bluuebunny/crossref_metadata_2025 huggingface dataset:
SYST-10 CSNO2012001 STUDY: A PHASE III TRIAL ON ADJUVANT TEMOZOLOMIDE CHEMOTHERAPY WITH OR WITHOUT INTERFERON-ALPHA IN NEWLY DIAGNOSED HIGH-GRADE GLIOMAS
Authors: Chen Zhongping , Guo Chengcheng
Published: August 2022

PURPOSE

The therapeutic efficacy and toxicity of the combination of temozolomide (TMZ) with interferon-alpha (IFN-α) and TMZ alone were compared in newly diagnosed high-grade glioma (HGG) patients.

PATIENTS AND METHODS

Following surgery, patients with newly diagnosed HGG were eligible and randomized into two groups. All the patients received standard radiotherapy concurrent with TMZ. After a 4-week break, patients in group A received standard TMZ (200mg/m2 for 5 days) combined with interferon-α (3mIU, subcutaneous, d1, d3, and d5) every 28 days. Patients in group B received standard TMZ.

RESULTS

A total of 199 HGG patients were enrolled, with a median follow-up time of 77.9 months. The median overall survival (OS) of patients in the TMZ+IFN group was significantly longer than that in the standard group (TMZ+IFN: 26.67 months, TMZ: 18.83 months, P=0.005), although the progression-free survival (PFS) of both groups was similar (TMZ+IFN:14.83 months, TMZ:12.90months, P=0.114). In grade 3 gliomas, the median OS was 39.57 months in the TMZ+IFN group versus 29.40 months in TMZ alone (P=0.043). The median PFS was also longer in the TMZ+IFN group (24.33 months) than that in the TMZ group (14.13 months) (P=0.046). In grade 4 gliomas, the difference in PFS survival between TMZ+IFN and TMZ group showed no significant difference (TMZ+IFN:12.00 months, TMZ:12.83 months, P=0.582). However, the TMZ+IFN group had a longer OS than that of the TMZ alone group (TMZ+IFN:20.53 months, TMZ:17.70 months, P=0.044). TMZ+IFN also significantly improved the OS in O6-methylguanine-DNA methyltransferase (MGMT) unmethylation patients. The incidence of toxic effects such as neutropenia, thrombocytopenia, anemia, increased transaminase, skin reactions, fatigue, nausea, or vomiting, and skin reactions were similar in both groups.

CONCLUSIONS

Compared with the standard regimen, TMZ+IFN combination treatment could prolong the survival time of HGG patients, especially MGMT promoter unmethylated patients, and the toxicity remained tolerable.
Safety of the utilization of telemedicine for brain tumor neurosurgery follow-up
Authors: Morell Alexis A , Patel Nitesh V , Eatz Tiffany A , Levy Adam S , Eichberg Daniel G , Shah Ashish H , Luther Evan , Lu Victor M , Kader Michael , Higgins Dominique M O , Ivan Michael E , Komotar Ricardo J
Published: August 2022

Background

There is a need to evaluate the outcomes of patients who underwent brain tumor surgery with subsequent telemedicine or in-person follow-up during the COVID-19 pandemic.

Methods

We retrospectively included all patients who underwent surgery for brain tumor resection by a single neurosurgeon at our Institution from the beginning of the COVID-19 pandemic restrictions (March 2020) to August 2021. Outcomes were assessed by stratifying the patients using their preference for follow-up method (telemedicine or in-person).

Results

Three-hundred and eighteen (318) brain tumor patients who were included. The follow-up method of choice was telemedicine (TM) in 185 patients (58.17%), and in-person (IP) consults in 133 patients. We found that patients followed by TM lived significantly farther, with a median of 36.34 miles, compared to a median of 22.23 miles in the IP cohort (P = .0025). We found no statistical difference between the TM and the IP group, when comparing visits to the emergency department (ED) within 30 days after surgery (7.3% vs 6.01%, P = .72). Readmission rates, wound infections, and 30-day mortality were similar in both cohorts. These findings were also consistent after matching cohorts using a propensity score. The percentage of telemedicine follow-up consults was higher in the first semester (73.17%) of the COVID-19 pandemic, compared to the second (46.21%), and third semesters (47.86%).

