvia , Collins D. Louis ,   for Alzheimer’s Disease Neuroimaging Initiative
Published: September 2021

Background

Research suggests that cerebral small vessel disease (CSVD), amyloid, and pTau contribute to age-related cognitive decline. It remains unknown how these factors relate to one another, nor how they jointly contribute to cognitive decline in normal aging. This project examines the association between these pathologies and their relationship to cognitive decline in cognitively normal older adults without subjective cognitive decline.

Methods

A total of 230 subjects with CSF Aß42, CSF pTau181, white matter hyperintensities (WMHs) used as a proxy of CSVD and cognitive scores from the Alzheimer’s Disease Neuroimaging Initiative were included. Associations between each pathology and cognitive score were investigated using regression models. Furthermore, relationships between the three pathologies were also examined using regression models.

Results

At baseline, there was an inverse association between WMH load and Aß42 (t=-4.20, p<.001). There was no association between WMH load and pTau (t=0.32, p=0.75), nor with Aß42 and pTau (t=0.51, p=.61). Correcting for age, sex and education, baseline WMH load was associated with baseline ADAS-13 scores (t=2.59, p=.01) and lower follow-up executive functioning (t= -2.84, p=.005). Baseline Aß42 was associated with executive function at baseline (t=3.58, p<.004) but not at follow-up (t=1.05, p=0.30), nor with ADAS-13 at baseline (t=-0.24, p0.81) or follow-up (t=0.09, p=0.93). Finally, baseline pTau was not associated with any cognitive measure at baseline or follow-up.

Conclusion

Both baseline Aß42 and WMH load are associated with some baseline cognition scores, but only baseline WMH load is associated with follow-up executive functioning, indicating that it may be one of the earliest pathologies that contributes to future cognitive decline, in cognitively healthy older adults. Given that healthy older adults with WMH pathology exhibit declines in cognitive functioning, they may be less resilient to future pathology increasing their risk for cognitive impairment due to dementia than those without WMHs.
Overcoming microenvironment-mediated chemoprotection through stromal galectin-3 inhibition in acute lymphoblastic leukemia
Authors: Tarighat Somayeh S. , Fei Fei , Joo Eun Ji , Abdel-Azim Hisham , Yang Lu , Geng Huimin , Bum-Erdene Khuchtumur , Grice I. Darren , Itzstein Mark von , Blanchard Helen , Heisterkamp Nora
Published: September 2021

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells including a dose-dependent reduction of viability and proliferation, induction of apoptosis and, importantly, inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.
Phostensin Enables Lymphocyte Integrin Activation and Population of Peripheral Lymphoid Organs
Authors: Lee Ho-Sup , Sun Hao , Lagarrigue Frédéric , Fox Jay W. , Sherman Nicholas E. , Gingras Alexandre R. , Ginsberg Mark H.
Published: September 2021

Rap1 GTPase drives assembly of the Mig-10/RIAM/lamellipodin–Integrin–Talin (MIT) complex that enables integrin-dependent lymphocyte functions. Here we used tandem affinity tag-based proteomics to isolate and analyze the MIT complex and reveal that Phostensin (PTSN), a regulatory subunit of protein phosphatase 1, is a component of the complex. PTSN mediates de-phosphorylation of Rap1 thereby preserving the activity and membrane localization of Rap1 to stabilize the MIT complex. CRISPR/Cas9-induced deletion of PPP1R18, which encodes PTSN, markedly suppresses integrin activation in Jurkat human T cells. We generated apparently healthy Ppp1r18-/- mice that manifest lymphocytosis and reduced population of peripheral lymphoid tissues ascribable to defective activation of integrins αLβ2 and α4β7. Ppp1r18-/- T cells exhibit reduced capacity to induce colitis in a murine adoptive transfer model. Thus, PTSN enables lymphocyte integrin-mediated functions by dephosphorylating Rap1 to stabilize the MIT complex. As a consequence, loss of PTSN ameliorates T cell-mediated colitis.

