bluuebunny/crossref_metadata_2025 huggingface dataset:
Negative pressure wound therapy: Where are we in 2022?
Authors: Quacinella Michael A. , Yong Taylor M. , Obremskey William T. , Stinner Daniel J.
Published: July 2023

The use of negative pressure wound therapy (NPWT) continues to be an important tool for surgeons. As the use and general acceptance of NPWT have grown, so have the indications for its use. These indications have expanded to include soft tissue defects in trauma, infection, surgical wound management, and soft tissue grafting procedures. Many adjuvants have been engineered into newer generations of NPWT devices such as wound instillation of fluid or antibiotics allowing surgeons to further optimize the wound healing environment or aid in the eradication of infection. This review discusses the recent relevant literature on the proposed mechanisms of action, available adjuvants, and the required components needed to safely apply NPWT. The supporting evidence for the use of NPWT in traumatic extremity injuries, infection control, and wound care is also reviewed. Although NPWT has a low rate of complication, the surgeon should be aware of the potential risks associated with its use. Furthermore, the expanding indications for the use of NPWT are explored, and areas for future innovation and research are discussed.
Improving Postpartum Depression Screening in the NICU: Partnering with Students to Improve Outreach
Authors: Brady Sinead , Steinwurtzel Rochelle , Kim Rachel , Abascal Elena , Lane Mariellen , Brachio Sandhya
Published: July 2023

Introduction:

Infants born to mothers with postpartum depression (PPD) are at risk for adverse developmental outcomes. Mothers of premature infants are 40% more likely to develop PPD when compared with the general population. Current published studies on implementing PPD screening in the Neonatal Intensive Care Unit (NICU) do not comply with the American Academy of Pediatrics (AAP) guideline, which recommends multiple screening points in the first year postpartum and includes partner screening. Our team implemented PPD screening that follows the AAP guideline and includes partner screening for all parents of infants admitted to our NICU beyond 2 weeks of age.

Methods:

The Institute For Healthcare Improvement Model for Improvement was the framework for this project. Our initial intervention bundle included provider education, standardized identification of parents to be screened, and bedside screening performed by the nurse with social work follow-up. This intervention transitioned to weekly screening by phone by health professional students and the use of the electronic medical record for notification of team members of screening results.

Results:

Under the current process, 53% of qualifying parents are screened appropriately. Of the parents screened, 23% had a positive Patient Health Questionnaire-9 requiring referral for mental health services.

Conclusions:

Implementing a PPD screening program that complies with the AAP standard is feasible within a Level 4 NICU. Partnering with health professional students greatly improved our ability to screen parents consistently. Given the high percentage of parents with PPD uncovered with appropriate screening, this type of program has a clear need within the NICU.
Facility Recommendations for Medical Aesthetic Procedures in Canada
Authors: Sudetic Jacklyn
Published: July 2023

This article articulates core facility recommendations for regulated health care providers and professionals performing medical aesthetic procedures involving the use of topical and local anesthesia in a private clinic setting in Canada. The recommendations help ensure patient safety, confidentiality, and ethics. Information is provided about the setting/environment where medical aesthetic procedures are performed, safety equipment and emergency medications that should be on-site for medical aesthetic procedures, infection prevention and control measures, the way that medications and medical supplies should be stored, how to handle biomedical hazardous waste, and how to protect patient information.
Conservative Management of a Rare Entity—Aplasia Cutis Congenita: A Case Report
Authors: Chang-Azancot Luis , Campello Manuel , Montón Javier
Published: July 2023

Aplasia cutis congenita (ACC) is a rare entity characterized by a congenital localized absence of the skin, dermal appendages, and subcutaneous tissue. The cause of ACC is not clear, but inheritance is the most widely accepted cause. We report a rare case of a full-term (37 + 5 weeks) female newborn who showed complete absence of skin in localized areas of the upper and lower extremities. The patient was diagnosed with ACC associated with epidermolysis bullosa (EB; a disease that causes the skin to blister easily) and was initially treated using conservative measures. We applied mupirocin topical ointment and a nonocclusive polyester mesh impregnated with hydrocolloid and petroleum jelly daily. Complete healing of the affected areas occurred after 3 weeks. Managing patients with ACC is often challenging and based on the severity of the lesions, the approach may include both surgical and conservative treatment. Our case report suggests that a conservative approach can be effective for managing certain types of ACC and EB lesions. However, further research is warranted to better understand the pathogenesis and optimal management of this entity.
The Effect of Hand Massage on Anxiety Levels in Preoperative Patients: A Case Study
Authors: Rahmi Upik , Rahmayati El , Andriyani Septian
Published: July 2023

Surgery can trigger high levels of anxiety in preoperative patients. If this anxiety is not managed effectively, it can disrupt the surgical plan. Preoperative nurses can help prepare patients for their surgical experience by implementing interventions that reduce the stress that causes preoperative anxiety. One intervention that can be used to manage preoperative anxiety is hand massage. We report our experience with Mr. S, a 34-year-old man scheduled for surgery to remove a lump in his left upper back. The lump appeared approximately 3 years ago. It was initially small, but enlarged over time. The patient sought medical treatment and was diagnosed with a soft tissue tumor (STT) of his left scapula. His surgeons recommended surgical excision of the tumor. Our study aimed to determine the effect of hand massage on reducing anxiety in a preoperative patient with a diagnosis of STT of the scapula.
Megameatus intact prepuce, a rare variant of hypospadias: report of two cases and literature review
Authors: Hakimi Turyalai
Published: July 2023

