bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of drought and nutrient deficiencies on the allocation of recently fixed carbon in a plant–soil–microbe system
Authors: Xia Huijuan , Zhang Tiantian , Li Xinshuai , He Tiehu , Wang Xia , Zhang Jiehao , Zhang Kerong
Published: August 2023

Carbon (C) allocation plays an important role in plant adaptation to water and nutrient stresses. However, the effects of drought and nutrient deficiencies on the allocation of recently fixed C in the plant–soil–microbe system remain largely unknown. Herein, we studied the response of C allocation of Sophora moorcroftiana (an indigenous pioneer shrub in Tibet) to drought, nitrogen (N) deficiency and phosphorus (P) deficiency using a microcosm experiment. The 13CO2 continuous labeling was used to trace C allocation in the plant–soil–microbe system. We found that drought significantly reduced plant 13C, but it increased 13C accumulation in soil. The decreased plant 13C under drought was attributed to the decrease of 13C in stem and root rather than that in leaf. The excess 13C fraction in the microbial biomass (MB13C) was reduced by N deficiency, but it was not affected by the combination of drought and N deficiency, indicating that drought weakened the effects of N deficiency on MB13C. By contrast, MB13C increased under the combination of drought and P deficiency, suggesting that drought enhanced the effects of P deficiency on MB13C. Drought and nutrient deficiencies regulated the belowground 13C allocation. Specifically, drought and P deficiency increased the allocation of 13C to root and N deficiency regulated the allocation of 13C to microbial biomass C and dissolved organic C in soil. Notably, soil 13C decreased with increasing plant 13C, while MB13C first decreased and then increased with increasing plant 13C. Overall, our study demonstrated that drought and nutrient deficiencies interactively affected C allocation in a plant–soil–microbe system and provided insights into C allocation strategies in response to multiple resource (water and nutrient) stresses under environmental changes.
Complete Genome Sequence of a Copper-Resistant Xanthomonas campestris pv. campestris Strain Isolated from Broccoli in Mauritius Suggests Adaptive Gene Gain Through Horizontal Gene Transfer
Authors: Boyer Claudine , Lefeuvre Pierre , Richard Damien , Lobin Kanta Kumar , Pruvost Olivier
Published: August 2023

Bacterial adaptation is facilitated by the presence of mobile genetic elements and horizontal gene transfer of genes, such as those coding for virulence factors or resistance to antimicrobial compounds. A hybrid assembly of Nanopore MinIon long-read and Illumina short-read data was produced from a copper-resistant Xanthomonas campestris pv.  campestris strain isolated from symptomatic broccoli leaves in Mauritius. We obtained a 5.2-Mb high-quality chromosome and no plasmid. We found four genomic islands, three of which were characterized as integrative conjugative elements or integrative mobilizable elements. These genomic islands carried type III effectors and the copper resistance copLABMGF system involved in pathogenicity and environmental adaptation, respectively.
Pain Medication Use Two Years After Adolescent Idiopathic Scoliosis Fusion Surgery
Authors: Bastrom Tracey P. , Kelly Michael P. , Upasani Vidyadhar V. , Newton Peter O. ,   Harms Study Group
Published: August 2023

Study Design.

Observational case control.

Objective.

The objective of this study was to evaluate the prevalence of opioid use two years after surgical correction of adolescent idiopathic scoliosis (AIS) and its association with preoperative mental health.

Summary of Background Data.

Studies of opiate use have reported that up to 80% of users began their addiction with misuse of prescription opioids. Identifying opioid use and those at risk in the AIS population is critical for optimal outcomes.

Materials and Methods.

A query of a multicenter prospective AIS surgical fusion registry was performed to identify patients of all curve types with responses to question 11 on the Scoliosis Research Society-22 questionnaire at two years postoperative. Question 11 asks about pain medication usage for the patient’s back with five specific responses: narcotics daily, narcotics weekly or less, non-narcotics daily, non-narcotics weekly/less, or none. Ordinal regression was used to evaluate the association between preoperative Scoliosis Research Society-22 Mental Health (MH) domain scores and two-year postoperative pain medication usage.

Results.

A total of 2595 patients who underwent surgery from 2002 to 2019 met inclusion. The average primary curve was 56±12°, average age 14.7±3 years, and 81.5% were female. Forty (1.5%) patients reported utilizing opioids two years after surgery, and a significant difference in preoperative MH scores was observed. Patients taking daily opioids postoperatively had the lowest median preoperative MH score (3.75), followed by non-narcotic group (4), and no medication (4.2, P<0.001). Three patients reporting opioid use postoperatively reported preoperative usage. The rate of two-year postoperative medication use based on the year of surgery demonstrated a small linear decrease in opioid use over time, with a slight increase in nonopioid daily use.

Conclusions.

Less than 2% of patients reported taking opioids for back pain two years after surgical correction of AIS. A lower MH score before surgery may place a patient at increased risk for opioid use two years after surgery. An analysis of the year of surgery suggests that changes in prescription practices over time may be occurring.

Level of Evidence.