Phostensin, a protein phosphatase 1 regulatory subunit, supports lymphocyte integrin-dependent functions by mediating dephosphorylation of Rap1 to stabilize the MIT complex thereby enabling the population of peripheral lymphoid organs and T cell-mediated colitis.
Cell-adaptable dynamic hydrogel reinforced with stem cells improves the functional repair of spinal cord injury by alleviating neuroinflammation
Authors: Yuan Xin , Yuan Weihao , Ding Lu , Shi Ming , Luo Liang , Wan Yong , Oh Jiwon , Zhou Yanfang , Bian Liming , Deng David Y.B.
Published: September 2021

Spinal cord injury (SCI) is one of the most challenging clinical issues. It is characterized by the disruption of neural circuitry and connectivity, resulting in neurological disability. Adipose-derived stem cells (ADSCs) serve as a promising source of therapeutic cells for SCI treatment. However, the therapeutic outcomes of direct ADSCs transplantation are limited in the presence of an inflammatory microenvironment. Herein, a cell-adaptable neurogenic (CaNeu) hydrogel was developed as a delivery vehicle for ADSCs to promote neuronal regeneration after SCI. The dynamic network of CaNeu hydrogel loaded with ADSCs provides a cell-infiltratable matrix that enhances axonal growth and eventually leads to improved motor evoked potential, hindlimb strength, and coordination of complete spinal cord transection in rats. Furthermore, the CaNeu hydrogel also establishes an anti-inflammatory microenvironment by inducing a shift in the polarization of the recruited macrophages toward the pro-regeneration (M2) phenotype. Our study showed that the CaNeu-hydrogel‒mediated ADSCs delivery resulted in significantly suppressed neuroinflammation and apoptosis, and that this phenomenon involved the PI3K/Akt signaling pathway. Our findings indicate that the CaNeu hydrogel is a valuable delivery vehicle to assist stem cell therapy for SCI, providing a promising strategy for central nervous system diseases.
Pericyte-mediated constriction of renal capillaries evokes no-reflow and kidney injury following ischemia
Authors: Freitas Felipe , Attwell David
Published: September 2021

Acute kidney injury is common, with ∼13 million cases and 1.7 million deaths/year worldwide. A major cause is renal ischemia, typically following cardiac surgery, renal transplant or severe hemorrhage. We examined the cause of the sustained reduction in renal blood flow (“no-reflow”), which exacerbates kidney injury even after an initial cause of compromised blood supply is removed. After 60 min kidney ischemia and 30-60 min reperfusion, renal blood flow remained reduced, especially in the medulla, and kidney tubule damage was detected as Kim-1 expression. Constriction of the medullary descending vasa recta and cortical peritubular capillaries occurred near pericyte somata, and led to capillary blockages, yet glomerular arterioles and perfusion were unaffected, implying that the long-lasting decrease of renal blood flow contributing to kidney damage was generated by pericytes. Blocking Rho kinase to decrease pericyte contractility from the start of reperfusion increased the post-ischemic diameter of the descending vasa recta capillaries at pericytes, reduced the percentage of capillaries that remained blocked, increased medullary blood flow and reduced kidney injury. Thus, post-ischemic renal no-reflow, contributing to acute kidney injury, reflects pericytes constricting the descending vasa recta and peritubular capillaries. Pericytes are therefore an important therapeutic target for treating acute kidney injury.
Maturyoshka: a maturase inside a maturase, and other peculiarities of the novel chloroplast genomes of marine euglenophytes
Authors: Maciszewski Kacper , Dabbagh Nadja , Preisfeld Angelika , Karnkowska Anna
Published: September 2021

Organellar genomes often carry group II introns, which occasionally encode proteins called maturases that are important for splicing. The number of introns varies substantially among various organellar genomes, and bursts of introns have been observed in multiple eukaryotic lineages, including euglenophytes, with more than 100 introns in their plastid genomes. To examine the evolutionary diversity and history of maturases, an essential gene family among euglenophytes, we searched for their homologs in newly sequenced and published plastid genomes representing all major euglenophytes’ lineages. We found that maturase content in plastid genomes has a patchy distribution, with a maximum of eight of them present in Eutreptiella eupharyngea. The most basal lineages of euglenophytes, Eutreptiales, share the highest number of maturases, but the lowest number of introns. We also identified a peculiar convoluted structure of a gene located in an intron, in a gene within an intron, within yet another gene, present in some Eutreptiales. Further investigation of functional domains of identified maturases shown that most of them lost at least one of the functional domains, which implies that the patchy maturase distribution is due to frequent inactivation and eventual loss over time. Finally, we identified the diversified evolutionary origin of analysed maturases, which were acquired along with the green algal plastid or horizontally transferred. These findings indicate that euglenophytes’ plastid maturases have experienced a surprisingly dynamic history due to gains from diversified donors, their retention, and loss.
Fabrication and delivery of mechano-actived microcapsules containing osteogenic factors in a large animal model of osteochondral injury
Authors: Zlotnick Hannah M. , Locke Ryan C. , Hemdev Sanjana , Stoeckl Brendan D. , Gupta Sachin , Peredo Ana P. , Steinberg David R. , Carey James L. , Lee Daeyeon , Dodge George R. , Mauck Robert L.
Published: September 2021

