bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatially explicit simulation of deforestation using the Ising-like neutral model
Authors: Stepinski Tomasz F
Published: June 2023

Deforestation is a prominent example of anthropogenic land change. Here we investigate deforestation from a landscape ecology perspective by process-based modeling of a sequence of consecutive landscape patterns starting from a homogeneous forest and ending in homogeneous agricultural land. We propose an Ising-like neutral model to mimic the deforestation dynamics. Our goal is to demonstrate that such a simple conceptualization of the deforestation process is capable of simulating an evolutionary sequence of landscape patterns matching empirical data. The model has only two parameters, one representing an external pressure (for or against deforestation), and another representing a propensity of land for spatial autocorrelation. We perform a suite of simulations to link a process, as parameterized by the values of the two parameters, to the sequence of landscape patterns. We have found a narrow range of parameters for which the model quantitatively and visually matches empirical data. This indicates that the Ising-like neutral model captures the essential aspects of a deforestation process and that the temporal sequence of intermediate landscape patterns does not depend on the details of the process.
A remark on quantitative unique continuation from subsets of the boundary of positive measure
Authors: Burq Nicolas , Zuily Claude
Published: June 2023

The question of uniqueness of harmonic functions in a domain

Ω
⊂

R

d

\Omega \subset \mathbb {R}^d

with boundary

∂
Ω

\partial \Omega

, satisfying Dirichlet boundary conditions and with normal derivatives vanishing on a subset of the boundary

ω
\omega

of positive

d
−
1

d-1

dimensional measure has attracted a lot of attention (see e.g. V. Adolfsson and L. Escauriaza [Comm. Pure Appl. Math. 50 (1997), pp. 935–969]; F.-H. Lin [Comm. Pure Appl. Math. 44 (1991), pp. 287–308]; X. Tolsa [Comm. Pure Appl. Math. 76 (2023), pp. 305–336]). It is essentially a consequence of Carleman estimates when

ω
\omega

contains an open subset of the boundary (uniqueness for second order elliptic operators across an hypersurface). The main open questions (about uniqueness) concern now Lipschitz domains and variable coefficients. Here, using results by Logunov and Malinnikova [Nodal sets of Laplace eigenfunctions: estimates of the Hausdorff measure in dimensions two and three, Birkhäuser/Springer, Cham, 2018, pp. 333-344; Proceedings of the International Congress of Mathematicians–Rio de Janeiro 2018, World Scientific Publishing, Hackensack, NJ, 2018, pp. 2391–2411], we consider the simpler case of

W

2
,
∞

W^{2, \infty }

domains but prove quantitative uniqueness both for Dirichlet and Neumann boundary conditions. As an application, we deduce quantitative estimates for the Dirichlet and Neumann Laplace eigenfunctions on a

W

2
,
∞

W^{2, \infty }

domain with boundary.
Pediatric Hand and Wrist Fractures in Osteogenesis Imperfecta: An Analysis of Incidence, Patient-specific Risk Factors, and Fracture-specific Characteristics
Authors: Chhabra Barkha N. , Phillips Todd , Mitchell Thomas W. , Gattu Nikhil , Ezeokoli Ekene U. , Bell Bryce
Published: June 2023

Background:

Children with osteogenesis imperfecta (OI) frequently present with fractures; however, hand and wrist fractures (HWFs), those distal to the radial and ulnar diaphysis, are seldom observed. Yet, HWFs remain among the most common fractures in children with non-OI. The objective of this study was to identify the incidence of OI HWFs. Secondary objectives aimed at identifying patient-specific risk factors for HWFs in OI and comparing clinical courses to non-OI HWFs.

Methods:

A retrospective cohort study was conducted. Database query by ICD-10 codes identified 18 patients with OI HWF, 451 patients with OI without HWFs, and 26,183 patients with non-OI HWF. Power analysis estimated appropriate sample sizes and random sampling was utilized to collect patients. Patient demographics, OI-specific variables, fracture morphology, and fracture clinical courses were recorded. Data were analyzed for patient-specific and fracture-specific factors affecting OI HWF incidence.

Results:

Of patients with OI, 3.8% (18/469) sustained HWFs. Patients with OI HWF were significantly older than patients with OI without HWFs (P= 0.002) with no differences in height, weight, ethnicity, sex, or ambulatory status. Compared with non-OI HWFs, patients with OI HWF were significantly shorter (P< 0.001), weighed less (P= 0.002), and were less likely to be ambulatory (P< 0.001). OI HWFs were more commonly on the side of hand dominance (P< 0.001) with transverse patterns (P= 0.001). OI HWFs were less frequent in the thumb (P= 0.048) and trended towards significance in the metacarpals (P= 0.054). All OI HWFs were treated nonoperatively with similar union rates and refracture rates to non-OI HWFs. Multivariate regression showed that older patient age (odds ratio: 1.079, 95% CI: 1.005,1.159,P= 0.037) and OI type I (odds ratio: 5.535, 95% CI: 1.069, 26.795,P= 0.041) were significant prognosticators for HWFs in patients with OI.

Conclusion:

OI HWFs are uncommon (3.8%, 18/469) but specific HWF morphologies and locations are more common in patients with OI; however, these are not pathognomonic. Older patients with mild penetrance of type I OI are at the highest risk for HWFs. OI HWFs do well when managed nonoperatively with noninferior clinical courses compared with non-OI HWFs.

