bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between cost-sharing and drug prescribing in Korean elderly veterans with chronic diseases: A real-world claims data study
Authors: Kim Jin , Je Nam Kyung , Choo Eunjung , Jang Eun Jin , Lee Iyn-Hyang
Published: September 2022

This study aimed to investigate the relationship between cost-sharing and drug prescribing and its appropriateness in Korean elderly veterans with chronic conditions. This is a cross-sectional study using real-world claims data. Veterans with primary hypertension or dyslipidemia were compared with two controls with higher levels of cost-sharing. Study subjects (age ≥65 years) were selected through stratified random sampling and matching the individual attributes. The primary outcome was the annual amount of drugs prescribed per patient, and the secondary outcomes included several other measures investigating multifaceted aspects of drug prescribing, medical institution utilization behavior, and prescribing appropriateness. Gamma regression models or logistic regression models were employed. Veterans were prescribed 59%~74% more drugs (exp (β) = 1.59 [95% confidence interval [CI] = 1.55–1.64] ~ 1.74 [1.70–1.79]) compared to the National Health Insurance (NHI) patients. This was attributed mainly to longer prescribing days (44%) and slightly more prescriptions (6%~7%) than NHI patients. Veterans spent 14%~15% higher medication costs. Veterans were less likely to visit multiple medical institutions by estimates of 0.77 (0.76–0.79) ~ 0.80 (0.79–0.82). Similar but smaller differences were observed between veterans and medical aid (MedAid) patients. The veteran patients showed a more than 50% increased risk of therapeutic duplication than the other two controls (adjusted odds ratio [ORs] = 1.47 [1.37–1.57] ~ 1.61 [1.50–1.72]). Inappropriate drug prescribing was also more common in veterans than the two controls (adjusted ORs = 1.20 [1.11–1.31] ~ 1.32 [1.22–1.43]). In Korean elderly veterans with chronic illnesses, a level of cost-sharing was associated with having more prescribed medicines, and increased inappropriate prescribing.
Effect of two combinations of low-dose oral contraceptives on adolescent bone mass: A clinical trial with 2 years follow-up
Authors: Caldeirão Talita Domingues , Orsolini Lilian Rodrigues , da Silva Carla Cristiane , Bisi Rizzo Anapaula da Conceição , Teixeira Altamir Santos , Nunes Hélio Rubens de Carvalho , Goldberg Tamara Beres Lederer
Published: September 2022

Introduction:

Most contraceptive combinations can interfere with the processes of bone formation and resorption.

Aim:

The aim of this study was to evaluate the effect of 2 combinations of low-dose oral hormonal contraceptives (20 µg ethinyl estradiol [EE]/150 mg desogestrel [COC1] or 30 µg EE/3 mg drospirenone [COC2]) on bone mass acquisition in adolescents over 2 years by means of bone densitometry and measurement of biomarkers of bone remodeling.

Methods:

Parallel-group, non-randomized controlled clinical trial of 127 adolescents divided into a control group and 2 groups receiving either COC1 or COC2. The participants were submitted to anthropometric assessment and evaluation of secondary sexual characteristics (Tanner criteria) and bone age. Bone densitometry by dual-energy X-ray absorptiometry and measurement of bone biomarkers (bone alkaline phosphatase, osteocalcin, and C-terminal telopeptide) were performed at baseline and after 24 months.

Results:

No significant differences in the variables analyzed were observed between COC1 or COC2 users and the control group at baseline. After 24 months, non-users had incorporated more bone mass (content and density) than either group of contraceptive users. This negative impact was more pronounced in the COC2 group than in the COC1 group. A significant reduction in the percentage values of bone alkaline phosphatase and osteocalcin was observed in users of oral contraceptives.

Conclusion:

Bone mass acquisition was compromised in adolescent users of combined hormonal contraceptives. The negative impact was more pronounced in adolescents using contraceptives that contain 30 µg EE/3 mg drospirenone.
Changes in self-harm attempts after the COVID-19 pandemic based on pre-hospital medical records
Authors: Kim Na Min , Seo Young Woo , Gyu Kwak Sang
Published: September 2022

Although many concerns have been raised on increased self-harm or suicide attempts since the emergence of the coronavirus disease 2019 (COVID-19) pandemic, the numbers of studies reported no consistent increase. This study aimed to analyze the data on the request for emergency medical service (EMS) in Daegu Metropolitan City in Korea to investigate the effects of the COVID-19 pandemic on the incidence and types of suicidal patients. Data of 4480 cases requesting EMS related to self-harm or suicide 1 year before and after the COVID-19 pandemic were retrospectively comparatively analyzed (February 19, 2019–February 18, 2021). The number of EMS requests for self-harm and suicide increased after the pandemic compared to that before the pandemic (daily mean request 5.83 [±2.597] vs 6.43 [±2.918]). In particular, the number of female patients increased per day on average (2.61 [±1.717] vs 3.17 [±1.893]). With respect to the reasons for the request, committed self-harm and attempts to commit self-harm increased, whereas the presumption against suicide decreased. With respect to consciousness levels, the number of alert patients increased, whereas the number of transport cases decreased. For the method of the attempt, hanging and carbon monoxide/gas poisoning decreased, whereas jumping from a height and drowning increased. The number of patients with psychiatric history and those with other chronic illnesses increased. In multivariate regression analysis, women (OR 1.227, 95% CI = 1.072–1.405, P = .003), patients with psychiatric diseases (OR 1.223, 95% CI = 1.031–1.450, P = .021), patients with other chronic illnesses (OR 1.510, 95% CI = 1.127–2.023, P = .006), and CO or gas poisoning (not attempted) (OR 1.349, 95% CI = 1.038–1.753, P = .025) showed statistically significant differences. Among the request for EMS, requests for committed self-harm and attempts to commit suicide increased. Medical support and measures for mental health and emergency medical systems should be established for female patients and patients with psychiatric or other chronic diseases.
Precise quantitative evaluation of pharmacokinetics of cisplatin using a radio-platinum tracer in tumor-bearing mice
Authors: Obata Honoka , Tsuji Atsushi B. , Sudo Hitomi , Sugyo Aya , Minegishi Katsuyuki , Nagatsu Kotaro , Ogawa Mikako , Zhang Ming-Rong
Published: September 2022