Chondral and osteochondral repair strategies are limited by adverse bony changes that occur after injury. Bone resorption can cause entire scaffolds, engineered tissues, or even endogenous repair tissues to subside below the cartilage surface. To address this translational issue, we fabricated poly(D,L-lactide-co-glycolide) (PLGA) microcapsules containing the pro-osteogenic agents triiodothyronine and ß-glycerophosphate, and delivered these microcapsules in a large animal model of osteochondral injury to preserve bone structure. We demonstrate that developed microcapsules rupturedin vitrounder increasing mechanical loads, and readily sink within a liquid solution, allowing for gravity-based positioning onto the osteochondral surface. In a large animal, these mechano-active microcapsules (MAMCs) were assessed through two different delivery strategies. Intra-articular injection of control MAMCs enabled fluorescent quantification of MAMC rupture and cargo release in a synovial joint setting over time in vivo. This joint-wide injection also confirmed that the MAMCs do not elicit an inflammatory response. In the contralateral hindlimbs, chondral defects were created, MAMCs were locally administered, and nanofracture (Nfx), a clinically utilized method to promote cartilage repair, was performed. The NFx holes enabled marrow-derived stromal cells to enter the defect area and served as repeatable bone injury sites to monitor over time. Animals were evaluated 1 and 2 weeks after injection and surgery. Analysis of injected MAMCs showed that bioactive cargo was released in a controlled fashion over 2 weeks. A bone fluorochrome label injected at the time of surgery displayed maintenance of mineral labeling in the therapeutic group, but resorption in both control groups. Alkaline phosphatase (AP) staining at the osteochondral interface revealed higher AP activity in defects treated with therapeutic MAMCs. Overall, this study establishes a new micro-fluidically generated delivery platform that releases therapeutic factors in an articulating joint, and reduces this to practice in the delivery of therapeutics that preserve bone structure after osteochondral injury.
Mammals adjust diel activity across gradients of urbanization
Authors: Gallo Travis , Fidino Mason , Gerber Brian , Ahlers Adam A. , Angstmann Julia L. , Amaya Max , Concilio Amy L. , Drake David , Gray Danielle , Lehrer Elizabeth W. , Murray Maureen H. , Ryan Travis J. , St. Clair Colleen Cassady , Salsbury Carmen M. , Sander Heather A. , Stankowich Theodore , Williamson Jacque , Belaire J. Amy , Simon Kelly , Magle Seth B.
Published: September 2021

Time is a fundamental component of ecological processes. How animal behavior changes over time has been explored through well-known ecological theories like niche partitioning and predator-prey dynamics. Yet, changes in animal behavior within the shorter 24-hour light-dark cycle have largely gone unstudied. Understanding if an animal can adjust their temporal activity to mitigate or adapt to environmental change has become a recent topic of discussion and is important for effective wildlife management and conservation. While spatial habitat is a fundamental consideration in wildlife management and conservation, temporal habitat is often ignored. We formulated a temporal resource selection model to quantify the diel behavior of eight mammal species across ten U.S. cities. We found high variability in diel activity patterns within and among species and species-specific correlations between diel activity and human population density, impervious land cover, available greenspace, vegetation cover, and mean daily temperature. We also found that some species may modulate temporal behaviors to manage both natural and anthropogenic risks. Our results highlight the complexity with which temporal activity patterns interact with local environmental characteristics, and suggest that urban mammals may use time along the 24-hour cycle to reduce risk, adapt, and therefore persist in human-dominated ecosystems.
Aging reduces calreticulin expression and alters spontaneous calcium signals in astrocytic endfeet of the mouse dorsolateral striatum
Authors: Zarate Sara M. , Huntington Taylor E. , Bagher Pooneh , Srinivasan Rahul
Published: September 2021