Conclusions

Telehealth follow-up alternatives may be safely offered to patients after brain tumor surgery, thereby reducing patient burden in those with longer distances to the hospital or special situations as the COVID-19 pandemic.
Gamma-ray bursts, supernovae Ia, and baryon acoustic oscillations: A binned cosmological analysis
Authors: Dainotti Maria Giovanna , Sarracino Giuseppe , Capozziello Salvatore
Published: August 2022

Cosmological probes at any redshift are necessary to reconstruct consistently the cosmic history. Studying properly the tension on the Hubble constant, H0, obtained by supernovae type Ia (SNe Ia) and the Planck measurements of the cosmic microwave background radiation would require complete samples of distance indicators at any epoch. Gamma-ray bursts (GRBs) are necessary for the aforementioned task because of their huge luminosity that allows us to extend the cosmic ladder to very high redshifts. However, using GRBs alone as standard candles is challenging, because their luminosity varies widely. To this end, we choose a reliable correlation for GRBs with a very small intrinsic scatter: the so-called fundamental plane correlation for GRB afterglows corrected for selection biases and redshift evolution. We choose a well defined sample: the platinum sample, composed of 50 long GRBs. To further constrain the cosmological parameters, we use baryon acoustic oscillations (BAOs) given their reliability as standard rulers. Thus, we have applied GRBs, SNe Ia, and BAOs in a binned analysis in redshifts so that the GRB contribution is fully included in the last redshift bin, which reaches z = 5. We use the fundamental plane correlation (also known as the 3D Dainotti relation), together with SNe Ia and BAOs, to constrain H0 and the density matter today, ΩM. This methodology allows us to assess the role of GRBs combined with SNe Ia and BAOs. We have obtained results for H0 and ΩM using GRBs+SNe Ia+BAOs with better precision than SNe Ia alone for every bin, thus confirming the beneficial role of BAOs and GRBs added together. In addition, consistent results between GRBs+SNe Ia+BAOs are obtained when compared with SNe Ia+BAOs, showing the importance of GRBs since the distance ladder is extended up to z = 5 with a similar precision obtained with other probes without including GRBs.
Infrequent Random Portfolio Decisions in an Open Economy Model
Authors: Bacchetta Philippe , van Wincoop Eric , Young Eric R
Published: August 2022

We introduce a portfolio friction in a two-country DSGE model where investors face a constant probability to make new portfolio decisions. The friction leads to a more gradual portfolio adjustment to shocks and a weaker portfolio response to changes in expected excess returns. We apply the model to monthly data for the US and the rest of the world for equity portfolios. We show that the model is consistent with a broad set of evidence related to portfolios, equity prices, and excess returns for an intermediate level of friction. The evidence includes portfolio inertia, limited sensitivity to expected excess returns, a significant impact of financial shocks, excess return predictability, and asset price momentum and reversal.
Comparing Past and Present Inflation
Authors: Bolhuis Marijn A , Cramer Judd N L , Summers Lawrence H
Published: August 2022

There have been important methodological changes in the Consumer Price Index (CPI) over time. These distort comparisons of inflation from different periods, which have become more prevalent as inflation has risen to 40-year highs. To better contextualize the current run-up in inflation, this article constructs new historical series for CPI headline and core inflation that are more consistent with current practices and expenditure shares for the post-war period. Using these series, we find that current inflation levels are much closer to past inflation peaks than the official series would suggest. In particular, the rate of core CPI disinflation caused by Volcker-era policies is significantly lower when measured using today’s treatment of housing: only 5 percentage points of decline instead of 11 percentage points in the official CPI statistics.
Treatments for Social Interaction Impairment in Animal Models of Schizophrenia: A Critical Review and Meta-analysis
Authors: Hazani Reut , Lavidor Michal , Weller Aron
Published: August 2022

Background

While pharmacological treatments for positive symptoms of schizophrenia are widely used, their beneficial effect on negative symptoms, particularly social impairment, is insufficiently studied. Therefore, there is an increasing interest in preclinical research of potentially beneficial treatments, with mixed results. The current review aims to evaluate the efficacy of available treatments for social deficits in different animal models of schizophrenia.