Megameatus intact prepuce is an unusual variety of the distal hypospadias, characterized by a widely splayed (fishmouth) coronal or subcoronal meatus, a deep glanular groove with normal prepuce, and no chordee. Physically, the glans penis has disunion with an abnormally large meatus associated with a deep glans cleft. Because the foreskin is intact, the condition is frequently overlooked; as a result, the patient seeks medical attention later, when the purpose is to address other urogenital issues. Cosmetic remodeling should be performed to avoid affecting a child’s psychological state. We present 2 cases of the mentioned condition (circumcised and uncircumcised) with blunderbuss external urethral meatuses, admitted to our pediatric surgery department. Both patients underwent tubularized incised plate urethroplasty along with spongioplasty and a vascularized dartos flap over the urethroplasty for fistula prevention. The cosmetic and functional results were satisfactory.
Brain-heart interactions in novice meditation practitioners during breath focus and an arithmetic task
Authors: Soriano Javier R. , Rodriguez-Larios Julio , Varon Carolina , Castellanos Nazareth , Alaerts Kaat
Published: July 2023

Objectives

The study of neural and visceral oscillatory activities reveals that both subsystems and their interactions influence human cognition. In particular, cardiac and neural changes during self-regulation processes can be studied through a comparison of stress-inducing procedures and meditation practices.

Methods

In this study, we investigate the characteristic profiles of neural-cardiac interactions during a stress-inducing arithmetic task and a breath focus meditation period in a sample of 21 young participants (10 women, age range 20-29) with no prior experience in meditation practices. Using recordings of electroencephalography (EEG) and electrocardiography (ECG), we assessed instantaneous cross-frequency relationships between the alpha neural band and heart rate in both conditions.

Results

Our results indicate significant heart rate and alpha frequency decelerations during breath focus compared to the stress-inducing task. Regarding alpha: heart rate cross-frequency relationships, the stress-inducing arithmetic task exhibited ratios of smaller magnitude than the breath focus task, including a higher incidence of the specific 8:1 cross-frequency relationship, compared to the breath-focus task, proposed to enable cross-frequency coupling among neural and cardiac rhythms during mild cognitive stress. The change in cross-frequency relationships were mostly driven by changes in heart rate frequency between the two tasks, as indicated through surrogate data analyses.

Conclusions

Our results provide novel evidence that stress responses and changes during meditation practices can be better characterized by integrating physiological markers and, more crucially, their interactions. Together, this physiologically comprehensive approach can aid in guiding interventions such as physiology modulation protocols (biofeedback and neurofeedback) for emotion and stress-regulation.
Social Capital Associates with Cognitive Health, Oral Health and Epigenetic Age Deceleration: A Cross-sectional Analysis of the Canadian Longitudinal Study on Aging (CLSA)
Authors: Liang A , Gomaa N
Published: July 2023

Objectives

To quantify the association of social capital, defined as social relationships and networks, with cognitive health, oral inflammation, and epigenetic aging.

Methods

We used data from the Canadian Longitudinal Study on Aging (CLSA) (n=1,479; ages 45-85 years), categorizing social capital as structural and cognitive capital. Oral inflammation was determined as the presence of gum bleeding. Epigenetic aging was computed as the difference between chronological age and DNA methylation age. Multivariable regression models adjusted for covariates were used.

Results

Higher structural social capital was associated with decelerated epigenetic aging and better cognitive health outcomes. Higher cognitive social capital was also associated with better cognitive outcomes and less oral inflammation.

Conclusion

Enhancing social capital may contribute to better clinical and biological outcomes around aging.

Visual Abstract
ESQmodel: biologically informed evaluation of 2-D cell segmentation quality in multiplexed tissue images
Authors: Lee Eric , Lee Dongkyu , Fan Wayne , Lytle Andrew , Fu Yuxiang ,   IMAXT Consortium, Scott David W. , Steidl Christian , Aparicio Samuel , Roth Andrew
Published: July 2023

Motivation

Single cell segmentation is critical in the processing of spatial omics data to accurately perform cell type identification and analyze spatial expression patterns. Segmentation methods often rely on semi-supervised annotation or labeled training data which are highly dependent on user expertise. To ensure the quality of segmentation, current evaluation strategies quantify accuracy by assessing cellular masks or through iterative inspection by pathologists. While these strategies each address either the statistical or biological aspects of segmentation, there lacks an unified approach to evaluating segmentation accuracy.

Results

In this paper, we present ESQmodel, a Bayesian probabilistic method to evaluate single cell segmentation using expression data. By using the extracted cellular data from segmentation and a prior belief of cellular composition as input, ESQmodel computes per cell entropy to assess segmentation quality by how consistent cellular expression profiles match with cell type expectations.