Aging-related impairment of the blood brain barrier (BBB) and neurovascular unit (NVU) increases risk for neurodegeneration. Among the various cells participating in BBB and NVU function, spontaneous Ca2+ signals in astrocytic endfeet are crucial for maintaining BBB and NVU integrity. To assess if aging is associated with changes in spontaneous Ca2+ signals within astrocytic endfeet of the dorsolateral striatum (DLS), we expressed a genetically encoded Ca2+ indicator, Lck-GCaMP6f in DLS astrocytes of young (3-4 month) and aging (20-24 month) mice. Compared to young mice, endfeet in the DLS of aging mice demonstrated a decrease in calreticulin (CALR) expression, and dramatic alterations in the dynamics of endfoot membrane-associated and mitochondrial Ca2+ signals. While young mice required both extracellular and endoplasmic reticulum (ER) Ca2+ sources for generating endfoot Ca2+ signals, aging mice showed exclusive dependence on ER Ca2+. These data suggest that aging is associated with significant changes in Ca2+ buffers and Ca2+ signals within astrocytic endfeet, which has important implications for understanding mechanisms involved in aging-related impairment of the BBB and NVU.

Graphical abstract

Highlights

Aging mice show reduced calreticulin expression in astrocytic endfeet

Aging astrocytic endfeet show dramatic changes in spontaneous Ca2+ activity

Ca2+ signals in aging endfeet depend exclusively on endoplasmic reticulum Ca2+
Hemodynamic evaluation of chemical mediators of sepsis during systemic inflammatory response in an experimental animal model
Authors: Vieira Guilherme de Souza , Antunes Fernanda , Machado Josias Alves , Morales Isabella Cristina , de Jesus Priscilla Olivieri Benck , do Amaral Alexandra de Faria , de Abreu Oliveira André Lacerda
Published: September 2021

The early diagnosis of sepsis increases the chances of its successful treatment. Biomarkers are able to distinguish between systemic inflammatory response syndrome and sepsis and are used to monitor pro- and anti-inflammatory changes associated with the host response to pathogens. A total of 11 rats underwent sepsis induction and measured systolic, diastolic and mean arterial blood pressure. Leukocyte counts, procalcitonin, and nitric oxide also were measured 0, 2, and 4 hours after the induction of sepsis using the cecal ligation and puncture method. The animals were divided into two groups: control (SHAM) and induced. Procalcitonin levels remained within the normal range for an inflammatory response throughout the experiment. There was a statistically insignificant increase in nitric oxide levels. All animals showed increased diastolic arterial blood pressure; however, the increase in the induced animals was even more pronounced. Procalcitonin and nitric oxide levels can increase due to surgical manipulation, while arterial blood pressure was not a good predictor for the onset of sepsis during the time period studied here.
Topological insights into the neural basis of flexible behavior
Authors: Rouse Tevin C. , Ni Amy M. , Huang Chengcheng , Cohen Marlene R.
Published: September 2021

It is widely accepted that there is an inextricable link between neural computations, biological mechanisms, and behavior, but it is challenging to simultaneously relate all three. Here, we show that topological data analysis (TDA) provides an important bridge between these approaches to studying how brains mediate behavior. We demonstrate that cognitive processes change the topological description of the shared activity of populations of visual neurons. These topological changes constrain and distinguish between competing mechanistic models, are connected to subjects’ performance on a visual change detection task, and, via a link with network control theory, reveal a tradeoff between improving sensitivity to subtle visual stimulus changes and increasing the chance that the subject will stray off task. These connections provide a blueprint for using TDA to uncover the biological and computational mechanisms by which cognition affects behavior in health and disease.