4
Mesothelin-targeted CAR-NK Cells Derived From Induced Pluripotent Stem Cells Have a High Efficacy in Killing Triple-negative Breast Cancer Cells as Shown in Several Preclinical Models
Authors: Yang Mei , Guan Tian , Chen Chun-Fa , He Li-Fang , Wu Hao-Ming , Zhang Ren-Dong , Li Yun , Lin Yan-Chun , Zeng Haoyu , Wu Jun-Dong
Published: August 2023

The emergence of immunotherapy has introduced a promising, novel approach to cancer treatment. While multiple chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable clinical efficacy against leukemia, their effect on solid tumors has been limited. One potential option for treating solid tumors is the engineering of natural killer (NK) cells with CARs. Mesothelin (MSLN), a tumor differentiation antigen, is expressed on triple-negative breast cancer (TNBC) cells, making it a potential target for CAR-NK therapy in the treatment of TNBC. We first constructed induced pluripotent stem cells with stable anti-MSLN-CAR expression and subsequently differentiated these cells into mesothelin-targeted CAR-NK (MSLN-NK) cells. We then assessed the effects of MSLN-NK cells on TNBC cells both in vitro (using the MDA-MB-231 cell line), in vivo (in a CDX mouse model), and ex vivo (using patient-specific primary cells and patient-specific organoids), in which MSLN surface expression was confirmed. Our CDX study results indicated that MSLN-NK cells effectively killed MDA-MB-231 (MD231) cells in vitro, reduced tumor growth in the CDX mouse model of TNBC, and lysed patient-specific primary cells and patient-specific organoids derived from the tumor samples of TNBC patients. Our data demonstrated that MSLN-NK cells had high efficacy on killing TNBC cells in in vitro, in vivo, and ex vivo. Therefore, MSLN-NK could be a promising treatment option for TNBC patients.
Assessment of the Blue Light Ocular Hazard by Solar Measurements and the Impact of Selected Sunglasses Based upon the Limits of the International Commission on Non-Ionizing Radiation Protection Guideline
Authors: Krejci Martin , Caruso Giuseppe
Published: August 2023

A quantitative assessment of the blue light hazard for the human eye related to direct solar irradiation is presented. For six radiation situations, missing eye protection was compared to protection by nine different commercial sunglasses with and without an optimized blue light filter. Measurements of the solar irradiance were performed on Earth’s surface as well as at an elevation of 12 km in the cockpit of an airliner. An irradiation time limit was calculated from the measurement data, within which the maximum blue light dose of 100 J m−2, recommended by the International Commission on Non-Ionizing Radiation Protection and mandatory for the safe operation of lamps according to the norm ICE 62471, is reached. The results suggest that the blue light dose limit is violated within less than 3 s when looking without eye protection directly into the sun. For Category 3 sunglasses without the optimized blue light filter, time limits of 10 to 25 s on Earth’s surface and 7 to 8 s at 12 km altitude were observed. The investigated Category 3 sunglasses with optimized blue light protection and suited for traffic use allow a time limit of more than 40 s on Earth’s surface and 18 to 95 s in the airliner’s cockpit. The outcome of the study is that the eye protection against blue light hazard related to solar radiation can be quantified using existing limits and that the choice of sunglasses is relevant: Traffic-worthy sunglasses optimized for protection against blue light hazard offer a better protection than non-optimized sunglasses.
Primary Transscleral Diode Laser Cyclophotocoagulation for Management of Glaucoma in Nanophthalmic Eyes
Authors: Abdelrahman Ahmed M. , Ismail Yomna M.
Published: August 2023

Purpose:

The aim of this study was to assess the efficacy and safety of double-row transscleral cyclophotocoagulation in controlling intraocular pressure in patients with secondary angle closure glaucoma due to nanophthalmos, not being controlled by medical therapy.

Patients and Methods:

A prospective case series study that included 13 eyes of 8 patients diagnosed with secondary angle closure glaucoma due to nanophthalmos at the Giza Eye Subspeciality Center, treated by 24 cyclodiode applications in a double-row technique. Success was defined as complete success by control of intraocular pressure <21 mm Hg without medication and qualified success in which control of pressure <21 mm Hg achieved with 1 or 2 medications.

Results:

The average reduction in intraocular pressure at 3 months was 57.3±20.14% and at 6 months 44.5±32%, with an average eye drop intake of 1.3±0.8 drops. There was a significant reduction of intraocular pressure at 6 months compared with the preprocedure pressure (P=0.01). Complete success achieved in 3 eyes, pressure controlled without any medication, and qualified success in 9 eyes.

Conclusion:

Transscleral cyclophotocoagulation is a safe and effective primary therapy for managing glaucoma in nanophthalmic eyes.
A Case of Uveitis-Glaucoma-Hyphema Syndrome Related to a Hydrus Microstent
Authors: Kaplan Tyler M. , Sit Arthur J.
Published: August 2023

Uveitis-Glaucoma-Hyphema (UGH) syndrome is characterized by episodes of anterior chamber inflammation, elevated intraocular pressure and hyphema. It is caused by a mechanical chafing of the iris or ciliary body typically by a malpositioned intraocular lens. We present a rare case of UGH syndrome related to the insertion of a Hydrus Microstent. Because of the increased number of microinvasive glaucoma surgeries being performed and a reduction of UGH syndrome patients related to the insertion of intraocular lenses, it is an important diagnosis to consider in patients with recurrent postoperative inflammation.
Developing the Baptist Health Injury Risk Assessment Phase 1
Authors: Lewis C. Preston , Schenkenfelder Reece , Davies Claire C. , Monroe Martha , Acton Deanna , Phillips Tracy
Published: August 2023

OBJECTIVES

The aim of this study was to explore risk factors for developing hospital-acquired pressure injuries (HAPIs) among critically ill adult inpatients.

BACKGROUND

Hospital-acquired pressure injuries remain a priority quality focus for Magnet® organizations. Recent studies cite medical devices as a primary cause, yet published risk assessments lack inclusion of those threats.