Objective

The platinum-based antineoplastic drug cisplatin is commonly used for chemotherapy in clinics. This work aims to demonstrate a radio-platinum tracer is useful for precisely quantifying small amounts of platinum in pharmacokinetics studies.

Methods

A cisplatin radiotracer (radio-cisplatin) was synthesized, and a comprehensive evaluation of cisplatin over 7 days after its intravenous injection into nude mice bearing a subcutaneous lung tumor (H460) was conducted.

Results

A biphasic retention curve in the whole body and blood was observed [T
1/2(α) = 1.14 h, T
1/2(β) = 5.33 days for the whole body, and T
1/2(α) = 23.9 min, T
1/2(β) = 4.72 days for blood]. The blood concentration decreased within 1 day after injection. Most of the intact cisplatin was excreted via the kidneys in the early time points, and a small part was distributed in tissues including tumors. The plasma protein binding rate of cisplatin increased rapidly after injection, and the protein-bound cisplatin remained in the blood longer than intact cisplatin. The peak uptake in H460 tumors was 4.7% injected dose per gram at 15 min after injection, and the area under the curve (AUC0–7 days) was approximately one-half to one-third of the AUC0–7 days in the kidneys, liver, and bone, where some toxicity is observed in humans.

Conclusion

The radio-platinum tracer revealed the highly quantitative biodistribution of cisplatin, providing insights into the properties of cisplatin, including its adverse effects. The tracer enables a precise evaluation of pharmacokinetics for platinum-based drugs with high sensitivity.
Metastasectomy in renal cell carcinoma: where are we now?
Authors: Lloyd Alexander , Reeves Fairleigh , Abu-Ghanem Yasmin , Challacombe Ben
Published: September 2022

Purpose of review

Metastatic RCC has a variable natural history. Treatment choice depends on disease and patient factors, but most importantly disease burden and site of metastasis. This article highlights key variables to consider when contemplating metastasectomy for RCC and provide a narrative review on the evidence for metastasectomy in these patients.

Recent findings

Tumour subtype is associated with differing patterns of recurrence. Patients with single or few metastatic sites have better outcomes, and those with greater time interval from initial nephrectomy. Local recurrence is particularly amenable to minimally invasive surgical resection and is oncologically sound. Very well selected cases of liver or brain metastases may benefit from metastectomy, although lung and endocrine metastases have more favourable outcomes. Although site and burden of disease is important, the key determinate of outcome in metastasectomy depends mostly on the ability to achieve a complete resection. Adjuvant treatment is not currently advocated.

Metastasectomy should be generally reserved for cases where complete resection is achievable, unless the goal of treatment is to palliate symptoms. This field warrants ongoing research, particularly as systemic therapy and minimally invasive surgical techniques evolve. Elucidating tumour biology to inform patient selection will be important in future research.
Effect of Fist Clenching on Vein Visibility and Palpability
Authors: Eren Handan , Calıskan Nurcan , Durmus Iskender Mahinur
Published: September 2022

No information exists on the minimum number of times that fist clenching should be performed to increase vein visibility and palpability. In this study, the researchers aimed to determine the average number and duration of fist clenching to increase vein visibility and palpability before peripheral intravenous catheter insertion. This observational study included 207 healthy individuals. Participants meeting the inclusion criteria were asked to perform fist clenching. The number and duration of fist clenches performed to increase dorsal metacarpal vein and cephalic vein grade were determined. The participants carried out fist clenching 7.57 ± 4.26 times for the first increase and 22.16 ± 7.93 times for the second increase in dorsal metacarpal vein grade. Fist clenching was carried out 10.05 ± 7.30 times for the first increase and 21.30 ± 7.86 times for the second increase in cephalic vein visibility. A statistically significant, weak, but positive relationship was observed between the duration of fist clenching and the change in dorsal metacarpal vein grade and anxiety level (r = 0.194, P < .005). However, the relationship was negative between room temperature and the duration of fist clenching in dorsal metacarpal vein grade (r = –0.207, P = .003). This inexpensive and simple technique should be performed in specified numbers before catheter insertion.
Achieving Reductions in Opioid Dispensing: A Qualitative Comparative Analysis of State-Level Efforts to Improve Prescribing
Authors: Underwood Natasha L. , Kane Heather , Cance Jessica , Emery Kyle , Elek Elvira , Zule William , Rooks-Peck Cherie , Sargent Wesley , Mells Jamie
Published: September 2022

Objective:

To determine whether any combinations of state-level public health activities were necessary or sufficient to reduce prescription opioid dispensing.