Level of Evidence:

Level III.
Periocular Microcystic Adnexal Carcinoma: A Case Report and a Major Review
Authors: Cheung Jesse , Rabinowitz Michael P. , Tuluc Madalina , Milman Tatyana
Published: June 2023

Purpose:

To describe a patient with periocular microcystic adnexal carcinoma (MAC) and to review the clinical presentation, systemic work-up, histopathologic features, and outcome of all previously reported periocular MAC.

Methods:

A major literature review. PubMed/MEDLINE and Google Scholar databases were searched for all well-documented cases of periocular MAC.

Results:

The final analysis yielded 93 patients with MAC, 48 (52%) females, 39 (42%) males, and 6 with sex not specified (6%) with an average age of 56 years (range 3 days–95 years). Most tumors were localized to the eyebrow (26/93, 28%) and lower eyelid (20/93, 22%). Of patients with known information, MAC most commonly presented as a nodule (37/68, 54%) or plaque (20/68, 29%) with poorly-defined margins (20/51, 39%) and distortion of eyelid margin (13/51, 25%). Orbital involvement at any point of the disease course was seen in 20 of 93 (22%) patients. An accurate histopathologic diagnosis on initial biopsy was made in 25 of 70 (36%) cases. Initial management included surgical excision (47/93, 51%), Mohs micrographic surgery (17/93, 18%), and excision with frozen section control of margins (8/93, 9%). Aggressive or recurrent MAC was managed with multimodal therapies, including adjuvant radiation (10/34, 29%). The average follow-up after the last treatment was 3 years (median 2, range 0.2–20 years). In total, 33 of 86 (38%) tumors recurred, and 6 of 87 (7%) metastasized. Disease-related mortality occurred in 3 of 79 (4%) of patients.

Conclusions:

Periocular MAC is frequently misdiagnosed on initial biopsy and has a tendency for recurrence and locally aggressive behavior, highlighting the importance of accurate timely diagnosis, and appropriate management.
DETERMINANTS OF PRE-EXPOSURE PROPHYLAXIS CASCADE AMONG SEXUAL AND GENDER MINORITIES IN NIGERIA
Authors: RAMADHANI Habib O. , CROWELL Trevor A. , NOWAK Rebecca G. , ADEBAJO Sylvia , KAYODE Blessing O. , ONONAKU Uchenna , BARAL Stefan D. , NDEMBI Nicaise , CHARURAT Man E. ,   for the TRUST/RV368 Study Group
Published: June 2023

Background

Pre-exposure prophylaxis (PrEP) is effective in preventing human immunodeficiency virus (HIV) infection among sexual and gender minorities (SGM). We evaluated characteristics associated with engagement in seven steps of the PrEP cascade among SGM in Nigeria.

Methods

SGM without HIV from the Abuja site of TRUST/RV368 cohort who were surveyed on awareness of and willingness to use PrEP were approached for PrEP initiation upon availability of oral daily PrEP. To understand gaps in the uptake of oral daily PrEP, we categorized the HIV PrEP cascade as (i) education about PrEP, (ii) interest in PrEP, (iii) successful contact, (iv) appointment scheduled, (v) appointment attendance, (vi) PrEP initiation, and (vii) plasma protective levels of tenofovir (TDF). Multivariable logistic regression models were used to determine factors associated with each of the seven steps in the HIV PrEP cascade.

Results

Of 788 participants, 718 (91.1%) showed interest in taking oral daily PrEP every day and/or after a sexual act, 542 (68.8%) were successfully contacted, 433 (54.9%) scheduled an appointment, 409 (51.9%) attended a scheduled appointment, 400 (50.8%) initiated oral daily PrEP, and 59 (7.4%) had protective levels of TDF. Of initiators of PrEP, 23 (5.8%) seroconverted at a rate of 13.9 cases/100 person-years. Better social support, larger network density, and higher education were associated with engagement in 4-5 components of the cascade.

Conclusions

Our data highlight a gap between willingness and actual PrEP use. Despite PrEP’s effectiveness in preventing HIV, the optimal impact of PrEP for SGM in sub-Saharan Africa will require multifaceted approaches that combine social support, education, and de-stigmatization.
Chlamydia trachomatis sero-epidemiology and associated factors in fertility treatment-seeking patients in the Abu Dhabi Emirate, United Arab Emirates
Authors: Abdo Noor Motea , Aslam Irfan , Irfan Shazia , George Junu A. , Alsuwaidi Ahmed R. , Ahmed Luai A. , Al-Rifai Rami H.
Published: June 2023

Purpose

This study was designed to investigate the seroepidemiology of and identify factors associated with exposure to Chlamydia trachomatis (C. trachomatis) in fertility treatment-seeking patients in Abu Dhabi Emirate, UAE.

Methods

308 fertility treatment-seeking patients were surveyed. Seroprevalence of past (IgG positive), current/acute (IgM positive), and active infection (IgA positive) with C. trachomatis was quantified. Factors associated with exposure to C. trachomatis were identified.

Results

Overall, 19.0%, 5.2%, and 1.6% found to have past, acute/recent, and ongoing active infection with C. trachomatis, respectively. Overall, 22.0% of the patients were seropositive to any of the three to C. trachomatis antibodies. Males compared to females (45.7% vs 18.9%, p < 0.001) and current/ex-smokers compared to non-smokers (44.4% vs 17.8%) had higher seropositivity. Patients with a history of pregnancy loss had higher seropositivity compared to other patients (27.0% vs 16.8%), particularly recurrent pregnancy losses (33.3%). Current smoking (aOR: 3.8, 95% CI: 1.32–11.04) and history of pregnancy loss (aOR: 3.0, 95% CI: 1.5–5.8) were significantly associated with higher odds of exposure to C. trachomatis.