METHODS

Nurses at a 434-bed, 4-time Magnet®-designated hospital led a retrospective study acros 9 American Nurses Credentialing Center–designated facilities. Using a chart review tool, data were collected within 48 hours of a confirmed HAPI.

RESULTS

Of 207 HAPIs reported, 54% (n = 113) involved deep tissue pressure injuries and 50.2% (n = 104) involved 19 medical devices. Individuals with a HAPI also used 1 or more of 7 distinct types of mobility-limiting medical equipment.

CONCLUSIONS

Study findings support the development of a critical care risk assessment with inclusion of a medical device and mobility-limiting medical equipment as risk factors. A secondary study is underway for specificity and sensitivity testing of this assessment.
Moving Toward Equity and Transparency in NP Faculty Workload
Authors: Gourley Bridgitte , Idzik Shannon , Yingling Charles , Bigley Mary Beth , Ammerman Beth
Published: August 2023

Background:

Nurse practitioner (NP) programs rely on a highly educated and experienced faculty to deliver the curriculum. Full-time NP faculty are expected to be doctorally prepared, with responsibilities for instruction, an active clinical practice, scholarship, and service.

Problem:

Although the majority of faculty workload comes from effort in instruction, there is significant variability in how faculty workload is assigned. Absent a national model, schools of nursing are challenged to develop workload models for NP faculty to allocate effort for the full scope of work that NP faculty are expected to perform to meet requirements for academic credentialing bodies, licensure, and academic promotion.

Approach:

This article examines current practices in NP workload allocation and explores ways to allocate effort to the domains of work integral to NP education.

Conclusion:

NP faculty workload models should align with academic promotion expectations to encourage equity and transparency.
Case Report: Indirect Traumatic Optic Neuropathy from Subconcussive Soccer Headers in a 62-year-old Athlete
Authors: Pandya Radha P. , Pandya Shruti , Thomann Kelly H.
Published: August 2023

SIGNIFICANCE

Traumatic optic neuropathy is an uncommon but devastating cause of vision loss after injury to the head. Soccer players may have a heightened risk because of the game's emphasis on heading the ball, a technique in which a player hits the soccer ball with his/her head.

PURPOSE

This article reviews the case of an avid soccer player with traumatic optic neuropathy that occurred after numerous soccer ball headings during a game. This article also (1) provides a summary of the pathophysiology and epidemiology of traumatic optic neuropathy, (2) reviews the current literature on head and eye injuries in soccer, and (3) discusses biomechanical differences in orbital structure throughout aging, which may predispose older patients to traumatic optic neuropathy.

CASE REPORT

We present the case of a 62-year-old male patient who reported to the clinic, after repeated subconcussive soccer ball headers the previous day, with symptoms of blurred vision and “seeing stars” in the right eye and a right inferior visual field impairment. Physical examination, subsequent laboratory work, and neurologic consults implicated traumatic optic neuropathy as the primary diagnosis, and halting soccer playing resulted in symptom improvement.

CONCLUSIONS

Although not commonly encountered in soccer players, the potential for traumatic optic neuropathy exists. Older athletes may be predisposed because of morphological changes of the orbit. Future direction may look to further investigate hazards promoting traumatic optic neuropathy in older athletes and determine possible protections against injury.
Endoscopic Band Ligation in Blue Rubber Bleb Nevus Syndrome: A Report of Two Children
Authors: Samanta Arghya , Poddar Ujjal , Sarma Moinak Sen , Srivastava Anshu , Yachha Surender Kumar , Mohindra Samir
Published: August 2023

Blue rubber bleb nevus syndrome (BRBNS) is a rare congenital disorder presenting with multifocal venous malformations of the skin, soft tissues, and gastrointestinal (GI) tract. Patients usually present with chronic anemia resulting from occult GI bleeding and sometimes with massive GI bleeding. We report 2 children with blue rubber bleb nevus syndrome with GI bleeding: 1 with obscure GI bleeding and the other with overt GI bleeding. In both cases, the presence of cutaneous lesions provided useful clues toward diagnosis. Colonoscopy and upper GI endoscopy revealed bluish polypoidal lesions in the GI tract. Capsule endoscopy helped in disease mapping. Both of them were successfully treated with endoscopic band ligation and nonselective beta-blockers, which resulted in an improvement in their hemoglobin levels. Our cases highlight the successful use of endoscopic band ligation of GI lesions as a therapeutic modality. It is important for gastroenterologists to be aware of this rare condition for current diagnosis.
Gill function in an early arthropod and the widespread adoption of the countercurrent exchange mechanism
Authors: Hou Jin-Bo , Hughes Nigel C. , Hopkins Melanie J. , Shu Degan
Published: August 2023

Rising but fluctuating oxygen levels in the Early Palaeozoic provide an environmental context for the radiation of early metazoans, but little is known about how mechanistically early animals satisfied their oxygen requirements. Here we propose that the countercurrent gaseous exchange, a highly efficient respiratory mechanism, was effective in the gills of the Late Ordovician trilobite
Triarthrus eatoni
. In order to test this, we use computational fluid dynamics to simulate water flow around its gills and show that water velocity decreased distinctly in front of and between the swollen ends, which first encountered the oxygen-charged water, and slowed continuously at the mid-central region, forming a buffer zone with a slight increase of the water volume. In
T. eatoni
respiratory surface area was maximized by extending filament height and gill shaft length. In comparison with the oxygen capacity of modern fish and crustaceans, a relatively low weight specific area in
T. eatoni
may indicate its low oxygen uptake, possibly related to a less active life mode. Exceptionally preserved respiratory structures in the Cambrian deuterostome
Haikouella
are also consistent with a model of countercurrent gaseous exchange, exemplifying the wide adoption of this strategy among early animals.
Symbiotic bacteria, immune-like sentinel cells, and the response to pathogens in a social amoeba
Authors: Scott Trey J. , Larsen Tyler J. , Brock Debra A. , Uhm So Yeon Stacey , Queller David C. , Strassmann Joan E.
Published: August 2023