Design:

We examined 2016-2019 annual progress reports, 2014-2019 national opioid dispensing data (IQVIA), and interview data from states to categorize activities. We used crisp-set Qualitative Comparative Analysis to determine which program activities, individually or in combination, were necessary or sufficient for a better than average decrease in morphine milligram equivalent (MME) per capita.

Setting:

Twenty-nine US state health departments.

Participants:

State health departments implementing the Centers for Disease Control and Prevention's Prevention for States (PfS) program.

Main Outcome:

Combinations of prevention activities related to changes in the rate of prescription opioid MME per capita dispensing from 2014 to 2019.

Results:

Three combinations were sufficient for greater than average state-level reductions in MME per capita: (1) expanding and improving proactive reporting in combination with enhancing the uptake of evidence-based opioid prescribing guidelines and not moving toward a real-time Prescription Drug Monitoring Program; (2) implementing or improving prescribing interventions for insurers, health systems, or pharmacy benefit managers in combination with enhancing the uptake of evidence-based opioid prescribing guidelines; and (3) not implementing or improving prescribing interventions for insurers, health systems, or pharmacy benefit managers in combination with not enhancing the uptake of evidence-based opioid prescribing guidelines. Interview data suggested that the 3 combinations indicate how state contexts and history with addressing opioid overdose shaped programming and the ability to reduce MME per capita.

Conclusions:

States successful in reducing opioid dispensing selected activities that built upon existing policies and interventions, which may indicate thoughtful use of resources. To maximize impact in addressing the opioid overdose epidemic, states and agencies may benefit from building on existing policies and interventions.
“Regional-controlled tissue expanders increase skin expansion and thickness compared to standard tissue expanders in a rat model”
Authors: Xiong Zhezhen , Chen Yahong , Xu Peng , Chen Chuhsin , Xie Yun , Chang Yu , Pan Tingrui , Liu Kai
Published: September 2022

Background:

Skin and soft tissue expansion are widely used. However, it cannot expand targeted areas on the top flap. Thus, we developed a new expander with a partially thickened top. We hypothesized that pressure differences would lead to higher growth near non-thickened regions and lower growth near thickened regions, allowing targeted expansion.

Methods:

Eighteen Sprague Dawley rats (8 weeks old, male) were used; 20-ml rectangular regional-controlled expanders (n=12) and ordinary expanders (n=6) were implanted. Flaps on regional-controlled expanders were divided into non-thickened (RCE-nt) and thickened (RCE-t) regions and tattooed. Discontinuous inflation began 14 days post-operation, 3 ml every 3 days, until the volume reached 50 ml. Tattooed skin area and thickness were measured. Immunofluorescence staining detected cell proliferation (PCNA+) and vascular density (CD31+). Growth factors (TGF-β, EGF, VEGF, and bFGF) were assessed by ELISA.

Results:

The expanded skin area of RCE-nt (396.2±41.4 mm2) was 33.8%±10.0% larger than that of RCE-t (297.8±38.9 mm2). RCE-t had a 28.9%±14.6% thicker dermal layer (942.4±55.5 µm) than RCE-nt (737.1±64.5 µm). RCE-nt had 295.0%±145.0% more PCNA(+) cells (92.4±16.2/mm2) than RCE-t (25.6±7.4/mm2). The vascular density was 133.0%±61.7% higher in RCE-t (24.8±4.7/mm2) than in RCE-nt (11.1±2.7/mm2)(all above p<0.05).

Conclusions:

Regional-controlled expansion specifically expands only the targeted area, causing thicker skin flaps with abundant vessels for defect repair. Although this technique has great clinical potential, it should be further validated with large animals and humans.
Sequential Behavioral Analysis: A Novel Approach to Help Understand Clinical Decision-Making Patterns in Extended Reality Simulated Scenarios
Authors: Rochlen Lauryn R. , Putnam Elizabeth M. , Tait Alan R. , Du Hanxiang , Popov Vitaliy
Published: September 2022

Summary Statement

Extended reality (XR)-based simulation training offers unique features that facilitate collection of dynamic behavioral data and increased immersion/realism while providing opportunities for training health care professionals on critical events that are difficult to recreate in real life. Sequential analysis can be used to summarize learning behaviors by discovering hidden learning patterns in terms of common learning or clinical decision-making sequences. This project describes the use of sequential analysis to examine differential patterns of clinical decision-making behaviors in observed XR scenarios, allowing for new insights when using XR as a method to train for critical events and to trace clinical decision making.
Short Report: Race and Ethnicity Misclassification in Kidney Transplantation Research
Authors: Kernodle Amber B. , Thompson Valerie , Chen Xiaomeng , Norman Silas P. , Segev Dorry L. , Purnell Tanjala S. , McAdams-DeMarco Mara
Published: September 2022

Background.

Recently, the misuse of race as a biological variable, rather than a social construct, in biomedical research has received national attention for its contributions to medical bias. In national transplant registry data, bias may arise from measurement imprecision because of the collection of provider-perceived race rather than patients’ own self-report.

Methods.