Conclusions

The observed high seroprevalence of C. trachomatis, particularly in patients with a history of pregnancy loss, possibly indicates the contribution of C. trachomatis to the growing burden of infertility in the UAE.
Tranexamic Acid in Facial Feminization Surgery: Quantifying a High-risk Setting With Exogenous Estrogen Supplementation
Authors: Alper David P. , Almeida Mariana N. , Rivera Jean C. , Hosseini Helia , Williams Mica C.G. , Long Aaron S. , Prassinos Alexandre , Mookerjee Vikram , Persing John A. , Alperovich Michael
Published: June 2023

Tranexamic acid (TXA) has been increasingly utilized in orthognathic surgery, aesthetic surgery, and craniofacial surgery. However, the risk of increasing venous thromboembolic events (VTE) must be carefully considered as TXA is a prothrombotic agent. Our study aimed to investigate the safety of TXA in the setting of facial feminization surgery. These patients are at an elevated risk for VTE at baseline given their uniform history of exogenous estrogen supplementation. A retrospective review of all patients that underwent facial feminization surgery at our medical center between December 2015 and September of 2022 was performed. Demographic information, procedure type, Caprini scores, hematoma rate, VTE rate, estimated blood loss, and operative time were all studied. Unpaired t tests were used to compare patients that received TXA and those who did not. In total, there were 79 surgeries performed during our study period. There were 33 surgeries (41.77%) that used TXA intraoperatively. Ten patients (12.65%) received anticoagulation postoperatively, 5 of whom received TXA intraoperatively. Of the 33 patients who received TXA, 30 patients remained on estrogen therapy. There was no statistically significant difference in VTE rates in patients who received TXA (n=33, 41.77%) and those who did not (n=46, 58.23%). Bleeding events, Caprini scores, estimated blood loss, and operative time were also not found to be significantly different between the 2 cohorts. The authors found no significant increase in VTE in facial feminization patients undergoing estrogen supplementation when intraoperative TXA was utilized. This is the first known report investigating the safety of TXA in this higher risk patient population.
Tamarix articulataextract offers protection against toxicity induced by beauty products in Hs27 human skin fibroblasts
Authors: Alnuqaydan Abdullah M , Ali Zainy Faten M. , Almutary Abdulmajeed G , Said-Sadier Najwane , Rah Bilal
Published: June 2023

The current study evaluates the cytotoxicity and chemical analysis of selected beauty products and evaluation of the protective effect ofTamarix articulata(TA) extract against toxicity induced by beauty products in skin fibroblasts (Hs27). MTT and Crystal violet (CV) assays were used to determine the dose-dependent cytotoxic effects of products against Hs27 fibroblasts. DNA fragmentation assay was conducted to determine the mode of cell killing induced by evaluated beauty products. Chemical analysis and heavy metals were evaluated to determine beauty products. Pre-treatment with TA extract for different time points followed by time-dependent exposure with beauty products to assess the protective effect of TA extract in Hs27 cells was analysed by MTT and CV assays. Owing to the presence of various harmful heavy metals such as arsenic (As), chromium (Cr), cadmium (Cd), nickel (Ni), and lead (Pb) in beauty products, our results revealed that all beauty products induce significant cytotoxicity over time (1, 4 h) in a dose-dependent (125, 250, 500 µg/mL) manner. DNA fragmentation assay revealed that the induced cytotoxicity was caused by necrosis. However, pre-incubation with a safe dose (50 µg/mL) of TA for different times (24, 48 h) followed by exposure to various doses (62.5, 125, 250, 500 µg/mL) of beauty products for different times (1, 4 h) revealed significant (*p≤0.05, **p≤0.01) protection against product-mediated cytotoxicity. The effect was more pronounced for 1 h exposure to products compared to 4 h. Our study demonstrates that the due to the presence of heavy metals in synthetic beauty products exhibits marked toxicity to skin fibroblasts. However, the presence of abundant bioactive polyphenols with promising antiscavenging activity in TA extracts significantly nullifies cytotoxicity promoted by examined beauty products in skin fibroblasts (Hs27).
Th2 infiltration is a better predictor of survival than tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC)
Authors: Brousse Susie , Godey Florence , Tas Patrick , Campillo-Gimenez Boris , Lafont Elodie , Poissonnier Amanda , Levêque Jean , Lavoué Vincent , Gallo Matthieu Le
Published: June 2023

Purpose

Triple-negative breast cancers (TNBC) account for 15% of all breast cancers but carry the worst prognosis. Because of their heterogenicity, these tumors are not all prone to targeted therapies. However, due to their high immune infiltration, targeting their immune microenvironment is of tremendous interest and is becoming the standard of care for high-risk early-stage TNBC. Nevertheless, the characterization of this immune infiltrate is often limited to general tumor-infiltrating lymphocytes (TILs) counting, without characterization of lymphocytes subtypes. Thus, we aimed at precisely characterizing these sub-populations and evaluating their prognostic significance.

Methods

We selected 91 TNBC tumors for which we had both the TILs count on hematoxylin and eosin (H&E) slides determined by an expert pathologist and the immune microenvironment cell subtypes characterization using flow cytometry (FC). We then compared the prognostic value of immune microenvironment subpopulations vs total TILs count.