Some endosymbionts living within a host must modulate their hosts' immune systems in order to infect and persist. We studied the effect of a bacterial endosymbiont on a facultatively multicellular social amoeba host. Aggregates of the amoeba
Dictyostelium discoideum
contain a subpopulation of sentinel cells that function akin to the immune systems of more conventional multicellular organisms. Sentinel cells sequester and discard toxins from
D. discoideum
aggregates and may play a central role in defence against pathogens. We measured the number and functionality of sentinel cells in aggregates of
D. discoideum
infected by bacterial endosymbionts in the genus
Paraburkholderia
. Infected
D. discoideum
produced fewer and less functional sentinel cells, suggesting that
Paraburkholderia
may interfere with its host's immune system. Despite impaired sentinel cells, however, infected
D. discoideum
were less sensitive to ethidium bromide toxicity, suggesting that
Paraburkholderia
may also have a protective effect on its host. By contrast,
D. discoideum
infected by
Paraburkholderia
did not show differences in their sensitivity to two non-symbiotic pathogens. Our results expand previous work on yet another aspect of the complicated relationship between
D. discoideum
and
Paraburkholderia
, which has considerable potential as a model for the study of symbiosis.
An environmental habitat gradient and within-habitat segregation enable co-existence of ecologically similar bird species
Authors: Ayebare Samuel , Doser Jeffrey W. , Plumptre Andrew J. , Owiunji Isaiah , Mugabe Hamlet , Zipkin Elise F.
Published: August 2023

Niche theory predicts that ecologically similar species can coexist through multidimensional niche partitioning. However, owing to the challenges of accounting for both abiotic and biotic processes in ecological niche modelling, the underlying mechanisms that facilitate coexistence of competing species are poorly understood. In this study, we evaluated potential mechanisms underlying the coexistence of ecologically similar bird species in a biodiversity-rich transboundary montane forest in east-central Africa by computing niche overlap indices along an environmental elevation gradient, diet, forest strata, activity patterns and within-habitat segregation across horizontal space. We found strong support for abiotic environmental habitat niche partitioning, with 55% of species pairs having separate elevation niches. For the remaining species pairs that exhibited similar elevation niches, we found that within-habitat segregation across horizontal space and to a lesser extent vertical forest strata provided the most likely mechanisms of species coexistence. Coexistence of ecologically similar species within a highly diverse montane forest was determined primarily by abiotic factors (e.g. environmental elevation gradient) that characterize the Grinnellian niche and secondarily by biotic factors (e.g. vertical and horizontal segregation within habitats) that describe the Eltonian niche. Thus, partitioning across multiple levels of spatial organization is a key mechanism of coexistence in diverse communities.
The resuscitation-promoting factor (Rpf) from Micrococcus luteus and its putative reaction product 1,6-anhydro-MurNAc increase culturability of environmental bacteria
Authors: Guzman Juan , Raval Dipansi , Hauck Dirk , Titz Alexander , Poehlein Anja , Degenkolb Thomas , Daniel Rolf , Vilcinskas Andreas
Published: August 2023

Bacterial dormant cells do not divide and are not immediately culturable, but they persist in a state of low metabolic activity, a physiological state having latent clinical relevance, for instance in tuberculosis. Resuscitation promoting factors (Rpf) are proteins that act as signaling molecules mediating growth and replication. In this study we aimed to test the effect of Rpf on the number and diversity of cultured bacteria using insect and soil samples, and to examine if the increase in culturability could be reproduced with the putative reaction product of Rpf, 1,6-anhydro-MurNAc. The rpf gene from Micrococcus luteus was amplified and cloned into a pET21b expression vector and the protein was expressed in E. coli BL21(DE3) cells and purified by affinity chromatography using a hexa-histidine tag. 1,6-anhydro-N-acetylmuramic acid (1,6-anhydro-MurNAc) was prepared using reported chemical synthesis methods. Recombinant Rpf protein or 1,6-anhydro-MurNAc were added to R2A cultivation media, and their effect examined on the culturability of bacteria from eight environmental samples including four cockroach guts and four soils. Colony forming units, 16S rRNA gene copies and Illumina amplicon sequencing of the 16S rRNA were measured for all eight samples subjected to three different treatments: control, Rpf or 1,6-anhydro-MurNAc. Both Rpf and 1,6-anhydro-MurNAc increased the number of colony forming units, and 16S rRNA gene copies across the samples although the protein was more effective. The Rpf and 1,6-anhydro-MurNAc promoted the cultivation of a diverse set of bacteria and specially certain clades of the phyla Actinomycetota and Bacillota. This study opens the path for improved cultivation strategies aiming to isolate and study yet undescribed living bacterial organisms.
A Scoping Review of ‘Pacing’ for Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Lessons Learned for the Long COVID Pandemic
Authors: Sanal-Hayes Nilihan E.M. , Mclaughlin Marie , Hayes Lawrence D. , Mair Jacqueline L. , Ormerod Jane , Carless David , Hilliard Natalie , Meach Rachel , Ingram Joanne , Sculthorpe Nicholas F.
Published: August 2023

Background

Controversy over treatment for people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a barrier to appropriate treatment. Energy management orpacingis a prominent coping strategy for people with ME/CFS that involves regulating activity to avoid post exertional malaise (PEM), the worsening of symptoms after an activity. Until now, characteristics of pacing, and the effects on patients’ symptoms had not been systematically reviewed. This is problematic as the most common approach to pacing, pacing prescription, and the pooled efficacy of pacing was unknown. Collating evidence may help advise those suffering with similar symptoms, including long COVID, as practitioners would be better informed on methodological approaches to adopt, pacing implementation, and expected outcomes.