Significance Statement

As the fields of systems, computational, and cognitive neuroscience strive to establish links between computations, biology, and behavior, there is an increasing need for an analysis framework to bridge levels of analysis. We demonstrate that topological data analysis (TDA) of the shared activity of populations of neurons provides that link. TDA allows us to distinguish between competing mechanistic models and to answer longstanding questions in cognitive neuroscience, such as why there is a tradeoff between visual sensitivity and staying on task. These results and analysis framework have applications to many systems within neuroscience and beyond.
Inactivation of the entire Arabidopsis group II GH3s confers tolerance to salinity and drought
Authors: Casanova-Sáez Rubén , Mateo-Bonmatí Eduardo , Šimura Jan , Pěnčík Aleš , Novák Ondřej , Staswick Paul , Ljung Karin
Published: September 2021

Indole-3-acetic acid (IAA) controls a plethora of developmental processes. Thus, regulation of their levels is of great relevance for plant performance. Cellular IAA concentration depends on the combined result of its transport, biosynthesis and various redundant pathways to inactivate IAA, including oxidation and conjugation. Group II members of the GRETCHEN HAGEN 3 (GH3) gene family code for acyl acid amido synthetases catalysing the conjugation of IAA to amino acids. However, the high level of functional redundancy among them has hampered thorough analysis of their roles in plant development. In this work, we generated an Arabidopsis gh3.1,2,3,4,5,6,9,17 (gh3oct) mutant to knock-out the group II GH3 pathway. The gh3oct plants had an improved root architecture, were more tolerant to osmotic stresses due to locally increased IAA levels and were more drought tolerant. IAA metabolite quantification in gh3oct plants suggested the existence of additional GH3-like enzymes in IAA metabolism. Moreover, our data suggested that oxIAA production depends, at least partly, on the GH3 pathway. Targeted stress-hormone analysis further suggested an involvement of ABA in the differential response to salinity of gh3oct plants. Taken together, our data provide new insights into the roles of group II GH3s in IAA metabolism and hormone-regulated plant development.
Gene structure-based homology search identifies highly divergent putative effector gene family
Authors: Stern David L. , Han Clair
Published: September 2021

Homology of highly divergent genes often cannot be determined from sequence similarity alone. For example, we recently identified in Hormaphis cornu a family of rapidly evolving bicycle genes, which encode novel proteins implicated as plant gall effectors. Sequence similarity search methods yielded few putative bicycle homologs in other species. Coding sequence-independent features of genes, such as intron-exon boundaries, often evolve more slowly than coding sequences, however, and can provide complementary evidence for homology. We found that a linear logistic regression classifier using only structural features of bicycle genes identified many putative bicycle homologs in other species. Independent evidence from sequence features and intron locations supported homology assignments. To test the potential roles of bicycle genes in other aphids, we sequenced the genome of a second gall- forming aphid, Tetraneura ulmi, and found that many bicycle genes are strongly expressed in the salivary glands of the gall forming foundress. In addition, bicycle genes are strongly overexpressed in the salivary glands of a non-gall forming aphid, Acyrthosiphon pisum, and in the non-gall forming generations of Hormaphis cornu. These observations suggest that Bicycle proteins may be used by multiple aphid species to manipulate plants in diverse ways. Incorporation of gene structural features into sequence search algorithms may aid identification of deeply divergent homologs, especially of rapidly evolving genes involved in host-parasite interactions.
Eco1-dependent cohesin acetylation anchors chromatin loops and cohesion to define functional meiotic chromosome domains
Authors: Barton Rachael E. , Massari Lucia F. , Robertson Daniel , Marston Adele L.
Published: September 2021

Cohesin organizes the genome by forming intra-chromosomal loops and inter-sister chromatid linkages. During gamete formation by meiosis, chromosomes are reshaped to support crossover recombination and two consecutive rounds of chromosome segregation. Here we show that Eco1 acetyltransferase positions both chromatin loops and sister chromatid cohesion to organize meiotic chromosomes into functional domains in budding yeast. Eco1 acetylates the Smc3 cohesin subunit in meiotic S phase to establish chromatin boundaries, independently of DNA replication. Boundary formation by Eco1 is critical for prophase exit and for the maintenance of cohesion until meiosis II, but is independent of the ability of Eco1 to antagonize the cohesin-release factor, Wpl1. Conversely, prevention of cohesin release by Wpl1 is essential for centromeric cohesion, kinetochore monoorientation and co-segregation of sister chromatids in meiosis I. Our findings establish Eco1 as a key determinant of chromatin boundaries and cohesion positioning, revealing how local chromosome structuring directs genome transmission into gametes.
Insight into mammary gland development and tumor prevention in a newly developed metastatic mouse model of breast cancer
Authors: To Briana , Broeker Carson , Jhan Jing-Ru , Rempel Rachel , Rennhack Jonathan P. , Hollern Daniel , Jackson Lauren , Judah David , Swiatnicki Matt , Bylett Evan , Kubiak Rachel , Honeysett Jordan , Reaz Shams , Nevins Joseph , Andrechek Eran
Published: September 2021