Availability and implementation

Source code is available on Github at:https://github.com/Roth-Lab/ESQmodelunder the MIT license.
The impact of digital health insurance for low-income women in Kenya
Authors: de Groot R. , Abajobir A. , Wainaina C. , Sidze E. , Pradhan M. , Janssens W.
Published: July 2023

Objective

This study evaluates how a subsidized, mobile phone-based health insurance program affected insurance uptake, healthcare utilization and health expenditures for low-income women and their family members in Western Kenya. The program, targeting pregnant women and mothers of children below age four, addressed both demand- and supply-side constraints, providing subsidies through mobile money and support in digital registration while upgrading selected facilities and digitally training community health workers.

Methods

The research was based on a cluster-RCT conducted between 2019 and 2021 in 24 villages in Kakamega County. After a baseline survey, 240 households (more than 1,300 individuals) were interviewed every week during 18 months to collect detailed financial and health data while the program was rolled out in the treatment communities, moving to phone-based interviewing after the onset of COVID-19.

Results

The intervention had a significant impact on individual insurance uptake of 65.8 percentage points (from a baseline control mean 18.9 percent). We find weak positive impacts on formal healthcare utilization, and substantial increases in financial coverage of medical costs and associated reductions in out-of-pocket expenditures, particularly for medicines. Results are strongest for women, young children and individuals living closest to the clinics. Dynamic analyses show that impacts become increasingly pronounced over time, suggesting that women may need some time to get used to the digital insurance scheme.

Conclusion

The program not only reduced the costs of enrolment, but also eliminated other (administrative, logistical, trust) barriers. The introduction of the scheme by trusted local agents, the hands-on assistance with the digital registration procedures at women’s homes, and support in retrieving the necessary documentation such as children’s birth certificates, have likely all contributed to the high enrolment rates, thereby improving access to good-quality care. Digital insurance has the potential to substantially enhance universal health coverage and financial protection for poor households.
Observational study of effects of HIV Acquisition and Antiretroviral Treatment on Biomarkers of Systemic Immune Activation
Authors: Kosmider Ewelina , Wallner Jackson , Gervassi Ana , Bender Ignacio Rachel A , Pinto-Santini Delia , Gornalusse German , Pandey Urvashi , Hladik Florian , Edlefsen Paul T. , Lama Javier R. , Duerr Ann C. , Frenkel Lisa M.
Published: July 2023

Objective

Assess whether biomarkers of systemic inflammation are associated with HIV acquisition or with the timing of ART initiation (“immediate”, at diagnosis, versus “deferred”, at 24 weeks postdiagnosis) in men-who-have-sex-with-men (MSM) and transgender women.

Design

A retrospective study comparing inflammatory biomarkers in participants’ specimens collected before and after ≥2 years of effective ART.

Methods

Inflammatory biomarkers were measured in four longitudinally collected plasma specimens, including two plasma specimens collected from each participant before and two after HIV acquisition and confirmed ART-suppression. Biomarkers were quantified by enzyme-linked immuno-assay or Meso Scale Discovery. Statistical measures compared intra-participant and between-group changes in biomarkers.

Results

Across 50 participants, the levels of C-reactive protein (CRP), monocyte chemo-attractant protein-1, tumor necrosis factor-α and interferon gamma-induced protein-10 significantly increased while leptin and lipopolysaccharide binding protein (LBP) significantly decreased following HIV infection. Randomization to deferred-ART initiation was associated with greater increases in CRP and no decreases in LBP. Multiple biomarkers varied significantly within participants’ two pre-infection or two post-ART-suppression specimens.

Conclusions

Acquisition of HIV appeared to induce systemic inflammation, with elevation of biomarkers previously associated with infections and cardiovascular disease. Initiation of ART during the early weeks of infection tempered the increase in pro-inflammatory biomarkers compared to those who delayed ART for ∼24 weeks after HIV diagnosis, perhaps because immediate-ART limited the size of the HIV reservoir or limited immune dysregulation. Some but not all biomarkers appeared sufficiently stable to assess intraparticipant changes over time. Given that pro-inflammatory biomarkers predict multiple co-morbidities, our findings suggest that immediate-ART initiation may improve health outcomes.
Genome-wide Association Clustering Meta-analysis in European and Chinese Datasets for Systemic Lupus Erythematosus identifies new genes
Authors: Saeed Mohammad
Published: July 2023

Genome-wide association studies (GWAS) face multiple challenges in order to identify reliable susceptibility genes for complex disorders, such as Systemic lupus erythematosus (SLE). These include high false positivity due to number of SNPs genotyped, false negativity due to statistical corrections and the proportional signals problem. Association clustering methods, by reducing the testing burden, have increased power than single variant analysis. Here, OASIS, a locus-based test, and its novel statistic, the OASIS locus index (OLI), is applied to European (EU) and Chinese (Chi) SLE GWAS to identify common significant non-HLA, autosomal genes. Six SLE dbGAP GWAS datasets, 4 EU and 2 Chi involving 19,710 SLE cases and 30,876 controls were analyzed. OLI is defined as the product of maximum −logP at a locus with the ratio of actual to predicted number of significant SNPs and compared against the standard P-value using Box plots and Wilcoxon Signed Rank Test. OLI outperformed the standard P-value statistic in detecting true associations (Wilcoxon Signed Test Z= - 4.11, P<1×10−4). Top non-HLA significant loci, common in both ethnicities were 2q32.2 (STAT4, rs4274624, P=9.7×10−66), 1q25.3 (SMG7, rs41272536, P=3.5×10−52), 7q32.1 (IRF5, rs35000415, P=1.9×10−45), 8p23.1 (BLK, rs2736345, P=1.5×10−25) and 6q23.3 (TNFAIP3, rs5029937, P=4.4×10−24). Overall, OASIS identified 19 highly significant and 16 modestly significant (P>10−8) non-HLA SLE associated genes common to EU and Chi ethnicities. Interaction of these 35 genes elucidated important SLE pathways viz NOD, TLR, JAK-STAT and RIG-1. OASIS aims to advance GWAS by rapid and cost-effective identification of genes of modest significance for complex disorders.