Objectives

In this scoping review of the literature, we aggregated type of, and outcomes of, pacing in people with ME/CFS.

Eligibility criteria

Original investigations concerning pacing were considered in participants with ME/CFS.

Sources of evidence

Six electronic databases (PubMed, Scholar, ScienceDirect, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials [CENTRAL]) were searched; and websites MEPedia, Action for ME, and ME Action were also searched for grey literature.

Methods

A scoping review was conducted. Review selection and characterisation was performed by two independent reviewers using pretested forms.

Results

Authors reviewed 177 titles and abstracts, resulting in included 17 studies: three randomised control trials (RCTs); one uncontrolled trial; one interventional case series; one retrospective observational study; two prospective observational studies; four cross-sectional observational studies; and five cross-sectional analytical studies. Studies included variable designs, durations, and outcome measures. In terms of pacing administration, studies used educational sessions and diaries for activity monitoring. Eleven studies reported benefits of pacing, four studies reported no effect, and two studies reported a detrimental effect in comparison to the control group.

Conclusions

Highly variable study designs and outcome measures, allied to poor to fair methodological quality resulted in heterogenous findings and highlights the requirement for more research examining pacing. Looking to the long COVID pandemic, future studies should be RCTs utilising objectively quantified digitised pacing, over a longer duration of examination, using the core outcome set for patient reported outcome measures.
Causal relationships between anthropometric traits, bone mineral density, osteoarthritis and spinal stenosis: a Mendelian randomization investigation
Authors: Sobczyk Maria K , Faber Benjamin G , Southam Lorraine , Frysz Monika , Hartley April , Zeggini Eleftheria ,   The Genetics of Osteoarthritis Consortium, Tang Haotian , Gaunt Tom R
Published: August 2023

Background

Spinal stenosis is a common condition among older individuals, with significant morbidity attached. Little is known about its risk factors but degenerative conditions, such as osteoarthritis (OA) have been identified for their mechanistic role. This study aims to explore causal relationships between anthropometric risk factors, osteoarthritis, and spinal stenosis using Mendelian randomization (MR) techniques.

Methods

We applied two-sample univariable and multivariable MR to investigate the causal relationships between genetic liability for select risk factors (including adiposity and skeletal traits) and spinal stenosis. Next, we examined the genetic relationship between osteoarthritis and spinal stenosis with LD score regression and CAUSE MR method. Using multivariable MR, osteoarthritis and BMI were then tested as potential mediators of the causal pathways identified.

Results

Our analysis revealed strong evidence for the effect of higher BMI (OR=1.54, 95% CI: 1.41-1.69, p-value=2.7 x 10-21), waist (OR=1.43, 95% CI: 1.15-1.79, p-value=1.5 x 10-3) and hip (OR=1.50, 95% CI: 1.27-1.78, p-value=3.3 x 10-6) circumference on spinal stenosis. Strong associations were observed for higher bone mineral density (BMD): total body (OR=1.21, 95% CI: 1.12-1.29, p-value=1.6 x 10-7), femoral neck (OR=1.35, 95% CI: 1.09-1.37, p-value=7.5 x 10-7), and lumbar spine (OR=1.38, 95% CI: 1.25-1.52, p-value=4.4 x 10-11). We detected high genetic correlations between spinal stenosis and osteoarthritis (rg range: 0.47-0.66), with Bayesian CAUSE results supporting a causal effect of osteoarthritis on spinal stenosis (ORall OA=1.6, 95% CI:1.41-1.79). Direct effects of BMI, total body/femoral neck/lumbar spine BMD on spinal stenosis remained after adjusting for osteoarthritis and/or BMI in the multivariable MR.

Conclusions

Genetic susceptibility to anthropometric risk factors, particularly higher BMI and bone mineral density can increase the risk of spinal stenosis, independent of osteoarthritis status. These results improve our understanding of spinal stenosis aetiology and may inform preventative strategies and treatments.
Modifications of Two ESCRT-I Subunits with Distinct Ubiquitin Chains Regulate Plant Immunity
Authors: Wang Chaofeng , Zhang Yi , Zhou Bangjun , Verma Pooja , Hamera Sadia , Zeng Lirong
Published: August 2023

Sensing of pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs) by pattern recognition receptors (PRRs) at the cell surface induces the first layer of host immunity against invading microbial pathogens. The immune receptor FLS2 perceives bacterial flagellin to initiate host immune signaling upon pathogen infections. It has been known that the FLS2 abundance is crucial for plant pattern-triggered immunity. Nevertheless, the underpinning regulatory mechanisms remain largely unclear. In this study, we demonstrate that XBAT35.2 positively modulates the protein level of FLS2. In addition to the Golgi, XBAT35.2 localizes at the plasma membrane and constitutively associates with FLS2, BAK1, and BIK1. Flg22 treatment increases the association of XBAT35.2 with FLS2 and BAK1 but reduces the interaction with BIK1. XBAT35.2 ubiquitinates two key components of the ESCRT-I complex, VPS37-1 and VPS28-2 with K48 and K63-linked polyubiquitin chains respectively, leading to degradation of VPS37-1 and diminished interaction of VPS28-2 with FLS2. Additionally, VPS37-1 and VPS28-2 play redundant, negative roles in FLS2-mediated immunity by promoting vacuolar breakdown of FLS2. Thus, by intercepting the function of VPS28-2 and VPS37-1, XBAT35.2 stabilizes FLS2 for host immunity. Our findings reveal a new regulatory circuit for modulating the FLS2 abundance and deepen our understanding of controlling the homeostasis of cell surface receptors.