Results

TNBCs contained a mean of 22.8±25.9% TILs in the tumor surface area, including mainly CD4+ helper T lymphocytes (14.1%), mostly Th2 (11.7%), CD8+ cytotoxic T lymphocytes (11.1%), and myeloid cells (8.4%) including antigen presenting cells (APC). The TILs count was correlated with the abundance of these cellular subpopulations (p≤0.004). TILs percentage was predictive of overall survival (OS) in univariate analysis (p=0.044), high APC infiltration was predictive of relapse-free survival (RFS) in univariate analysis (p≤0.030), and Th2 infiltration was predictive of both RFS and OS in univariate (p=0.009, 0.008 respectively) and multivariate analyses (p=0.002, 0.010 respectively).

Conclusion

The characterization of TILs composition is essential to better understand the potential antitumoral functions of these cells, and to strongly improve the associated prognostic and predictive values. We here demonstrate that Th2 subpopulation is associated with a better overall survival in TNBC and could be of use to predict response to the newly used immunotherapies.
Fundamental Bound on Epidemic Overshoot in the SIR Model
Authors: Nguyen Maximilian M. , Freedman Ari S. , Ozbay Sinan A. , Levin Simon A.
Published: June 2023

Abstract

We derive an exact upper bound on the epidemic overshoot for the Kermack-McKendrick SIR model. This maximal overshoot value of 0.2984… occurs at. Using the general analysis framework presented within, we then consider more complex SIR models, such as those that incorporate vaccination or contact heterogeneity. We analyze models that consider vaccinations and show that the presence of vaccinated individuals decreases the maximum possible overshoot. For epidemics where the contact structure is given by a network, we numerically find that increased contact heterogeneity lowers the maximal overshoot value and weakens the dependency of overshoot on transmission.
Risk of Parkinson’s Disease in Stroke Survivors: A Nationwide Cohort Study in South Korea
Authors: Choi Hea Lim , Ahn Jong Hyeon , Chang Won Hyuk , Jung Wonyoung , Youn Jinyoung , Shin Dong Wook
Published: June 2023

BACKGROUND

Previous studies have examined the risk of stroke in patients with Parkinson’s disease (PD), but the incidence of PD onset among stroke survivors and its risk according to severity of post-stroke disabilities is scarcely investigated. This study aims to determine whether the risk of PD is increased among stroke survivors using a retrospective cohort with a large population-based database.

METHOD

We used data collected by the Korean National Health Insurance Service from 2010–2018 and examined 307,361 stroke survivors and 380,917 sex-and age-matched control subjects to uncover the incidence of PD. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI), and the risk of PD was compared according to presence and severity of disability.

RESULTS

During 4.31 years of follow-up, stroke survivors had a 1.67 times higher risk of PD compared to matched control subjects (adjusted HR, 1.67; 95% CI, 1.57–1.78). The risk of PD was greater among stroke survivors with disabilities than among those without disabilities, even after adjustment for multiple covariates (adjusted HR, 1.72; 95% CI, 1.55– 1.91 and adjusted HR, 1.66; 95% CI, 1.56–1.77, respectively).

CONCLUSION

Our study demonstrated increased risk of PD onset among stroke survivors. Health professionals need to pay careful attention to detecting movement disorders as clues for diagnosing PD.
Standardization of weightage assigned to different segments of the hand X-ray for assessment of bone age by the Greulich Pyle method
Authors: Oza Chirantap , Khadilkar Anuradha V , Goel Pranay , Aeppli Tim , Mondkar Shruti , Shah Nikhil , Lohiya Nikhil , Prasad Hemchand Krishna , Patil Prashant , Kajale Neha , Khadilkar Vaman , Sävendahl Lars
Published: June 2023

Objectives

Bone age (BA) assessment is important in evaluating disorders of growth and puberty; the Greulich and Pyle atlas method (GP) is most used. We aimed to determine the weightage to be attributed by raters to various segments of the hand x-ray, namely, distal end of radius-ulna (RU), carpals, and short bones for rating bone age using the GP atlas method.

Methods

692 deidentified x-rays from a previous study (PUNE-dataset) and 400 from the Radiological Society of North America (RSNA-dataset) were included in the study. Mean of BA assessed by experienced raters was termed reference rating. Linear regression was used to model reference age as function of age ratings of the three segments. The root-mean-square-error (RMSE) of segmental arithmetic mean and weighted mean with respect to reference rating were computed for both datasets.

Results

Short bones were assigned the highest weightage. Carpals were assigned higher weightage in pre-pubertal PUNE participants as compared to RSNA, vice-versa in RU segment of post-pubertal participants. The RMSE of weighted mean ratings was significantly lower than for the arithmetic mean in the PUNE dataset.

Conclusion

We thus determined weightage to be attributed by raters to segments of the hand x-ray for assessment of bone age by the GP method.
Myeloid cell influx into the colonic epithelium is associated with disease severity and non-response to anti-Tumor Necrosis Factor Therapy in patients with Ulcerative Colitis
Authors: Jha Divya , Al-Taie Zainab , Krek Azra , Eshghi Shadi Toghi , Fantou Aurelie , Laurent Thomas , Tankelevich Michael , Cao Xuan , Meringer Hadar , Livanos Alexandra E , Tokuyama Minami , Cossarini Francesca , Bourreille Arnaud , Josien Regis , Hou Ruixue , Canales-Herrerias Pablo , Ungaro Ryan C. , Kayal Maia , Marion James , Polydorides Alexandros D , Ko Huaibin M. , D’souza Darwin , Merand Raphael , Kim-Schulze Seunghee , Hackney Jason A. , Nguyen Allen , McBride Jacqueline M. , Yuan Guo-Cheng , Colombel Jean Frederic , Martin Jerome C. , Argmann Carmen , Suárez-Fariñas Mayte , Petralia Francesca , Mehandru Saurabh
Published: June 2023