Key Messages

GWAS are challenged by risk genes of modest effect.

OASIS, a clustering algorithm, can help identify genes of modest significance for complex disorders such SLE, rapidly and cost-effectively using publicly available GWAS datasets.

This meta-analysis identified 35 genes common to both European and Chinese populations.

Interaction of these genes identify major SLE pathways to be NOD, TLR, JAK-STAT and RIG-1.
Reliability and Performance of the IRRAflow® System for Intracranial Lavage and Evacuation of Hematomas - A Technical Note
Authors: Haldrup Mette , Nazari Mojtaba , Gu Chenghao , Rasmussen Mads , Dyrskog Stig , Simonsen Claus Ziegler , Grønhøj Mads , Poulsen Frantz Rom , Rehman Naveed Ur , Korshoej Anders Rosendal
Published: July 2023

Background

Intraventricular hemorrhage (IVH) is a severe condition with poor outcomes and high mortality. IRRAflow®(IRRAS AB) is a new technology introduced to accelerate IVH clearance by minimally invasive wash-out. The IRRAflow®system performs active and controlled intracranial irrigation and aspiration with physiological saline, while simultaneously monitoring and maintaining a stable intracranial pressure (ICP). We addressed important aspects of the device implementation and intracranial lavage.

Method

To allow versatile investigation of multiple device parameters, we designed anex vivolab setup. We evaluated 1) compatibility between the IRRAflow®catheter and the Silverline f10 bolt (Spiegelberg), 2) the physiological and hydrodynamic effects of varying the IRRAflow®settings, 3) the accuracy of the IRRAflow®injection volumes, and 4) the reliability of the internal ICP monitor of the IRRAflow®.

Results

The IRRAflow®catheter was not compatible with Silverline bolt fixation, which was associated with leakage and obstruction. Design space exploration of IRRAflow®settings revealed that a balanced saline influx and efflux required adjustments of the drainage bag to adapt to different irrigation rates. High irrigation rates could be compensated by lowered drain bag height and vice versa. Appropriate settings included irrigation rate 20 ml/h with a drainage bag height at 0 cm, irrigation rate 90 ml/h with a drainage bag height at 19 cm and irrigation rate 180 ml/h with a drainage bag height at 29 cm. We found the injection volume performed by the IRRAflow®to be stable and reliable, while the internal ICP monitor was compromised in several ways due to the proximal location of the pressure sensor within the cassette of the device rather than within the parenchyma of the brain. Furthermore, we observed a significant mean drift difference of 3.16 mmHg (variance 0.4, p=0.05) over a 24-hour test period with a mean 24-hour drift of 3.66 mmHg (variance 0.28) in the pressures measured by the IRRAflow®compared to 0.5 mmHg (variance 1.12) in the Raumedic measured pressures.

Conclusion

Bolting of the IRRAflow®catheter using the Medtronic Silverline® bolt is not recommendable. Increased irrigation rates are recommendable followed by a decrease in drainage bag level. ICP measurement using the IRRAflow®device was unreliable and should be accompanied by a control ICP monitor device in clinical settings.
Differential modulation of attentional ERPs in smoked and insufflated cocaine-dependent associated with neuropsychological performance
Authors: Aragón-Daud Agustina , Oberti de Luca Sofía Milagros , Schurmann Vignaga Sofía , Prado Pilar , Figueras Rosario , Lizaso Lucia , González-Gadea María Luz , Manes Facundo , Cetkovich Marcelo , Pallavicini Carla , Torralva Teresa , de la Fuente Laura Alethia
Published: July 2023

Background

Cocaine consumption is associated with reduced attentional event-related potentials (ERPs), namely P3a and P3b, indicating bottom-up and top-down deficits respectively. At cognitive level, these impairments are larger for faster routes of administration (e.g., smoked cocaine [SC]) than slower routes (e.g., insufflated cocaine [IC]). Here we assess these ERPs considering the route of cocaine administration. We hypothesized that SC dependent (SCD) would exhibit reduced modulation of the P3a, while both SCD and IC dependent (ICD) would show reduced modulation of the P3b.

Methods

We examined 25 SCD, 22 ICD matched by poly-consumption profiles, and 25 controls matched by demographic variables. We combined EEG data from the Global-Local task with behavioral data from attentional cognitive tasks.