One-sentence summary

Targeting the ESCRT-I subunits VPS28-2 and VPS37-1 with distinct ubiquitin chains by the E3 ligase XBT35.2 stabilizes FLS2 and positively modulates plant immunity.
Selective inhibition of fibroblast-specific Domain Discoidin Receptor 1 (DDR1) reduces collagen deposition and modulates fibroblast-specific cytokine release within the breast microenvironment
Authors: Fein Daniel E.C. , Traugh Nicole , Rauner Gat , Mal Youssof , Trepicchio Colin , Kuperwasser Charlotte
Published: August 2023

Fibroblasts are a major cell type within breast microenvironment which play key roles in tissue remodeling during the processes of normal development, injury, and malignancy. During wound healing and tumorigenesis, fibroblasts facilitate production and degradation of the extracellular matrix and produce inflammatory mediators which act as immune regulators. Domain Discoidin Receptor 1 (DDR1) is a cell surface tyrosine kinase receptor expressed by epithelial and stromal cells which is activated by collagen. In the breast, DDR1 expression and activity has been implicated in the development of fibrosis as well as chemotherapy resistance. We set out to examine whether selective inhibition of DDR1 would modulate fibroblast immunomodulatory function to generate an immune-permissive breast microenvironment and reduce stromal desmoplasia. In vivo, DDR1 inhibition resulted in mammary fibroblast tissue remodeling, reduced collagen deposition, and changes in immunomodulatory cytokine expression. Furthermore, DDR1 inhibition was associated with increased CD45.2+ immune cell infiltration and reduced Ly6G+/Ly6C− neutrophil infiltration. Mechanistically, we developed an ex-vivo 3D collagen hydrogel model of desmoplasia to study the effects of DDR1 inhibition on the expression of immune modulating factors and fibroblast functions and features. We found that DDR1 regulates the expression and secretion of key immunomodulatory cytokines (IL-6, IL-8, and MCP-1). Collectively these findings suggest that breast fibroblast-specific DDR1 mediates collagen deposition and immunomodulatory function within the mammary gland and warrants further investigation as a potential target for fibroblast-modulating therapy in benign and neoplastic breast disorders.
DEPOT: graph learning delineates the roles of cancers in the progression trajectories of chronic kidney disease using electronic medical records
Authors: Song Qianqian , Liu Xiang , Li Zuotian , Zhang Pengyue , Eadon Michael , Su Jing
Published: August 2023

Chronic kidney disease (CKD) is a common, complex, and heterogeneous disease impacting aging populations. Determining the landscape of disease progression trajectories from midlife to senior age in a real-world context allows us to better understand the progression of CKD, the heterogeneity of progression patterns among the risk population, and the interactions with other clinical conditions like cancers. In this study, we use electronic health records (EHRs) to outline the CKD progression trajectory roadmap for the Wake Forest Baptist Medical Center (WFBMC) patient population. We establish an EHR cohort (n = 79,434) with patients’ health status identified by 18 Essential Clinical Indices across 508,732 clinical encounters. We develop the DisEase PrOgression Trajectory (DEPOT) approach to model CKD progression trajectories and individualize clinical decision support. The DEPOT is an evidence-driven, graph-based clinical informatics approach that addresses the unique challenges in longitudinal EHR data by systematically using the graph artificial intelligence (graph-AI) model for representation learning and reverse graph embedding for trajectory reconstruction. Moreover, DEPOT includes a prediction model to assign new patients along the progression trajectory. We successfully establish the EHR-based CKD progression trajectories with DEPOT in the WFUBMC cohort. We annotate the trajectories with clinical features, including kidney function, age, and other indices, including cancer. This CKD progression trajectory roadmap reveals diverse kidney failure pathways associated with different clinical conditions. Specifically, we have identified one high-risk trajectory and two low-risk trajectories. Switching pathways from low-risk trajectories to the high-risk one is associated with accelerated decline in kidney function. On this roadmap, high-risk patients are enriched in the skin and GU cancers, which differs from low-risk patients, suggesting fundamentally different disease progression mechanisms. Overall, the CKD progression trajectory roadmap reveals novel diverse renal failure pathways in type 2 diabetes mellitus and highlights disease progression patterns associated with cancer phenotypes.
Modulations in high-density EEG during the suppression of phantom-limb pain with neurostimulation in upper-limb amputees
Authors: Kleeva Daria , Soghoyan Gurgen , Biktimirov Artur , Piliugin Nikita , Matvienko Yury , Sintsov Mikhail , Lebedev Mikhail
Published: August 2023