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC. Prominently, reduced frequencies of matureBEST4+OTOP2+absorptive andBEST2+WFDC2+secretory epithelial enterocytes were associated with the replacement of homeostatic, residentTRDC+KLRD1+HOPX+γδ+T cells withRORA+CCL20+S100A4+TH17cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified byS100A8, HIF1A, TREM1, CXCR1) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649). Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.
Effect of gedunin on glioblastoma proliferation and invasiveness:In vitroandin vivoapproaches
Authors: Costa Thadeu Estevam Moreira Maramaldo , Pádua Tatiana Almeida , Pereira Jonathas Xavier , Rodrigues Vinicius Gonçalves , Seito Leonardo Noboru , da Cunha Erika Marques , Filgueiras Claudio C. , Abreu-Villaça Yael , Manhães Alex C. , Maya-Monteiro Clarissa Menezes , Henriques Maria das Graças , Krahe Thomas Eichenberg , Penido Carmen
Published: June 2023

Glioblastoma is the most invasive and malignant brain tumor, for which no effective treatment is currently available. Heat shock protein 90 (HSP90) is a potential target for the treatment of different types of cancer. Herein, we investigated the effect of gedunin, an HSP90 inhibitor, in murine GL261 glioblastomain vitroandin vivomodels. Gedunin treatment decreased GL261 cell proliferation and triggered apoptosis in a concentration- dependent manner. Gedunin also reduced GL261 cell migration and metalloproteinase-2 activity, suggesting that it impairs glioblastoma cell invasion. Despite the reduction of total protein content in gedunin-treated cells, the phosphorylation of STAT3 and ERK1/2 pathways was enhanced within 24 h.In situtreatment with gedunin did not significantly reduce tumor volume but reduced the presence of vascular structures in xenograft glioblastoma in C57BL/6 mice, a clinical feature associated with morbidity and mortality. Our results demonstrate that gedunin is a promising compound for the treatment of glioblastoma.

Graphical Abstract

Highlights

Gedunin reduces GL261 cell proliferation, migration and invasionin vitro.

Gedunin induces GL261 cell apoptosis and ERK activationin vitro.

Gedunin reduces the presence of tumoral vascular structuresin vivo.
Divergent associations of slow-wave sleep vs. REM sleep with plasma amyloid-beta
Authors: Rosenblum Yevgenia , Pereira Mariana , Stange Oliver , Weber Frederik D. , Bovy Leonore , Tzioridou Sofia , Lancini Elisa , Neville David A. , Klein Nadja , de Wolff Timo , Stritzke Mandy , Kersten Iris , Uhr Manfred , Claassen Jurgen A.H.R. , Steiger Axel , Verbeek Marcel M. , Dresler Martin
Published: June 2023

Background

Recent evidence shows that during slow-wave sleep (SWS), the brain is cleared from potentially toxic metabolites, such as the amyloid-beta protein. Poor sleep or elevated cortisol levels can worsen amyloid-beta clearance, potentially leading to the formation of amyloid plaques, a neuropathological hallmark of Alzheimer’s disease. Here, we explore how nocturnal neural and endocrine activity affects amyloid-beta fluctuations in the peripheral blood as a reflection of cerebral clearance.

Methods

Simultaneous polysomnography and all-night blood sampling were acquired in 60 healthy volunteers aged 20–68 years old. Nocturnal plasma concentrations of two amyloid-beta species (amyloid-beta-40 and amyloid-beta-42), cortisol, and growth hormone were assessed every 20 minutes from 23:00–7:00. Amyloid-beta fluctuations were modeled with sleep stages, (non)-oscillatory power, and hormones as predictors while controlling for age and multiple comparisons. Time lags between the predictors and amyloid-beta ranged from 20 to 120min.

Findings

The amyloid-beta-40 and amyloid-beta-42 levels correlated positively with growth hormone concentrations, SWS proportion, slow-wave (0.3–4Hz) oscillatory and high-band (30–48Hz) non-oscillatory power, but negatively with cortisol concentrations and rapid eye movement sleep (REM) proportion measured 40–100min before (all t-values>|3|, p-values<0.003). Older participants showed higher amyloid-beta-40 levels.

Interpretation

Slow-wave oscillations are associated with higher plasma amyloid-beta levels, reflecting their contribution to cerebral amyloid-beta clearance across the blood-brain barrier. REM sleep is related to decreased amyloid-beta plasma levels; however, this link may reflect passive aftereffects of SWS and not REM’s effects per se. Strong associations between cortisol, growth hormone, and amyloid-beta presumably reflect the sleep-regulating role of the corresponding releasing hormones. A positive association between age and amyloid-beta-40 may indicate that peripheral clearance becomes less efficient with age. Our study provides important insights into the specificity of different sleep features’ effects on brain clearance and suggests that cortisol nocturnal fluctuations may serve as a new marker of clearance efficiency.
Stability of navigation in catheter-based endovascular procedures
Authors: Hartquist Chase M. , Lee Jin Vivian , Qiu Michael Y. , Suskin Charles , Chandrasekaran Vinay , Lowe Halle R. , Zayed Mohamed A. , Osbun Joshua W. , Genin Guy M.
Published: June 2023