We linked Scientific Registry of Transplant Recipients data to a prospective, multicenter cohort study of adult kidney transplant patients (December 2008–February 2020) that collects patient-reported race. We computed Cohen’s kappa statistic to estimate agreement between provider-perceived and patient-reported race in the 2 data sources. We used an unadjusted generalized linear model to examine changes in agreement over time.

Results.

Among 2942 kidney transplant patients, there was almost perfect agreement among Asian (kappa = 0.88, 95% confidence interval [CI], 0.84-0.92), Black (kappa = 0.97, 95% CI, 0.96-0.98), and White categories (kappa = 0.95, 95% CI, 0.93-0.96) and worse agreement among Hispanic/Latino (kappa = 0.66, 95% CI, 0.57-0.74) and Native Hawaiian/Other Pacific Islander categories (kappa = 0.40, 95% CI, 0.01-0.78). The percent agreement decreased over time (difference in percent agreement = –0.55, 95% CI, –0.75 to –0.34). However, there were differences in these trends by race: –0.07/y, 95% CI, –0.21 to 0.07 for Asian; –0.06/y, 95% CI, –0.28 to 0.16 for Black; –0.01/y, 95% CI, –0.21 to 0.19 for Hispanic/Latino; –0.43/y, 95% CI, –0.58 to –0.28 for White categories.

Conclusions.

Race misclassification has likely led to increasingly biased research estimates over time, especially for Asian, Hispanic/Latino, and Native Hawaiian/Other Pacific Islander study populations. Improvements to race measurement include mandating patient-reported race, expanding race categories to better reflect contemporary US demographics, and allowing write-ins on data collection forms, as well as supplementing data with qualitative interviews or validated measures of cultural identity, ancestry, and discrimination.
The Efficacy of Selective Estrogen Receptor Modulators Monotherapies in Postmenopausal Women with Osteopenia
Authors: Kim Kyung Wook , Kim Young Il , Kim Ki-Choul
Published: September 2022

Background: The impact of osteopenia as a risk factor for fractures is underrecognized. Moreover, the efficacy of selective estrogen receptor modulators (SERMs) in postmenopausal women with osteopenia is limited. This study aimed to evaluate the efficacy of SERMs in postmenopausal women with osteopenia.Methods: Thirty-two postmenopausal women with osteopenia were treated with 3 types of SERMs medication: raloxifene (group I, N=15), bazedoxifene (group II, N=8), and raloxifene with cholecalciferol (group III, N=9). Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry scans before treatment to after 3 years of treatment once a year.Results: Patients in group I showed significant increases in hip BMD, -1.93 to -1.73 and spine BMD, -1.85 to -1.67. In addition, patients in groups II and III showed significant increases in hip BMD, -1.93 to -1.69 and -2.22 to -1.86, respectively and spine BMD, -2.1 to -1.3 and -2.22 to -1.37, respectively. The BMD increased in the hip and spine by 9.7% and 10.3%, respectively in group I, 38.0% and 12.4%, respectively in group II, and 38.2% and 16.2%, respectively in group III.Conclusions: In this study, we found that SERMs could improve spine and hip BMD. In conclusion, preemptive treatment using SERMs is necessary for postmenopausal women with osteopenia. None of the patients experienced fractures during the follow-up period.
Calibration of Agent Based Models for Monophasic and Biphasic Tumour Growth using Approximate Bayesian Computation
Authors: Wang Xiaoyu , Jenner Adrianne L. , Salomone Robert , Warne David J. , Drovandi Christopher
Published: September 2022

Agent-based models (ABMs) are readily used to capture the stochasticity in tumour evolution; however, these models are often challenging to validate with experimental measurements due to model complexity. The Voronoi cell-based model (VCBM) is an off-lattice agent-based model that captures individual cell shapes using a Voronoi tessellation and mimics the evolution of cancer cell proliferation and movement. Evidence suggests tumours can exhibit biphasic growthin vivo. To account for this phenomena, we extend the VCBM to capture the existence of two distinct growth phases. Prior work primarily focused on point estimation for the parameters without consideration of estimating uncertainty. In this paper, approximate Bayesian computation is employed to calibrate the model toin vivomeasurements of breast, ovarian and pancreatic cancer. Our approach involves estimating the distribution of parameters that govern cancer cell proliferation and recovering outputs that match the experimental data. Our results show that the VCBM, and its biphasic extension, provides insight into tumour growth and quantifies uncertainty in the switching time between the two phases of the biphasic growth model. We find this approach enables precise estimates for the time taken for a daughter cell to become a mature cell. This allows us to propose future refinements to the model to improve accuracy, whilst also making conclusions about the differences in cancer cell characteristics.
The clustering of spatially associated species unravels patterns in Bornean tree species distributions
Authors: Pang Sean E. H. , Ferry Slik J. W. , Zurell Damaris , Webb Edward L.
Published: September 2022