Study Design

A systematic literature search generated 145 outcomes for the measures “total time” and “number” of social interactions. Standardized mean differences (SMD) and 95% confidence interval (CI) were calculated, and heterogeneity was tested using Q statistics in a random-effect meta-analytic model. Given the vast heterogeneity in effect sizes, the animal model, treatment group, and sample size were all examined as potential moderators.

Study Results

The results showed that in almost all models, treatment significantly improved social deficit (total time: SMD = 1.24; number: SMD = 1.1). The moderator analyses discovered significant subgroup differences across models and treatment subgroups. Perinatal and adult pharmacological models showed the most substantial influence of treatments on social deficits, reflecting relative pharmacological validity. Furthermore, atypical antipsychotic drugs had the highest SMD within each model subgroup.

Conclusions

Our findings indicate that the improvement in social interaction behaviors is dependent on the animal model and treatment family used. Implications for the preclinical and clinical fields are discussed.
Cutaneous Ganglioneuromas With Overlying Epidermal Hyperplasia: A Case Series Presentation and Proposal of Potential Etiopathogenesis
Authors: Zuraski Connor R. , Wales Cameron , Nguyen Cuong V. , Chan Edward F. , Kovarik Carrie , Seykora John T. , Elenitsas Rosalie , Moshiri Ata S.
Published: August 2022

Cutaneous ganglioneuromas (GNs) are exceptionally uncommon tumors, and many reported cases describe association with overlying epidermal hyperplasia that may be interpreted as seborrheic keratosis (SK) or SK-like proliferation. We report 5 cases of cutaneous GN in adult patients; all of which were discovered incidentally in the immediate vicinity of epidermal hyperplasia. A review of the literature demonstrates the current—although likely imperfect—understanding of the etiopathogenesis of both SK and GN in the skin. We explore the putative pathophysiologies of other common, well-characterized skin lesions and, taking them into account, provide rationale for the coexistence of cutaneous GN with overlying SK and SK-like epidermal changes. However, we ultimately acknowledge a dilemma of causality and, given the rarity of their co-occurrence, objectively question whether occasional cameo appearances by GN lying subjacent to SK and SK-like hyperplasia may be due merely to chance.
Double CD4/CD8-Positive, Nonpoikilodermic Mycosis Fungoides Expressing CD56 in a Young Man
Authors: Santonja Carlos , Sánchez-García Francisco-Javier , Rodríguez-Rodríguez Rosa-Nieves , Manso Rebeca , Requena Luis , Gil-Mateo María del Pino , Rodríguez-Pinilla Socorro-María
Published: August 2022

We report a case of mycosis fungoides (MF) in an 18-year-old man whose neoplastic T cells expressed CD4, CD8, and CD56, with no evidence of TCR-delta or Epstein–Barr virus (EBER) expression. Clinically, neither hypopigmentation nor hyperpigmentation nor poikilodermatous skin lesions were present, and the lesions subsided with oral corticoids and retinoids and environmental solar ultraviolet exposure. Our case represents the oldest patient reported so far with nonpoikilodermatous, CD8/CD56 MF and adds to the phenotypic diversity of MF in the pediatric population. This distinct phenotype does not seem to be linked to a more aggressive course than the classic CD-4 positive one.
Improvement in the Capacity for Activity Versus Improvement in Performance of Activity in Daily Life During Outpatient Rehabilitation
Authors: Lang Catherine E. , Holleran Carey L. , Strube Michael J , Ellis Terry D. , Newman Caitlin A. , Fahey Meghan , DeAngelis Tamara R. , Nordahl Timothy J. , Reisman Darcy S. , Earhart Gammon M. , Lohse Keith R. , Bland Marghuretta D.
Published: August 2022

Background and Purpose:

We addressed questions about the potential discrepancy between improvements in activity capacity and improvements in activity performance in daily life. We asked whether this discrepancy is:

Common in routine, outpatient care, or an artifact of intervention studies?