Phantom limb pain (PLP) is a distressing and persistent sensation that occurs after the amputation of a limb. While medication-based treatments have limitations and adverse effects, neurostimulation is a promising alternative approach whose mechanism of action needs research, including electroencephalographic (EEG) recordings for the assessment of cortical manifestation of PLP relieving effects. Here we collected and analyzed high-density EEG data in three patients (P01, P02, and P03). Peripheral nerve stimulation (PNS) suppressed PLP in P01 but was ineffective in P02. By contrast, transcutaneous electrical nerve stimulation (TENS) was effective in P02. In P03, spinal cord stimulation (SCS) was used to suppress PLP. Changes in EEG oscillatory components were analyzed using spectral analysis and Petrosian fractal dimension (FD). With these methods, changes in EEG spatio-spectral components were found in the theta, alpha, and beta bands in all patients, with these effects being specific to each individual. The changes in the EEG patterns were found for both the periods when PLP level was stationary and the periods when PLP was gradually changing after neurostimulation was turned on or off. Overall, our findings align with the proposed roles of brain rhythms in thalamocortical dysrhythmia or disrubtion of excitation and inhibition which has been linked to neuropathic pain. The individual differences in the observed effects could be related to the specifics of each patient’s treatment and the unique spectral characteristics in each of them. These findings pave the way to the closed-loop systems for PLP management where neurostimulation parameters are adjusted based on EEG-derived markers.
The interplay of TGF-β1 and cholesterol orchestrating hepatocyte cell fate, EMT, and signals for HSC activation
Authors: Wang Sai , Link Frederik , Han Mei , Chaudhary Roohi , Asimakopoulos Anastasia , Liebe Roman , Yao Ye , Hammad Seddik , Dropmann Anne , Krizanac Marinela , Rubie Claudia , Feiner Laura Kim , Glanemann Matthias , Ebert Matthias , Weiskirchen Ralf , Henis Yoav I , Ehrlich Marcelo , Dooley Steven
Published: August 2023

Background and Aims: Transforming growth factor-β1 (TGF-β1) plays important roles in chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD involves various biological processes including dysfunctional cholesterol metabolism and contributes to progression to metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). However, the reciprocal regulation of TGF-β1 signaling and cholesterol metabolism in MASLD is yet unknown. Methods: Changes in transcription of genes associated with cholesterol metabolism were assessed by RNA-Seq of murine hepatocyte cell line (AML12) and mouse primary hepatocytes (MPH) treated with TGF-β1. Functional assays were performed on AML12 cells (untreated, TGF-β1 treated, or subjected to cholesterol enrichment (CE) or depletion (CD)), and on mice injected with adeno-associated virus 8 (AAV8)-Control/TGF-β1. Results: TGF-β1 inhibited mRNA expression of several cholesterol metabolism regulatory genes, including rate-limiting enzymes of cholesterol biosynthesis in AML12 cells, MPHs, and AAV8-TGF-β1-treated mice. Total cholesterol levels and lipid droplet accumulation in AML12 cells and liver tissue were also reduced upon TGF-β1 treatment. Smad2/3 phosphorylation following 2 h TGF-β1 treatment persisted after CE or CD and was mildly increased following CD, while TGF-β1-mediated AKT phosphorylation (30 min) was inhibited by CE. Furthermore, CE protected AML12 cells from several effects mediated by 72 h incubation with TGF-β1, including EMT, actin polymerization, and apoptosis. CD mimicked the outcome of long term TGF- β1 administration, an effect that was blocked by an inhibitor of the type I TGF-β receptor. Additionally, the supernatant of CE- or CD-treated AML12 cells inhibited or promoted, respectively, the activation of LX-2 hepatic stellate cells. Conclusions: TGF-β1 inhibits cholesterol metabolism while cholesterol attenuates TGF-β1 downstream effects in hepatocytes.
Tissue Transglutaminase 2 has higher affinity for relaxed than for stretched fibronectin fibers
Authors: Selcuk Kateryna , Leitner Alexander , Braun Lukas , Le Blanc Fanny , Pacak Paulina , Pot Simon , Vogel Viola
Published: August 2023

Tissue transglutaminase 2 (TG2) plays a vital role in stabilizing extracellular matrix (ECM) proteins through enzymatic crosslinking during tissue growth, repair, and inflammation. TG2 also binds non-covalently to fibronectin (FN), an essential component of the ECM, facilitating cell adhesion, migration, proliferation, and survival. However, the interaction between TG2 and fibrillar FN remains poorly understood, as most studies have focused on soluble or surface-adsorbed FN or FN fragments, which differ in their conformations from insoluble FN fibers. Using a well-establishedin vitroFN-fiber stretch assay, we discovered that the binding of a crosslinking enzyme to ECM fibers is mechano-regulated. TG2 binding to FN is tuned by the mechanical tension of FN fibers, whereby TG2 predominantly co-localizes to low-tension FN fibers, while fiber stretching reduces their affinity for TG2. This mechano-regulated binding relies on the proximity between the N-terminal β-sandwich and C-terminal β-barrels of TG2. Crosslinking mass spectrometry (XL-MS) revealed a novel TG2-FN synergy site within TG2’s C-terminal β-barrels that interacts with FN regions outside of the canonical gelatin binding domain, specifically FNI2and FNIII14-15. Combining XL-MS distance restraints with molecular docking reveals the mechano-regulated binding mechanism between TG2 and modules FNI7-9by which mechanical forces regulate TG2-FN interactions. This highlights a previously unrecognized role of TG2 as a tension sensor for FN fibers. This novel interaction mechanism has significant implications in physiology and mechanobiology, including how force regulate ECM deposition and maturation, and how TG2 mediates cell-ECM adhesion in health and in various pathophysiological processes. Data are available via ProteomeXchange with identifier PXD043976.
Single-cell analysis reveals diversity of tumor-associated macrophages and their interactions with T lymphocytes in glioblastoma
Authors: Batchu Sai , Hanafy Khalid A. , Redjal Navid , Godil Saniya , Thomas Ajith J
Published: August 2023