Results

At the behavioral level, SCD exhibited attentional deficits in both bottom-up and top-down processes, while ICD only showed a tendency for top-down deficits. Modulation of P3a and P3b was lower in consumer groups. We observed subtle route-based differences, with larger differences in the P3a for SCD and in the P3b for ICD. Neurophysiological and behavioral data converged, with the P3a associated to bottom-up performance and P3b to top-down.

Conclusions

Different routes of administration lead to distinct modulations of attentional neurocognitive profiles. Specifically, SCD showed greater attentional impairment, mainly at bottom-up/P3a, while ICD showed a trend of top-down/P3b deficits. These findings emphasize the crucial role of considering the route of administration in both clinical and research settings and support the use of attentional ERPs as valid measures for assessing attentional deficits in substance abuse.
Poor Hemorrhagic Stroke Outcomes During the COVID-19 Pandemic Are Driven by Socioeconomic Disparities: Analysis of Nationally Representative Data
Authors: Bako Abdulaziz T. , Potter Thomas , Pan Alan , Borei Karim A. , Prince Taya , Britz Gavin , Vahidy Farhaan S.
Published: July 2023

Background

Nationally representative data demonstrating the impact of the COVID-19 pandemic on hemorrhagic stroke outcomes are lacking.

Methods

In this pooled cross-sectional analysis, we used the National Inpatient Sample (2016-2020) to identify adults (>=18 years) with primary intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH). We fit segmented logistic regression models to evaluate the differences in the rates of in-hospital outcomes (in-hospital mortality, home discharge, and receiving neurosurgical procedures) between the pre-pandemic (January 2016-February 2020) and pandemic periods (March 2020-December 2020). We used multivariable logistic regression models to evaluate the differences in mortality between patients admitted from April to December 2020, with and without COVID-19, and those admitted during a similar period in 2019. Stratified analyses were conducted among patients residing in low and high-income zip codes and among patients with extreme loss of function (E-LoF) and those with minor to major loss of function (MM-LoF).

Results

Overall, 309,965 ICH patients (mean age [SD]: 68[14.8], 47% female, 56% low-income) and 112,210 SAH patients (mean age [SD]: 60.2[15.4], 62% female, 55% low-income) were analyzed. Pre-pandemic, ICH mortality was decreasing by ≈ 1 % per month (adjusted odds ratio, 95% confidence interval: 0.99, 0.99-1.00). However, during the pandemic, the overall ICH mortality rate increased by ≈ 2% per month (1.02, 1.00-1.02) and ≈ 4% per month among low-income patients (1.04, 1.01-1.07). However, there was no change in trend among high-income ICH patients during the pandemic (1.00, 0.97-1.03). Patients with comorbid COVID-19 in 2020 had significantly higher odds of mortality compared to the 2019 comparison cohort, overall (ICH: 1.83, 1.33-2.51; SAH: 2.76, 1.68-4.54), and among patients with MM-LoF (ICH: 2.15, 1.12-4.16; SAH: 5.77, 1.57-21.17). However, patients with E-LoF and comorbid COVID-19 had similar mortality rates with the 2019 cohort.

Conclusion

Sustained efforts are needed to address socioeconomic disparities in healthcare access, quality, and outcomes during public health emergencies.
SPAT: Surface Protein Annotation Tool
Authors: Spinella JF , Theret L , Aubert L , Audemard E , Boucher Geneviève , Pfammatter S , Bonneil E , Bordeleau ME , Thibault P , Hébert J , Roux PP , Sauvageau G
Published: July 2023

Given the particular attractivity of antibody-based immunotherapies,in vitroexperimental approaches aiming to identify and quantify proteins directly located at the cell surface, such as the surfaceome, have been recently developed and improved. However, the “surface” enriched, yet noisy output obtained from available methods makes it challenging to accurately evaluate which proteins are more likely to be located at the surface of the plasma membrane and which are simple contaminants. To that purpose, we developed thein silicoSurface Protein Annotation Tool (SPAT), which unifies established annotations to grade proteins according to the chance they have to be located at the cell surface. SPAT accuracy was tested using in-house acute myeloid leukemia data, as well as public datasets, and despite using publicly available annotations, showed good performances when compared to more complex surfaceome predictors. Given its simple input requirement, SPAT is easily usable for the annotation of any gene/protein lists. Its output, in addition to the “surface” score, provides additional annotations including a “secretion” flag, references to verified antibodies targeting annotated proteins, as well as expression data and protein levels in essential human organs, making it a user-friendly tool for the community.
Molecular recognition of an aversive odorant by the murine trace amine-associated receptor TAAR7f
Authors: Gusach Anastasiia , Lee Yang , Khoshgrudi Armin Nikpour , Mukhaleva Elizaveta , Ma Ning , Koers Eline J. , Chen Qingchao , Edwards Patricia C. , Huang Fanglu , Kim Jonathan , Mancia Filippo , Verprintsev Dmitry B. , Vaidehi Nagarajan , Weyand Simone N. , Tate Christopher G.
Published: July 2023