Complex distribution data can be summarised by grouping species with similar or overlapping distributions to unravel patterns in species distributions and separate trends (e.g., of habitat loss) among spatially unique groups. However, such classifications are often heuristic, lacking the transparency, objectivity, and data-driven rigour of quantitative methods, which limits their interpretability and utility. Here, we develop and illustrate the clustering of spatially associated species, a methodological framework aimed at statistically classifying species using explicit measures of interspecific spatial association. We investigate several association indices and clustering algorithms and show how these methodological choices engender substantial variations in clustering outcome and performance. To facilitate robust decision making, we provide guidance on choosing methods appropriate to the study objective(s). As a case study, we apply the framework to model tree distributions in Borneo to evaluate the impact of land-cover change on separate species groupings. We identified 11 distinct clusters that unravelled ecologically meaningful patterns in Bornean tree distributions. These clusters then enabled us to quantify trends of habitat loss tied to each of those specific clusters, allowing us to discern particularly vulnerable species clusters and their distributions. This study demonstrates the advantages of adopting quantitatively derived clusters of spatially associated species and elucidates the potential of resultant clusters as a spatially explicit framework for investigating distribution-related questions in ecology, biogeography, and conservation. By adopting our methodological framework and publicly available codes, practitioners can leverage the ever-growing abundance of distribution data to better understand complex spatial patterns among species distributions and the disparate effects of global changes on biodiversity.

Statement of authorship

SEHP and ELW conceived the idea and designed methodology. SEHP conducted all analyses and developed the methodological framework with key inputs from ELW, JWFS, and DZ. All authors contributed to the interpretation of the results. SEHP and ELW wrote the first draft of the manuscript. All authors provided feedback on the writing.
Single-cell transcriptomics reveal distinct subsets of activated dendritic cells in the tumor microenvironment
Authors: To Tsun Ki Jerrick , Devalaraja Samir , Folkert Ian W. , Zhai Li , Lobel Graham P. , Haldar Malay
Published: September 2022

Dendritic cells (DCs) are rare in tumors where their heterogeneity remains unclear. To overcome the limitations of surface marker-based analyses, we utilized DC-reporter mice (Zbtb46GFP/+) to isolate tissue and tumor DCs and performed single-cell RNA sequencing (scRNA-seq). The known DC subsets were conserved across tissues, albeit at different frequencies. Activated and mature DCs formed a distinct cluster in both healthy and tumor tissues and displayed the hallmark DC migratory program (migratory DCs). We also identified a distinct subset of activated DCs in tumors that did not induce the migratory program, instead displaying signatures of interferon exposure (interferon-DCs or IFN-DCs). IFN-DCs were proficient in antigen-presentation, supported T cell proliferation, and expressed high levels of T cell-attracting chemokines. IFN-DCs further comprised of IFN1- and IFN2-DCs that were generated from CD11b+ DCs in response to type I or type II interferons respectively. We also identified IFN-DCs in scRNA-seq of human tumor-infiltrating leukocytes. These findings illustrate DC heterogeneity in tumors and suggest the existence of an interferon regulated ‘division of labor’ among activated DCs whereby the migratory DCs drive T cell priming in draining lymph nodes while the sessile IFN-DCs help recruit T cells and regulate their function in the tumor microenvironment.

One Sentence Summary

Tumors harbor an interferon-regulated activated sessile subset of dendritic cells.
Impact of female mate copying on male morph dynamics
Authors: Patil Srishti , Nöbel Sabine , Gokhale Chaitanya S.
Published: September 2022

Mate copying (MC), a type of non-independent mate choice, is a behaviour observed in many vertebrate and few invertebrate species. It occurs when an individual’s sexual preference gets socially inclined toward those of its conspecifics. Theoretical models and experimental studies of MC have been limited to choice between two options (or morphs). In this study we model the evolution of morphology in a population under varying extents of mate copying. Multiple morphs and multiple observations are considered and a generalisable model is presented. We quantify the level of copying needed to achieve pseudo-stable equilibria in the presence of multiple morphs. Moving closer to realistic scenarios we support our theoretical development with simulations and discuss relevance for empirical model systems.
Simulating Short-Term Synaptic Plasticity on SpiNNaker Neuromorphic Hardware
Authors: Azzalini Loïc J. , Lankarany Milad
Published: September 2022

Neuromorphic chips are well-suited for the exploration of neuronal dynamics in (near) real-time. In order to port existing research onto these chips, relevant models of neuronal and synaptic dynamics first need to be supported by their respective development environments and validated against existing simulator backends. At the time of writing, support for short-term synaptic plasticity on neuromorphic hardware is scarce. This technical paper proposes an implementation of dynamic synapses for the SpiNNaker development environment based on the popular synaptic plasticity model by Tsodyks and Markram (TM). This extension is undertaken in the context of existing research on neuromodulation and the study of deep brain stimulation (DBS) effects on singular-neuron responses. The implementation of the TM synapse is first detailed and then, simulated for various response types. Its role in studies of DBS effect on postsynaptic responses is also reviewed. Finally, given the real-time capabilities offered by the hardware, we provide some insight to lay the groundwork for future explorations of closed-loop DBS on neuromorphic chips.
Intrinsically disordered proteins SAID1/2 condensate on SERRATE/ARS2 for dual inhibition of miRNA biogenesis in Arabidopsis
Authors: Shang Baoshuan , Wang Lin , Yan Xingxing , Li Yanjun , Li Changhao , Wu Chaohua , Wang Tian , Xiang-Guo  , Choi Sukwon , Zhang Tianru , Wang Ziying , Tong Chun-Yip , Oh Taerin , Xiao-Zhang  , Wang Zhiye , Peng Xu , Zhang Xiuren
Published: September 2022