Unique to upper limb (UL) rehabilitation, or is it seen in walking rehabilitation too?

Only seen in persons with stroke, or a broader neurorehabilitation problem?

Methods:

A longitudinal, observational cohort of 156 participants with stroke or Parkinson disease (PD) receiving outpatient rehabilitation at 5 clinics was assessed around admission and monthly during their episode of care. Individual, longitudinal capacity (Action Research Arm Test or walking speed) and performance (wearable sensor measurements of use ratio or steps/day) data were modeled to extract predicted change scores. Simulation methods were used to determine whether an individual's change was greater than 1 standard error. Participants were classified into categories based on whether or not they improved in capacity (C+ or C−) and/or performance (P+ or P−).

Results:

A majority (59%) were classified as C+P−. Smaller portions of the sample were classified as C+P+ (20%) and C−P− (21%), with 1 participant (<1%) classified as C−P+. The proportions in the C+P− category were significantly larger in the stroke (χ2 = 48.7, P < 0.0001) and PD (χ2 = 24.3, P < 0.0001) walking subgroups than in the stroke UL subgroup.

Discussion and Conclusions:

The discrepancy between improvements in capacity and performance is a problem in routine, outpatient neurorehabilitation. If performance information were available, patients and clinicians could act to address it.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A396).
Cochlear Implantation in Noonan Syndrome With and Without Multiple Lentigines: A Case Report and Systematic Review
Authors: Blumenthal Daniel , Lovett Braeden , Leonard James , Wang Sixian , Blumgart Melissa , Hoa Michael
Published: August 2022

Objectives:

To describe outcomes after bilateral cochlear implantation (CI) in a patient with a pathologic PTPN11 variant associated with Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML). Additionally, to assess the utility of CI in this specific population based on our outcome and previous reports.

Study Design:

Retrospective case report with literature review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Patients:

A young boy with various multiorgan abnormalities, speech and language delay, and persistent hearing loss who was found to have a heterozygous PTPN11 gene mutation at age 2.

Interventions:

Bilateral tympanostomy tube placement, diagnostic imaging, and eventual staged bilateral CI.

Main Outcome Measures:

Objective audiometric testing and developmental milestone attainment.

Results:

Bilateral CI was successfully completed over a 2-month period. The patient illustrated significant improvement in objective audiologic measurement. However, he continues to sign as his main form of communication without significant speech progression.

Conclusions:

Early diagnostic and therapeutic intervention in patients with NS/NSML can help improve long-term audiologic and speech development. Given the heterogeneity of NS/NSML, a multidisciplinary approach is needed for optimal outcomes.
18F-FDG PET/CT Findings of MALT Lymphoma of Ureter
Authors: He Limeng , Deng Yujiao , Deng Ying , Xie Hongjun , Zhang Wei
Published: August 2022

Mucosa-associated lymphoid tissue (MALT) lymphoma origin from the ureter is exceedingly rare. We report FDG PET/CT findings of MALT lymphoma in the distal right ureter in a 55-year-old woman who presented right abdominal pain for 10 days. Ultrasound revealed a hypoechoic mass in the right pelvis, which was surrounding the distal right ureter. 18F-FDG PET/CT demonstrated a high FDG uptake by the mass along with several FDG-avid enlarged lymph nodes in the abdominal cavity. Postoperative pathology demonstrated the ureteral mass as a MALT lymphoma.
The evolving scenario of cancer care provision across the COVID-19 pandemic in Europe
Authors: Tagliamento Marco , Poggio Francesca , Perachino Marta , Pirrone Chiara , Fregatti Piero , Lambertini Matteo
Published: August 2022

Purpose of review

Over the past 2 years, the COVID-19 pandemic has had short-term and long-term effects on the delivery of cancer care. Some European countries faced an unprecedented widespread crisis during the first year of the SARS-CoV-2 pandemic, only being able afterwards to gradually recover, thanks to the improvement in preventive measures, changes in public health and reactive processes in cancer care and a better understanding of the ongoing heath emergency.

Recent findings

The development of SARS-CoV-2 vaccines and COVID-19 specific treatments, the growing testing and tracking capability to limit virus diffusion, and research efforts to better define areas of action have all greatly limited the negative impact of the health emergency on routine cancer care.