The development of breast cancer has been observed due to altered regulation of mammary gland developmental processes. Thus, a better understand of the normal mammary gland development can reveal possible mechanism in how normal cells are re-programmed to become malignant cells. E2F1-4 are part of the E2F transcription factor family with varied roles in mammary development. However, little is known about the role of E2F5 in mammary gland development. A combination of scRNAseq and predictive signature tools demonstrate the presence of E2F5 in the mammary gland and showed altered activity during the various phases of mammary gland development and function. Testing the hypothesis that E2F5 regulates mammary function, we generated a mammary-specific E2F5 knockout mouse model, resulting in modest mammary gland development changes. However, after a prolonged latency the E2F5 conditional knockout mice developed highly metastatic mammary tumors with metastases in both the lung and liver. Transplantation of the tumors revealed metastases to lymph nodes that was enriched through serial transplantation. Through whole genome sequencing and RNAseq analysis we identified, and then confirmedin vivo, that Cyclin D1 was dysregulated in E2F5 conditional knockout mammary glands and tumors. Based on these findings, we propose that loss of E2F5 leads altered regulation of Cyclin D1, which facilitates the development of mammary tumors.
Endotaxis: A neuromorphic algorithm for mapping, goal-learning, navigation, and patrolling
Authors: Zhang Tony , Rosenberg Matthew , Jing Zeyu , Perona Pietro , Meister Markus
Published: September 2021

An animal entering a new environment typically faces three challenges: explore the space for resources, memorize their locations, and navigate towards those targets as needed. Experimental work on exploration, mapping, and navigation has mostly focused on simple environments – such as an open arena [68], a pond [42], or a desert [44] – and much has been learned about neural signals in diverse brain areas under these conditions [12, 54]. However, many natural environments are highly structured, such as a system of burrows, or of intersecting paths through the underbrush. Similarly, for many cognitive tasks, a sequence of simple actions can give rise to complex solutions. Here we propose an algorithm that learns the structure of a complex environment, discovers useful targets during exploration, and navigates back to those targets by the shortest path. It makes use of a behavioral module common to all motile animals, namely the ability to follow an odor to its source [4]. We show how the brain can learn to generate internal “virtual odors” that guide the animal to any location of interest. Thisendotaxisalgorithm can be implemented with a simple 3-layer neural circuit using only biologically realistic structures and learning rules. Several neural components of this scheme are found in brains from insects to humans. Nature may have evolved a general mechanism for search and navigation on the ancient backbone of chemotaxis.
LRRC15 mediates an accessory interaction with the SARS-CoV-2 spike protein
Authors: Shilts Jarrod , Crozier Thomas W. M. , Teixeira-Silva Ana , Gabaev Ildar , Greenwood Edward J. D. , Watson Samuel James , Ortmann Brian M. , Gawden-Bone Christian M. , Pauzaite Tekle , Hoffmann Markus , Nathan James A. , Pöhlmann Stefan , Lehner Paul J. , Wright Gavin J.
Published: September 2021

The interactions between severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to COVID-19. The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary ACE2 receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was restricted to SARS-CoV-2, suggesting LRRC15 represents a novel class of spike binding interaction. We localized the interaction to the C-terminus of the S1 domain, and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19.

In brief

We present evidence from genome-wide screening that the spike protein of SARS-CoV-2 interacts with human cells expressing LRRC15. The interaction is distinct from previously known classes of spike attachment factors, and appears to have emerged recently within the coronavirus family. Although not sufficient for cell invasion, this interaction can modulate viral infection. Our data point to an unappreciated host factor for SARS-CoV-2, with potential relevance to COVID-19.

Highlights

- Two systematic cell-based screens for SARS-CoV-2 spike protein binding identify LRRC15 as a human host factor

- Interaction with LRRC15 is reproducible in different human cell lines and independent of known glycan or ACE2 binding pathways

- The C-terminal S1 domain of SARS-CoV-2 spike binds LRRC15 with sub-micromolar affinity, while related coronavirus spikes do not

- LRRC15 is expressed in tissues with high ACE2 levels and may modulate infection