Intrinsically disordered proteins (IDPs) SAID1/2 are hypothetic dentin sialophosphoprotein-like proteins, but their true functions are unknown. Here, we identified SAID1/2 as negative regulators of SERRATE(SE)/ARS2, a core factor in miRNA biogenesis complex (microprocessor). Loss-of-function double mutants of said1; said2 caused pleiotropic developmental defects and thousands of differentially-expressed genes that partially overlapped with those in se. said1; said2 also displayed increased assembly of microprocessor and elevated accumulation of miRNAs. Mechanistically, SAID1/2 promotes PRP4KA-mediated phosphorylation of SE, leading to its degradation in vivo. Unexpectedly, SAID1/2 have strong binding affinity to hairpin-structured pri-miRNAs and can sequester them from SE. Moreover, SAID1/2 directly inhibit pri-miRNA processing by microprocessor in vitro. Whereas SAID1/2 did not impact SE subcellular compartmentation, the proteins themselves exhibited liquid-liquid phase condensation that is nucleated on SE. Thus, we proposed that SAID1/2 reduce miRNA production through hijacking pri-miRNAs to prevent microprocessor activity while promoting SE phosphorylation and its destabilization in Arabidopsis.
A high-throughput strategy for enhancing aptamer performance across different environmental conditions
Authors: Wan Leighton , Yoshikawa Alex , Eisenstein Michael , Soh H. Tom
Published: September 2022

Aptamers selected under specific environmental conditions (e.g., pH, ion concentration, temperature) often exhibit greatly reduced affinity when used in other contexts. This can be especially problematic for biomedical applications, in which aptamers are exposed to sample matrices with distinctive chemical properties, such as blood, sweat, or urine. We present a high-throughput screening procedure for adapting existing aptamers for use in samples whose chemical composition differs considerably from the original selection conditions. Building on prior work from our group, we have utilized a modified DNA sequencer to screen more than 106 aptamer single and double mutants for target binding under the desired assay conditions. As an exemplar, we screened mutants of a previously reported glucose aptamer that was originally selected in high-ionic strength buffer and exhibits relatively low affinity under physiological conditions. After a single round of screening, we identified aptamer mutants with ∼4-fold increased affinity under physiological conditions. Interestingly, we found that the impact of single-base substitutions was relatively modest, but observed considerably greater binding improvements among the double mutants, highlighting the importance of cooperative effects between mutations. This approach should be generalizable to other aptamers and environmental conditions for a range of applications.
Accessory-cell-free differentiation of hematopoietic stem and progenitor cells into mature red blood cells
Authors: Boccacci Yelena , Dumont Nellie , Doyon Yannick , Laganière Josée
Published: September 2022

The culture and ex vivo engineering of red blood cells (RBCs) can help characterize genetic variants, model diseases, and may eventually spur the development of applications in transfusion medicine. In the last decade, improvements to the in vitro production of RBCs have enabled efficient erythroid progenitor proliferation and high enucleation levels from several sources of hematopoietic stem and progenitor cells (HSPCs). Despite these advances, there remains a need for refining the terminal step of in vitro human erythropoiesis — i.e., the terminal maturation of reticulocytes into erythrocytes — so that it can occur without feeder or accessory cells and animal components. Here, we describe the near-complete erythroid differentiation of cultured RBCs (cRBCs) from adult HSPCs in accessory-cell-free and animal-component-free conditions. The approach improves post-enucleation cell integrity and cell survival, and enables subsequent storage of cRBCs for up to 42 days in classical nutritive solution conditions, without any specialized equipment. We foresee that these improvements will facilitate the characterization of RBCs derived from gene-edited HSPCs.

KEY POINTS

Erythroid progenitors were differentiated into fully mature RBCs in a medium free of accessory cells

Cultured RBCs can be stored up to 42 days in a standard nutritive solution
Removal of extracellular human amyloid beta aggregates by extracellular proteases inC. elegans
Authors: Jongsma Elisabeth , María Mateos José , Ewald Collin Y.
Published: September 2022

The amyloid-beta (Aβ) plaques found in Alzheimer’s disease (AD) patients’ brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance extracellular aggregatesin vivo, we created a transgenicCaenorhabditis elegansstrain that expresses and secretes human Aβ1-42. This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease ADM-2, an orthologue of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we providein-vivoevidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal.

Highlights

Extracellular aggregates of amyloid beta are a hallmark of Alzheimer’s disease. Here we developed a novelC. eleganstransgenic line that secretes human amyloid beta, which forms aggregates in the extracellular matrix (ECM). We show that ECM dynamics can disturb aggregation and that ADM-2, an ortholog of Human ADAM9, is involved in removing these extracellular aggregates.
Severe fatigue as symptom of long COVID is characterized by increased expression of inflammatory genes in monocytes, increased serum pro-inflammatory cytokines, and increased CD8+ T-lymphocytes: A putative dysregulation of the immune-brain axis, the coagulation process, and auto-inflammation to explain the diversity of long COVID symptoms
Authors: Berentschot Julia C. , Drexhage Hemmo A. , Aynekulu Mersha Daniel G. , Wijkhuijs Annemarie J.M. , GeurtsvanKessel Corine H. , Koopmans Marion P.G. , Voermans Jolanda , Heijenbrok-Kal Majanka H. , Bek L. Martine , Ribbers Gerard M. , van den Berg-Emons Rita J.G. , Aerts Joachim G.J.V , Dik Willem A. , Hellemons Merel E.
Published: September 2022

Background

A significant proportion of patients with SARS-CoV-2 infection develops long COVID with fatigue as one of the most disabling symptoms. We performed clinical and immunologic profiling of fatigued and non-fatigued long COVID patients and age and gender matched healthy controls (HCs).