Glioblastoma (GBM) is an aggressive primary CNS malignancy and clinical outcomes have remained stagnant despite introduction of new treatments. Understanding the tumor microenvironment (TME) in which tumor associated macrophages (TAMs) interact with T cells has been of great interest. Although previous studies examining TAMs in GBM have shown that certain TAMs are associated with specific clinical and/or pathologic features, these studies used an outdated M1/M2 paradigm of macrophage polarization and failed to include the continuum of TAM states in GBM. Perhaps most significantly, the interactions of TAMs with T cells have yet to be fully explored. Our study uses single-cell RNA sequencing data from adult IDH-wildtype glioblastoma, with the primary aim of deciphering the cellular interactions of the 7 TAM subtypes with T cells in the GBM TME. Furthermore, the interactions discovered herein are compared to IDH-mutant astrocytoma, allowing for focus on the cellular ecosystem unique to GBM. The resulting ligand-receptor interactions, signaling sources, and global communication patterns discovered provide a framework for future studies to explore methods of leveraging the immune system for treating GBM.
Structural basis for coupling of the WASH subunit FAM21 with the endosomal SNX27-Retromer complex
Authors: Guo Qian , Chen Kai-en , Gimenez-Andres Manuel , Jellett Adam P. , Gao Ya , Simonetti Boris , Liu Meihan , Danson Chris M. , Heesom Kate J. , Cullen Peter J. , Collins Brett M.
Published: August 2023

Endosomal membrane trafficking is mediated by specific protein coats and formation of actin-rich membrane domains. The Retromer complex coordinates with sorting nexin (SNX) cargo adaptors including SNX27, and the SNX27–Retromer assembly interacts with the WASH complex which nucleates actin filaments establishing the endosomal reycling domain. Crystal structures, modelling, biochemical and cellular validation reveal how the FAM21 subunit of WASH interacts with both Retromer and SNX27. FAM21 binds the FERM domain of SNX27 using acidic-Asp-Leu-Phe (aDLF) motifs similar to those found in the SNX1 and SNX2 subunits of the ESCPE-1 complex. Overlapping FAM21 repeats and a specific Pro-Leu containing motif bind three distinct sites on Retromer involving both the VPS35 and VPS29 subunits. Mutation of the major VPS35-binding site does not prevent cargo recycling, however it partially reduces endosomal WASH association indicating that a network of redundant interactions promote endosomal activity of the WASH complex. These studies establish the molecular basis for how SNX27–Retromer is coupled to the WASH complex via overlapping and multiplexed motif-based interactions required for the dynamic assembly of endosomal membrane recycling domains.

Significance Statement

Cell surface transmembrane proteins are regulated by a constant cycle of internalization and recycling from intracellular endosomal compartments. The Retromer protein complex and the sorting nexin adaptor protein play a critical role in the retrieval of hundreds of proteins responsible for ion transport, glucose metabolism, neurotransmission, and other cell functions. We have defined the mechanism by which both Retromer and SNX27 engage the actin-nucleating complex called WASH through multiple repeated sequences in the subunit FAM21. Dysfunction in WASH, Retromer and SNX27 are implicated in various disorders including Parkinson’s disease, Alzheimer’s disease, hereditary spastic paraplegia, and this work provides important insights into the assembly of these essential endosomal sorting machineries.
Diatoms exhibit dynamic chloroplast calcium signals in response to high light and oxidative stress
Authors: Flori Serena , Dickenson Jack , Gaikwad Trupti , Cole Isobel , Smirnoff Nicholas , Helliwell Katherine , Brownlee Colin , Wheeler Glen
Published: August 2023

Diatoms are a group of silicified algae that play a major role in marine and freshwater ecosystems. Diatom chloroplasts were acquired by secondary endosymbiosis and exhibit important structural and functional differences from the primary plastids of land plants and green algae. Many functions of primary plastids, including photoacclimation and inorganic carbon acquisition, are regulated by calcium-dependent signalling processes. Calcium signalling has also been implicated in the photoprotective responses of diatoms, although the nature of calcium elevations in diatom chloroplasts and their wider role in cell signalling remains unknown. Using genetically encoded calcium indicators, we find that the diatomPhaeodactylum tricornutumexhibits dynamic chloroplast calcium elevations that are distinct from those found in land plants. Chloroplast calcium ([Ca2+]chl) acts independently from the cytosol and is not elevated by stimuli that induce large cytosolic calcium ([Ca2+]cyt) elevations. In contrast, high light and exogenous hydrogen peroxide (H2O2) induce large, sustained calcium elevations in the chloroplast stroma that are not replicated in the cytosol. Measurements using the fluorescent H2O2sensor roGFP2-Orp1 indicate that [Ca2+]chlelevations induced by these stimuli correspond to the accumulation of H2O2in the chloroplast. [Ca2+]chlelevations were also induced by the addition of methyl viologen, which acts to generate superoxide within the chloroplast, and by treatments that disrupt non-photochemical quenching (NPQ). The findings indicate that diatoms generate specific calcium elevations in the chloroplast in response to high light and oxidative stress that likely modulate the activity of calcium-sensitive components in photoprotection and other regulatory pathways.