Endovascular procedures provide surgeons and other interventionalists with minimally invasive methods to treat vascular diseases by passing guidewires, catheters, sheaths and treatment devices into the vasculature to and navigate toward a treatment site. The efficiency of this navigation affects patient outcomes, but is frequently compromised by catheter “herniation”, in which the catheter-guidewire system bulges out from the intended endovascular pathway so that the interventionalist can no longer advance it. Here, we showed herniation to be a bifurcation phenomenon that can be predicted and controlled using mechanical characterizations of catheter-guidewire systems and patientspecific clinical imaging. We demonstrated our approach in laboratory models and, retrospectively, in patients who underwent procedures involving transradial neurovascular procedures with an endovascular pathway from the wrist, up in the arm, around the aortic arch, and into the neurovasculature. Our analyses identified a mathematical navigation stability criterion that predicted herniation in all of these settings. Results show that herniation can be predicted through bifurcation analysis, and provide a framework for selecting catheter-guidewire systems to avoid herniation in specific patient anatomy.
Microbial Responses to Biochar Soil Amendment and Influential Factors: A Three-level Meta-analysis
Authors: Kerner Patricia , Struhs Ethan , Mirkouei Amin , Aho Ken , Lohse Kathleen A , Dungan Robert S , You Yaqi
Published: June 2023

Biochar is a multifunctional soil conditioner capable of enhancing soil health and crop production while reducing greenhouse gas emissions. Understanding how soil microbes respond to biochar amendment is a vital step towards precision biochar application. Here, we synthesized 3899 observations of 24 microbial responses from 61 primary studies, applied a three-level mixed-effects model to estimate biochar effects, and evaluated the importance of biochar characteristics (feedstock, pyrolysis temperature), soil properties (pH, C:N, cation exchange capacity, bulk or rhizosphere), and treatment protocols (application rate, fertilization, duration, field or laboratory). Biochar significantly boosts microbial abundance (microbial biomass carbon > CFU), nitrite reductase gene (nirS), the activity of C- and N-cycling enzymes (dehydrogenase > cellulase > urease > invertase), and potential nitrification rate. Biochar characteristics, soil properties, and treatment protocols strongly determine the direction and extent of microbial response changes. Feedstock, pyrolysis temperature, application rate, and soil pH are important predictors most frequently included in the final models. Our study highlights the promise of purpose-driven biochar production and application such that biochar production parameters can be tuned to elicit the desired microbial responses and application protocols could be optimized to invoke multiple benefits. It also underlines current knowledge gaps and future research needs.

Synopsis

Meta-analysis reveals overall effect sizes of soil microbial responses to biochar amendment and the most influential factors, highlighting the potential of purpose-driven precision biochar towards sustainable agriculture.
Conjunctive vector coding and place coding in hippocampus share a common directional signal
Authors: Zhou Yue-Qing , Puliyadi Vyash , Chen Xiaojing , Lee Joonhee Leo , Zhang Lan-Yuan , Knierim James J.
Published: June 2023

Vector coding is becoming increasingly understood as a major mechanism by which neural systems represent an animal’s location in both a global reference frame and a local, item-based reference frame. Landmark vector cells (LVCs) in the hippocampus complement classic place cells by encoding the vector relationship (angle and distance) between the individual and specific landmarks in the environment. How these properties of hippocampal principal cells interact is not known. We simultaneously recorded the activities of place cells and LVCs via in vivo calcium imaging of the CA1 region of freely moving rats during classic, cue-card rotation studies. The firing fields of place cells rotated relative to the center of the platform to follow the cue card rotation, whereas the firing fields of simultaneously recorded LVCs rotated by the same amount as the place cells, but the axis of rotation was the nearby local landmarks, not the environmental center. We identified a novel type of place cell that exhibited conjunctive coding of the classic place field properties and LVC properties. These results demonstrate the capacity of CA1 neurons to encode both world-centered spatial information and animals’ location relative to the local landmarks, with a common directional input presumably provided by the head direction cell system.
Haploid-resolved and chromosome-scale genome assembly inCitrus unshiuand its parental species,C. nobilisandC. kinokuni
Authors: Isobe Sachiko , Fujii Hiroyoshi , Shirasawa Kenta , Kawahara Yoshihiro , Endo Tomoko , Shimada Takehiko
Published: June 2023

Citrus, a member of the Rutaceae family, is a widely cultivated crop with numerous cultivars. In Japan, citrus fruits account for a significant portion of agricultural production. Although several new citrus varieties have been developed through conventional breeding programs, satsuma mandarin remains the dominant cultivar. In this study, chromosome-scale and haploid-resolved reference genome sequences of satsuma mandarin (Citrus unshiuMarc) and its parental varaieties, kishu mandarin (C. kinokunihort. ex Tanaka) and kunenbo mandarin (C. nobilisLour. var. kunip Tanaka) were generated using long-read sequencing and Hi-C technologies. The comparison of haploid and unphased genomes revealed structural differences between them, indicating distinct regions in each haploid. In addition, genetic linkage maps were constructed, and genetic and physical distances were compared. The results showed variations in polymorphism density across different regions of the chromosomes. Together, the obtained results provide valuable insights into the genomic characteristics and structural variations of satsuma mandarin and related citrus varieties. These insights will lead to the further elucidation and improvement of citrus cultivars through genome breeding strategies.
Melatonin suppression by light involves different retinal photoreceptors in young and older adults
Authors: Najjar Raymond P. , Prayag Abhishek S. , Gronfier Claude
Published: June 2023

Introduction

Age-related sleep and circadian rhythm disturbances may be due to altered non-visual photoreception. Here, we investigated the temporal dynamics of light-induced melatonin suppression in young and older individuals.