Methods

We included 37 long COVID patients with and 36 without severe fatigue and assessed inflammation-related monocyte gene expression, serum levels of inflammatory cytokines, and leukocyte and lymphocyte subsets 3-6 months after hospital discharge, and followed clinical symptoms up to one year.

Results

Long COVID with fatigue represented a severe variant with many symptoms (median 9 [IQR 5.0-10.0] symptoms) and signs of cognitive failure (41%) and depression (>24%). Symptoms persisted up to one year follow-up. Fatigued patients showed increased expression of inflammatory genes in monocytes, increased serum IL-6, TNF-α, galectin-9, and CXCL10, and increased CD8+ T-lymphocytes compared to HCs.

Non-fatigued long COVID patients were arbitrarily divided in those with moderately severe disease (4 [2.5-5.0] symptoms, primarily impaired fitness, n=25) and those with mild disease (1 [1.0-2.0] symptom, n=11). Symptoms in non-fatigued long COVID patients persisted up to one year follow-up. Moderately severe patients showed reduced CD45RO-naïve CD4+T-lymphocytes and CD25+FOXP3+ regulatory CD4+T-lymphocytes and limited monocyte and serum (galectin-9) inflammation. Mild patients showed monocyte and serum (IL-6, galectin-9) inflammation and decreased CD4+T-lymphocyte subsets (T-helper 1 cells).

Conclusion

Long COVID with fatigue is associated with many concurrent and persistent symptoms up to one year after hospitalization and with clear signs of low grade inflammation and increased CD8+T-lymphocytes. We showed that long COVID is a clinical and immunologic heterogeneous disorder. Diagnostic tools and personalized therapies combatting the diverse immune abnormalities might be required to alleviate the persisting disabling complaints of the patients.
Single cell transcriptomics reveals correct developmental dynamics and high-quality midbrain cell types by improved hESC differentiation
Authors: Nishimura Kaneyasu , Yang Shanzheng , Lee Ka Wai , Ásgrímsdóttir Emilía Sif , Nikouei Kasra , Paslawski Wojciech , Gnodde Sabine , Lyu Guochang , Hu Lijuan , Saltó Carmen , Svenningsson Per , Hjerling-Leffler Jens , Linnarsson Sten , Arenas Ernest
Published: September 2022

Stem cell technologies provide new opportunities for modeling cells in the healthy and diseased states and for regenerative medicine. In both cases developmental knowledge as well as the quality and molecular properties of the cells are essential for their future application. In this study we identify developmental factors important for the differentiation of human embryonic stem cells (hESCs) into midbrain dopaminergic (mDA) neurons. We found that Laminin-511, and dual canonical and non-canonical WNT activation followed by GSK3β inhibition plus FGF8b, improved midbrain patterning. In addition, mDA neurogenesis and differentiation was enhanced by activation of liver X receptors and inhibition of fibroblast growth factor signaling. Moreover, single-cell RNA-sequencing analysis revealed a developmental dynamics similar to that of the endogenous human ventral midbrain and the emergence of high quality molecularly-defined midbrain cell types, including mDA neurons that become functional. Thus, our study identifies novel factors important for human midbrain development and opens the door for a future application of molecularly-defined hESC-derived midbrain cell types in Parkinson’s disease.
Accumulation of mitochondrial ROS drives reductive glutamine metabolism
Authors: Sheng Xiangpeng
Published: September 2022

Hypoxia, mitochondrial defect or extracellular matrix detachment induces reductive glutamine metabolism that can produce citrate by carboxylating the glutamine-derived ketoglutarate (α-KG). Reductive carboxylation is required for maintaining redox homeostasis, lipogenesis and cancer cell growth. However, the fundamental mechanism(s) of how reductive glutamine metabolism may be controlled is not fully understood. This study here demonstrates that mitochondrial-derived reactive oxygen species (ROS) positively drives reductive carboxylation. Knockout of fatty acid synthase (FASN) causes increased mitochondrial ROS and significant reductive glutamine metabolism. Mitochondrial ROS accumulation is identified as a shared feature in cells that utilize reductive metabolism. Moreover, ROS scavenger could inhibit reductive carboxylation by decreasing ROS level in mitochondria. By contrast, ROS inducers activate reductive carboxylation via increasing mitochondrial ROS. Mitochondrial ROS level determines the degree of reductive carboxylation with a positive correlation. The results presented here not only reveal a fundamental mechanism of how reductive carboxylation is controlled, but also elucidate a critical role of ROS in reprogramming metabolism.
Three-dimensional motions of GroEL during substrate protein recognition
Authors: Stapleton Kevin , Mizobata Tomohiro , Miyazaki Naoyuki , Takatsuji Tomohiro , Kato Takayuki , Iwasaki Kenji , Standley Daron M , Kawamura Takeshi , Nakane Takanori , Takagi Junichi , Mizohata Eiichi
Published: September 2022