There are two main families of G protein-coupled receptors that detect odours in humans, the odorant receptors (ORs) and the trace amine-associated receptors (TAARs). Their amino acid sequences are distinct, with the TAARs being most similar to the aminergic receptors such as those activated by adrenaline, serotonin and histamine. To elucidate the structural determinants of ligand recognition by TAARs, we have determined the cryo-EM structure of a murine receptor, mTAAR7f, coupled to the heterotrimeric G protein Gsand bound to the odorant N,N-dimethylcyclohexylamine (DMCH) to an overall resolution of 2.9 Å. DMCH is bound in a hydrophobic orthosteric binding site primarily through van der Waals interactions and a strong charge-charge interaction between the tertiary amine of the ligand and an aspartic acid residue. This site is distinct and non-overlapping with the binding site for the odorant propionate in the odorant receptor OR51E2. The structure, in combination with mutagenesis data and molecular dynamics simulations suggests that the activation of the receptor follows a similar pathway to that of the β-adrenoceptors, with the significant difference that DMCH interacts directly with one of the main activation microswitch residues.
NECing goes: flexibility of the herpesvirus nuclear egress complex
Authors: Pražák Vojtěch , Mironova Yuliia , Vasishtan Daven , Hagen Christoph , Laugks Ulrike , Jensen Yannick , Sanders Saskia , Heumann John M. , Bosse Jens B. , Klupp Barbara , Mettenleiter Thomas C. , Grange Michael , Grünewald Kay
Published: July 2023

The nuclear egress complex (NEC) allows herpesvirus capsids to escape from the nucleus without breaking the nuclear envelope barrier. It assembles into a lattice on the inner nuclear membrane enveloping newly assembled nucleocapsids, which bud into the perinuclear space. The primary virion envelope subsequently fuses with the outer nuclear membrane, releasing the capsid into the cytosol. Here we interrogated the NEC in the context of intact cells infected with pseudorabies or herpes simplex virus using focused-ion beam milling and electron cryo- tomography. We determined the structure of NEC in different conformations and show that it consists of a flexible hexameric lattice that generates curvature through a combination of ordered and disordered domains. After interrogating the intermediate stages of capsid formation, we show that capsid vertex binding may initiate envelopment but does not directly induce curvature formation. These data and many examples of the intermediate stages of nuclear egress paint a detailed holistic view of a versatile transport system.
Emergent digital bio-computation through spatial diffusion and engineered bacteria
Authors: Fedorec Alex J.H. , Treloar Neythen J. , Wen Ke Yan , Dekker Linda , Ong Qing Hsuan , Jurkeviciute Gabija , Lyu Enbo , Rutter Jack , Rosa Luca , Zaikin Alexey , Barnes Chris P.
Published: July 2023

Building computationally capable biological systems has long been an aim of synthetic biology. The potential utility of biocomputing devices ranges from biosafety and environmental applications to diagnosis and personalised medicine. Here we present work for the design of bacterial computers which use spatial patterning to process information. Our computers are composed of bacterial colonies which, inspired by patterning in embryo development, receive information in the form of diffusible morphogen-like signals. A computation is encoded by the physical locations of the input sources of morphogen and the output receiver colonies. We demonstrate, mathematically and with engineeredEscherichia coli, the simple digital logic capability of single bacterial colonies and show how additional colonies are required to build complex functions. Inspired by electronic design automation, an algorithm for designing optimal spatial circuits computing two-level digital functions is presented. This enhances the capability of our system to complex digital functions without increasing the biological complexity. We extend our experimental system to incorporate biosensing colonies as morphogen sources, demonstrating how a diagnostic device might be constructed. Our approach will open up new ways to perform biological computation, with applications in bioengineering, biomaterials and biosensing. Ultimately, these computational bacterial communities will help us explore information processing in natural biological systems.
Sea lamprey enlightens the origin of the coupling of retinoic acid signaling to vertebrate hindbrain segmentation
Authors: Bedois Alice M. H. , Parker Hugo J. , Bronner Marianne E. , Krumlauf Robb
Published: July 2023

Retinoic acid (RA) is involved in antero-posterior patterning of the chordate body axis and, in jawed vertebrates, has been shown to play a major role at multiple levels of the gene regulatory network (GRN) regulating hindbrain segmentation. Knowing when and how RA became coupled to the core hindbrain GRN is important for understanding how ancient signaling pathways and patterning genes can evolve and generate diversity. Hence, we investigated the link between RA signaling and hindbrain segmentation in the sea lampreyPetromyzon marinus, an important jawless vertebrate model providing clues to decipher ancestral vertebrate features. Combining genomics, gene expression, and functional analyses of major components involved in RA synthesis (Aldh1as) and degradation (Cyp26s), we demonstrate that RA signaling is coupled to hindbrain segmentation in lamprey. Thus, the link between RA signaling and hindbrain segmentation is a pan vertebrate feature of the hindbrain and likely evolved at the base of vertebrates.
Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol
Authors: Wilson Zachary N. , West Matt , English Alyssa M. , Odorizzi Greg , Hughes Adam L.
Published: July 2023

Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains.