Methods

In a within-subject design study, young and older participants were exposed for 60 minutes (0030-0130 at night) to 9 narrow-band lights (range: 420 to 620 nm). Plasma melatonin suppression was calculated at 15, 30, 45, and 60 min time intervals. Individual spectral sensitivity of melatonin suppression and photoreceptor contribution were predicted for each interval and age group.

Results

In young participants, melanopsin solely drove melatonin suppression at all time intervals, with an invariant peak sensitivity at ∼485 nm established only after 15 minutes of light exposure. Conversely, in older participants, spectral light-driven melatonin suppression was best explained by a model combining melanopsin + L-cones with a stable peak sensitivity (∼499 nm) at 30, 45, and 60 minutes of light exposure.

Conclusion

Aging is associated with a distinct photoreceptor contribution to melatonin suppression by light. While in young adults melanopsin-only photoreception is a reliable predictor of melatonin suppression, in older individuals this process is jointly driven by melanopsin and L-cones. These findings offer new prospects for customizing light therapy for older individuals.
Mutation in mitochondrial chaperone TRAP1 results in male-specific autism
Authors: Rydzanicz Małgorzata , Kuzniewska Bozena , Magnowska Marta , Wójtowicz Tomasz , Borsuk Ewa , Gewartowska Olga , Gruchota Jakub , Hojka Anna , Miłek Jacek , Stawikowska Aleksandra , Wardaszka Patrycja , Chojnicka Izabela , Kondrakiewicz Ludwika , Puścian Alicja , Knapska Ewelina , Dziembowski Andrzej , Płoski Rafał , Dziembowska Magdalena
Published: June 2023

There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in theTRAP1gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identicalTRAP1variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-inTrap1p.Q641* mice display ASD-related behavioral abnormalities exclusively in males. Accordingly,Trap1p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, number of presynaptic mitochondria, and metabolic substrate consumption. Thus, theTRAP1p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis.

One-Sentence Summary

Patient mutation inTRAP1causes autism in male mice.
Antibody Complementarity-Determining Region Sequence Design using AlphaFold2 and Binding Affinity Prediction Model
Authors: Ueki Takafumi , Ohue Masahito
Published: June 2023

Affinity maturation in the immune response is limited in terms of affinity gain, and natural antibodies often do not have the binding affinity required for therapeutic applications. Therefore, improving the binding affinity of antibodies is essential for developing antibody-based therapeutics. Designing antibodies using experimental methods is expensive in terms of cost and time owing to the large range of complementarity-determining regions to be explored. Recently, computational methods have been developed as low-cost and fast means of designing and redesigning antibodies. This study evaluated the design performance of AlphaFold2 and the binder hallucination, which can predict protein 3D structures with high accuracy even without experimental antibodies, by redesigning antibody sequences to improve the binding affinity of existing antigen-antibody complexes. Therefore, antibody sequences with higher affinity can be designed for antigen-antibody complexes not included in the training data of AlphaFold2, indicating that the proposed method may be effective as an antibody design method.
Explaining Deep Neural Networks for the Prediction of Translation Rates
Authors: Korbel Frederick , Eroshok Ekaterina , Ohler Uwe
Published: June 2023

A recent convolutional neural network model accurately quantifies the relationship between massively parallel synthetic 5’ untranslated regions (5’UTRs) and translation levels, but the underlying sequence determinants remain elusive. Applying model interpretation, we extract representations of regulatory logic, revealing a complex interplay of regulatory sequence elements. Guided by insights from model interpretation, we adapt the model by human reporter data to obtain superior performance, which will promote applications in synthetic biology and precision medicine.
HDAC4-mediated deacetylation of GSDMD prevents pyroptosis by inhibiting GSDMD ubiquitination
Authors: Xu Weilv , Li Xinyue , Li Danyue , Fu Xinyu , Chen Nan , Lv Qian , Shi Yuhua , He Suhui , Dong Lu , Yang Yang , Shi Fushan
Published: June 2023

Gasdermin D (GSDMD) functions as a key pyroptotic executor and induces cytokine secretion after cleavage by inflammatory caspases. However, less is known about the role of posttranslational modifications (PTMs) in GSDMD-mediated pyroptosis. Here, we report that GSDMD can be acetylated at Lysine 248 residue and the acetylation of GSDMD promotes pyroptosis. We identified histone deacetylase 4 (HDAC4) as the specific deacetylase that mediates GSDMD deacetylation and subsequent pyroptosis inhibitionin vitroandin vivo. GSDMD deacetylation impairs the ubiquitination of GSDMD, for which pyroptosis is inhibited. Interestingly, the phosphorylation of HDAC4 is important for its ability of deacetylating GSDMD and suppressing GSDMD-mediated pyroptosis. The Protein phosphatase 1 (PP1) catalytic subunits (PP1α and PP1γ) mediate the dephosphorylation of HDAC4, thereby abrogating its deacetylase activity on GSDMD. Therefore, our work unravels a complex regulatory mechanism involving HDAC4, PP1 and GSDMD, and provides novel insights into the crosstalk among acetylation, ubiquitination and phosphorylation.
In silicosimulations reveal molecular mechanism of uranyl ion toxicity towards DNA-binding domain of PARP-1 protein
Authors: Bulavko Egor S. , Ivankov Dmitry N.
Published: June 2023