GroEL is a bacterial chaperonin responsible for the assisted folding of non-native and misfolded polypeptides into biologically active proteins. The adaptive nature of the recognition mechanism of chaperonins toward client polypeptides inherently lends itself to structural heterogeneity, which hampers detailed analyses of intermolecular recognition and binding. In this report, we used single-particle cryo-EM and multiple rounds of focused mask three-dimensional classification to reveal a landscape of distinct snapshots of endogenous GroEL complexed with an unfolded substrate, the water-soluble domain of human UDP glucuronosyltransferase 1A (UGT1A), at 2.7–3.5 Å resolution. We demonstrate that UGT1A occupies the GroEL ring asymmetrically, engaging with 2–3 contiguous subunits and that a subunit bound to UGT1A exhibits a wider range of conformational dynamics, consistent with AlphaFold models. These data reveal molecular motions during initial substrate capture at near-atomic detail.
PCNA recruits cohesin loader Scc2/NIPBL to ensure sister chromatid cohesion
Authors: Psakhye Ivan , Kawasumi Ryotaro , Abe Takuya , Hirota Kouji , Branzei Dana
Published: September 2022

Sister chromatid cohesion is essential for faithful chromosome segregation and genome duplication during cell division. Failure to establish cohesion during S phase by the ring-shaped multiprotein complex cohesin leads to genomic instability1-4. Replisome-associated proteins are required to generate cohesion by two independent pathways5. One mediates conversion of cohesins bound to unreplicated DNA ahead of replication forks into cohesive entities behind them, while the second promotes cohesin de novo loading onto newly-replicated DNAs6. The latter process depends on the cohesin loader Scc2/NIPBL and the alternative PCNA loader CTF18-RFC. However, the precise mechanism of de novo cohesin loading during replication is unknown. Here we show that PCNA physically recruits yeast cohesin loader Scc2 via its C-terminal PCNA-interacting protein motif. Binding to PCNA is crucial, as scc2-pip mutant deficient in Scc2-PCNA interaction is defective in cohesion when combined with replisome mutants of the cohesin conversion pathway. Moreover, scc2-pip mutant becomes inviable without its partner Scc4/MAU2 that localizes cohesin loader to centromeres. Importantly, the role of NIPBL recruitment to PCNA for cohesion generation is conserved in vertebrate cells. Our results demonstrate that PCNA, the maestro of replication-linked functions, is also crucially involved in the cohesion establishment through de novo cohesin loading onto replicated DNA.
ADRA2B and HTR1A: An updated study of the biogenic amine receptors reveals novel conserved motifs which play key role in Mental Disorders
Authors: Papageorgiou Louis , Christou Evangelia , Louka Effrosyni , Papakonstantinou Eleni , Diakou Io , Pierouli Katerina , Dragoumani Konstantina , Bacopoulou Flora , Chrousos George P , Eliopoulos Elias , Vlachakis Dimitrios
Published: September 2022

Mental disorders are strongly connected with several psychiatric conditions including depression, bipolar disorder, schizophrenia, eating disorder and suicides. There are many biological conditions and pathways that define these complicated illnesses. For example, eating disorders are complex mental health conditions that require the intervention of geneticists, psychiatrists and medical experts in order to alleviate their symptoms. A patient with suicidal ideation should first be identified and consequently monitored by a similar team of specialists. Both genetics and epigenetics can shed light on eating disorders and suicides as they are found in the main core of such investigations. In the present study, an analysis has been performed on two specific members of the GPCR family towards drawing conclusions regarding their functionality and implementation in mental disorders. Specifically, evolutionary and structural studies on the adrenoceptor alpha 2b (ADRA2B) and the 5-hydroxytryptamine receptor 1A (HTR1A) have been carried out. Both receptors are classified in the biogenic amine receptors sub-cluster of the GPCRs and have been connected in many studies with mental diseases and malnutrition conditions. The major goal of this study is the investigation of conserved motifs among biogenic amine receptors that play an important role in this family signaling pathway, through an updated evolutionary analysis and the correlation of this information with the structural features of the HTR1A and ADRA2B. Furthermore, structural comparison of ADRA2B, HTR1A, and other members of GPCRs related with mental disorders is performed.
Influence of temperature on growth and development of dictyostelid slime moulds and its implication on the evolution of cold-tolerance
Authors: Hashimura Hidenori , Inouye Kei
Published: September 2022

Environmental temperature is a major determinant of microbial life. Dictyostelids are soil amoebae capable of multicellular social behaviour upon starvation. They inhabit in a variety of environments from the tundra to the tropics, but how they have adapted to environmental temperature remains largely unknown. In this study, the effects of temperature on the growth and multicellular development of 36 dictyostelid species (58 strains/isolates) were examined. More than half of the species showed maximal growth and normal development at 28°C or above, whereas some could grow and develop at 4°C, or even at 0°C. Many of the isolates examined were from areas with temperatures far lower than their preferred range over a large part of the year. There was a significant correlation between thermal characteristics and phylogeny. Over 150 known dictyostelid species are divided into several taxonomic groups. Our phylogenetic analysis indicated that cold-tolerance evolved independently in major clades, most prominently in group 4 (genus Dictyostelium according to the new classification by Sheikh et al.), which contains many species that are often found in subarctic regions. These results suggest that ancestors that have acquired cold-tolerance expanded their ranges into cooler areas where they could proliferate and develop during summer and survive the severe winter.