Wilson and colleagues use electron tomography and time-lapse fluorescence microscopy to observe that mitochondrial-derived compartments (MDCs) are generated from outer mitochondrial membrane extensions that repeatedly elongate, coalesce, and invaginate to secure membrane cargo and cytosol within a distinct, protected domain.
Improving genome-scale metabolic models of incomplete genomes with deep learning
Authors: Boer Meine D. , Melkonian Chrats , Zafeiropoulos Haris , Haas Andreas F. , Garza Daniel , Dutilh Bas E.
Published: July 2023

Deciphering the metabolism of microbial species is crucial for understanding their function within complex ecosystems. Genome-scale metabolic models (GSMMs), which predict metabolic traits based on the enzymes encoded in a genome, are promising tools to study microbial ecosystems when genome sequences can be obtained. However, constructing GSMMs for uncultured bacteria is challenging, as metagenome-assembled genomes are typically incomplete, leading to metabolic reconstructions with numerous gaps. Existing methodologies often fill these gaps with the minimum set of reactions necessary to simulate an objective function such as growth. Here we introduce an artificial intelligence-based alternative: the Deep Neural Network Guided Imputation Of Reactomes (DNNGIOR). The DNNGIOR neural network learns weights for missing reactions in incomplete GSMMs from patterns in the presence and absence of metabolic reactions in genomes spanning the bacterial domain. We identified two important factors contributing to prediction accuracy: (1) the frequency of reaction across all bacteria, and (2) the phylogenetic distance between the query and the genomes in the training dataset. Reactions that occur in > 30% of the training genomes can be accurately predicted (Mean F1 score = 0.85). The weights generated by the DNNGIOR network improved the gap-filling of incomplete GSMMs, when assessed on a large and phylogenetically diverse testing dataset and a small set of high-quality manually curated models. The accuracy of DNNGIOR was on average 14 times greater than the standard unweighted gap-filling for draft reconstructions, and 2-9 times greater for manually curated models. DNNGIOR models could also simulate experimentally measured carbon usage profiles with similar accuracy as CarveMe. DNNGIOR is available athttps://github.com/MGXlab/DNNGIORor as a pip package (https://pypi.org/project/dnngior/).
An error correction strategy for image reconstruction by DNA sequencing microscopy
Authors: Kloosterman Alexander , Baars Igor , Högberg Björn
Published: July 2023

By pairing adjacent molecules in-situ and then mapping these pairs, DNA microscopy could significantly reduce workload in spatial omics methods by directly inferring geometry from sequencing data alone. However, experimental artefacts can lead to errors in the adjacency data which distort the spatial reconstruction. Here, we describe a method to correct two such errors: spurious crosslinks formed between any two nodes, and fused nodes that are formed out of multiple molecules. We build on the principle that spatially close molecules should be connected and show that these errors violate this principle, allowing for their detection and correction. Our method corrects errors in simulated data, even in the presence of up to 20% errors, and proves to be more efficient at removing errors from experimental data than a read count filter. Integrating this method in DNA microscopy will significantly improve the accuracy of spatial reconstructions with lower data loss.
Characterization and Expression Analysis ofNitrate Reductase 6-1ABDGene in Hexaploid Bread Wheat Under Different Nitrogen Regime
Authors: Gayatri  , Ravi Megavath , Chauhan Harsh , Mulani Ekta , Phogat Sachin , Venkatesh Karnam , Mandal Pranab Kumar
Published: July 2023

Nitrate reductase (NR) is the key rate-limiting enzyme of the nitrogen (N) assimilation process in plants, which has not been characterized in bread wheat under nitrogen stress, especially with respect to their homeologues. Total 9NRs were identified and classified into 3 groups, which showed a close relationship with different wheat ancestors. The occurrence of N-responsivecis-acting regulatory elements like MYB, MYC, G-Box and GATA-motif confirmed their N-responsiveness. Expression of all the three groups ofNRunder N-stress revealedNR 6-1ABDgroup to be the most N-responsive, which was characterized further in detail. The study was carried out in two genotypes contrasting for their N-responsiveness (HD 2967: Highly responsive to applied N, and Choti Lerma: Less responsive to applied N) selected on the basis of field evaluation. Homeologous differences within a genotype were found much more than the genotypic differences of a specific homeologue coding sequence. Among the three homeologues, thoughNR 6-1Dhomeologue was found most responsive to N-stress, the contribution was maximum for this homeologue followed byNR 6-1Aand least byNR 6-1B.We found that the expression of homeologues was linked to the presence of N-responsivecis-elements. All the homeologues ofNR 6-1in Choti Lerma were found less responsive to N-stress, in comparison to HD 2967, which might also be linked to N-use efficiency. Homeologous expression ofNR 6-1ABDrevealed negligible contribution ofB-homeologue to N-stress. Homeologous differences ofNR 6-1ABDwas found much more than the genotypic differences. Hence, our study on wheatNRwill be helpful in manipulating the specific homeologue of theNRgene in the future.
Metastatic prognostic ability of lung cancer stromal cells from a single-cell RNA-seq perspective
Authors: Moon Hyunjin , Kim Jonghwan , Jeon Hajin , Yang Jin Ok
Published: July 2023