The molecular toxicity of uranyl ion (UO22+) in living cells is mainly conditioned by its high affinity to both native and potential metal-binding sites frequently occurring in biomolecules structure. Recent advances in computational and experimental research shed light on the structural properties and functional impacts of uranyl binding to proteins, organic ligands, nucleic acids and their complexes. In the present work, we report the results of the theoretical investigation of the uranyl-mediated loss of DNA-binding activity of PARP-1, eukaryotic enzyme that participates in DNA reparation, cell differentiation, induction of inflammation, etc. Latest experimental studies showed that uranyl ion directly interacts with its DNA-binding subdomains – zinc fingers Zn1 and Zn2, – and changes their tertiary structure. Here, we propose an atomistic mechanism underlying this process and compute the free energy change along the suggested pathway to prove its relevance. According to the results of our QM/MM simulations of Zn2-UO22+complex, uranyl ion replaces zinc in its native binding site, but the corresponding state is destroyed because of the following spontaneous internal hydrolysis of the U–Cys162 coordination bond. Although the enthalpy of hydrolysis is +2.8 kcal/mol, the final value of the free energy of the reaction constitutes -0.6 kcal/mol, due to structure loosening evidenced by solvation and configuration thermodynamic properties calculated using GIST- and MIST-based trajectory processing techniques. The subsequent reorganization of the binding site includes association of uranyl ion with the Glu190/Asp191 acidic cluster and significant perturbations in the domain’s tertiary structure, which further decreases the free energy of the non-functional state by 6.8 kcal/mol. The disruption of the DNA-binding interface revealed in our computational simulations is consistent with previous experimental findings and appears to be associated with the loss of the Zn2 affinity for nucleic acids.
Tactile Imagery Affects Cortical Responses to Vibrotactile Stimulation of the Fingertip
Authors: Morozova Marina , Yakovlev Lev , Syrov Nikolay , Perevoznyuk Gleb , Lebedev Mikhail , Kaplan Alexander
Published: June 2023

Although imagery of tactile sensations is not so well studied compared to other types of mental imagery, it is potentially very useful for brain computer interfaces (BCIs) where it could produce neural modulations needed for BCI operations. Here we assessed neural modulations associated with tactile imagery (TI) by comparing its effects on cortical responses to the effects of actual vibrotactile stimulation of the fingertip. We found that both TI and vibrostimulation evoked event-related frequency changes of the electroencephalographic (EEG) activity. Moreover, TI affected somatosensory evoked potentials (SEPs) evoked by short pulses of vibration. EEG data were collected in 29 participants trained to perform tactile imagery task. Responses to vibratory pulses were measured with and without TI. These SEPs consisted of three prominent components: a P100 response in the centro-parietal regions, a P200 response in the frontal region, and a P300 response in the central regions. The TI consistently resulted in an increase in ipsilateral P100, ipsi- and contralateral P300 and frontal P200. Moreover, TI strengthened the θ-band ERS in the frontal region that occurred in response to vibration. These findings suggest that TI not only modulates EEG patterns by itself but also affects cortical processing of physical somatosensory stimuli. Such conjoint processing of both real and imagined somatic sensations could be utilized in BCIs, particularly in clinically relevant BCI that strive to restore somatosensory processing by combining centrally-induced and peripheral activities.

Significance Statement

While it is known that tactile imagery (TI) engages the same cortical areas that are active during the processing of real tactile inputs, neural mechanisms of such shared representation are not well understood. This study employed EEG recordings to examine the interaction between real and imagined somatic sensations. It was found that TI both changes EEG oscillatory activity and facilitates cortical responses to real tactile stimuli. Therefore combining TI with tactile stimulation could be useful for tactile-based brain-computer interfaces (BCIs), particularly the ones of clinical utility for neurorehabilitation and sensory substitution.
Machine Learning-Guided Antibody Engineering That Leverages Domain Knowledge To Overcome The Small Data Problem
Authors: Clark Thomas , Subramanian Vidya , Jayaraman Akila , Fitzpatrick Emmett , Gopal Ranjani , Pentakota Niharika , Rurak Troy , Anand Shweta , Viglione Alexander , Raman Rahul , Tharakaraman Kannan , Sasisekharan Ram
Published: June 2023

The application of Machine Learning (ML) tools to engineer novel antibodies having predictable functional properties is gaining prominence. Herein, we present a platform that employs an ML-guided optimization of the complementarity-determining region (CDR) together with a CDR framework (FR) shuffling method to engineer affinity-enhanced and clinically developable monoclonal antibodies (mAbs) from a limited experimental screen space (order of 10^2 designs) using only two experimental iterations. Although high-complexity deep learning models like graph neural networks (GNNs) and large language models (LLMs) have shown success on protein folding with large dataset sizes, the small and biased nature of the publicly available antibody-antigen interaction datasets is not sufficient to capture the diversity of mutations virtually screened using these models in an affinity enhancement campaign. To address this key gap, we introduced inductive biases learned from extensive domain knowledge on protein-protein interactions through feature engineering and selected model hyper parameters to reduce overfitting of the limited interaction datasets. Notably we show that this platform performs better than GNNs and LLMs on an in-house validation dataset that is enriched in diverse CDR mutations that go beyond alanine-scanning. To illustrate the broad applicability of this platform, we successfully solved a challenging problem of redesigning two different anti-SARS-COV-2 mAbs to enhance affinity (up to 2 orders of magnitude) and neutralizing potency against the dynamically evolving SARS-COV-2 Omicron variants.