Single-cell RNA sequencing (scRNA-seq) has been widely studied and analyzed to understand cancer heterogeneity. Metastasis and invasion through communication with immune cells have been widely studied; stromal cells are known to change during cancer progression and cause metastasis, but little is known about their inherent metastasis prognostic abilities. This study investigated the abilities of stromal cells by analyzing the scRNA-seq data of adjacent, tumor, and metastasized tissues, biopsied from 15 patients. We considered fibroblast and smooth muscle cells as cell subtypes of stromal cells. We detected decorin (DCN) and insulin-like growth factor-binding protein 7 (IGFBP7) as sub-cell type markers conserved in tumor and metastasis. We found an organic relationship that affects metastasis by assessing the interaction between the expression and related pathways among the assigned stromal cell subtypes. In addition to the interactions of sub-cell-types within stromal cells, we also studied communication between stromal cells and the five assigned lung cancer cell types, and observed its relation with migration and metastasis; the role ofDCNas a mediating factor was also studied. Results of our study indicated thatDCNandIGFBP7are factors that can be monitored in the follow-up of prognostic metastasis factors in patients with lung cancer. Therefore,DCNandIGFBP7, which are the assigned sub-cell types marker in lung cancer stromal cells, can be used as potential biomarkers for follow-up in lung cancer metastasis. Our study assigned stromal cell subtypes of lung cancer and detected markers that can be used as monitoring factors during metastasis of lung cancer. This suggests thatDCNandIGFBP7are potential biomarkers to evaluate metastatic ability and follow-up as metastatic prognostic factors in lung cancer patients.

Author Summary

Lung cancer is known to be a disease with high heterogeneity. In particular, it has been studied that stromal cells of lung cancer are involved in metastasis in cancer. Finding specific markers of stromal cell subtypes can lead to more accurate cancer markers. In this study, we assigned stromal cell subtypes as FB and SMC through scRNA-seq data analysis.DCNandIGFBP7, which are markers specifically expressed in stromal cell sub-cell types of NSCLC and metastatic NSCLC, were found. WhetherDCNandIGFBP7can be used as prognostic factors for metastasis was verified through co-expression analysis of FB and SMC and cell-cell communication. Specific expression as a marker was verified by confirming the role in the hub-gene network and the target genes of communication. Our findings suggest thatDCNandIGFBP7are potential biomarkers for evaluating the metastasis prognostic ability of stromal cells and can be monitored in the follow-up of metastasis prognostic factors in lung cancer patients.
Robust Phylogenetic Tree-based Microbiome Association Test using Repeatedly Measured Data for Composition Bias
Authors: Kim Kangjin , Won Sungho
Published: July 2023

Motivation

The effects of microbiota on the host phenotypes can substantially differ depending on his/her age. Longitudinally measured microbiome data allows us to detect the age modification effect and are useful for the detection of microorganisms related to the progression of disease which change identification over time. Moreover, longitudinal analysis enables the estimation of within-subject covariate effect, is robust against the between-subject confounders, and provides better evidence for the causal relationship than cross-sectional studies. However, they suffer from compositional bias, and few statistical methods can estimate their effect on host diseases with repeatedly measured 16S rRNA gene data. In this article, we proposed mTMAT which can be applied to longitudinal microbiome data and is robust against compositional bias.

Results

mTMAT normalized the microbial abundance and utilized the ratio of the pooled abundances for association analysis. mTMAT is based on generalized estimating equations with a robust variance estimator and can be applied to repeatedly measured microbiome data. With extensive simulation studies, we showed that mTMAT is statistically more powerful and is robust against compositional bias. mTMAT enables detection of microbial taxa associated with host diseases using repeatedly measured 16S rRNA gene data and can provide deeper insight into bacterial pathology.

Availability

The 16S rRNA amplicon sequencing metagenomics datasets for Korea Association REsource cohort is available from the NCBI Sequence Read Archive database under project accession number PRJNA716550. mTMAT was implemented in the R package. Detailed information is available athttps://healthstat.snu.ac.kr/software/mtmat.

Contact

won1@snu.ac.kr

Supplementary information

Supplementary data are available atBioinformaticsonline.
Evaluation of hypereosinophilia in a case ofFLT3-mutant acute myeloid leukemia treated with gilteritinib
Authors: Martinez-Gutierrez Leslie N. , Burgher Blake C. , Glynias Manuel J. , Alvarado Daniel , Griffiths Elizabeth A. , Glenn Sean T. , Sung Pamela J.
Published: July 2023

Acute myeloid leukemias (AMLs) frequently harbor activating mutations inFms-like tyrosine kinase 3(FLT3). The use of FLT3 inhibitors (FLT3i) is the standard of care for treatment of newly diagnosed and relapsed patients with AML. Differentiation responses including clinical differentiation syndrome have been previously reported with FLT3i when used as single agents in relapsed disease. We present a case of hypereosinophilia in a patient on FLT3i therapy with persistentFLT3polymerase chain reaction (PCR) positivity in peripheral blood. We sorted mature leukocytes by lineage to determine if the eosinophils were leukemia-derived.FLT3PCR and next-generation sequencing analysis demonstrated monocytic differentiation of theFLT3–ITDleukemic clone with reactive hypereosinophilia that was derived from a preleukemicSF3B1,FLT3wild-type clone. Our case is the first to definitively demonstrate the emergence of clonalFLT3–ITDmonocytes with FLT3i and the first to demonstrate a differentiation response following decitabine, venetoclax, and gilteritinib triplet therapy.