The need to protect those more vulnerable and to ensure continuity of care for oncology patients has been balanced across the pandemic, with the aim to guarantee an optimal standard of care.

This article aims to provide an overview on the evolving scenario of cancer care throughout the COVID-19 pandemic in Europe, focusing on the particular features that characterized the pandemic course as well as the main differences that were observed across it.
Assessment of the Optic Disc and Retinal Microvasculature by Optical Coherence Tomography Angiography in Patients With Pediatric Migraine
Authors: Kurtul Bengi Ece , Sipal Cansu , Akbas Yilmaz
Published: August 2022

Background:

Migraine, as a chronic neurovascular disease, is known to be a risk factor for retinal and optic nerve head damage. Herein, we aimed to evaluate the optic disc and retinal microvasculature in pediatric migraine (PM) patients using optical coherence tomography angiography (OCTA).

Methods:

Forty-six eyes of 23 patients with PM without aura (PM group) and 46 eyes of 23 age- and sex-matched healthy subjects (control group) were included in this cross-sectional prospective study. Demographic features and ophthalmological examination including OCTA measurements were evaluated. OCTA was performed with 6- × 6-mm sections for macula and 4.5- × 4.5-mm sections for optic nerve head in all eyes. Foveal retinal thickness (FRT), peripapillary retinal nerve fiber layer (RNFL) thickness, vessel density in different sections of the retina, and optic disc were analyzed and compared between the groups. All measurements of the PM patients were taken in the attack-free period.

Results:

The mean ages of the PM group and control group were 11.17 ± 3.3 and 11.83 ± 2.8 years, respectively (P = 0.479). Gender and mean intraocular pressures were similar between the groups. The mean central corneal thickness levels in the PM group were significantly lower than control group, 548.28 ± 26.3 µm and 562.04 ± 24.5 µm, respectively (P = 0.011). There was no significant difference regarding average and all quadrant RNFL thicknesses, foveal avascular zone and flow areas, deep vessel densities, and optic disc capillary densities between the groups. However, compared with the control group, the PM group showed significant higher values of FRT, and lower values of superficial whole and parafoveal vessel densities (247.28 ± 15.8 µm vs 285.93 ± 11.1, P < 0.001, 51.85 ± 2.4% vs 50.31 ± 4.0%, P = 0.02, 55.09 ± 2.3% vs 53.5 ± 3.5%, P = 0.01, respectively). Disease duration and attacks/year did not show any significant correlations with OCTA values.

Conclusions:

PM seems to be associated with lower superficial whole and parafoveal vessel densities because of hypoperfusion and ischemia. OCTA may be suggested for use in follow-up and management of PM patients.
Optimal drug treatment for reducing long-term drug resistance
Authors: Ghodsi Asnaashari Tina , Chang Young Hwan
Published: August 2022

The maximum-tolerated dose principle, the highest possible drug dose in the shortest possible time period, has been the standard care for cancer treatment. Although it is appealing in a homogeneous tumor settings, tumor heterogeneity and adaptation play a significant role in driving treatment failure. They are still major obstacles in cancer treatments despite great advances in modeling and cancer therapy using optimal control theory. To address this, we first generalize two population models and examine the long-term effects of differential selective treatment strategies. Second, we take into account different drug-imposed selective pressure into designing optimal treatment strategies. Numerical examples demonstrate that the proposed treatment strategy decreases long-term tumor burden by decreasing the rate of tumor adaptation.
Eco-evolutionary feedback can stabilize diverse predator-prey communities
Authors: Martis Stephen
Published: August 2022

Ecological models with random interactions have provided insight into the problem of diversity, particularly showing that high variance in the distribution of interaction rates can lead to instability, chaos and extinction. However, these models have traditionally neglected evolution, which is central to the generation of biological variation and can act on timescales comparable to ecological change. We demonstrate that when a stochastic predator-prey system is coupled to high-dimensional evolutionary dynamics, high variance interactions counter-intuitively stabilize the population, delaying extinction and increasing the total population size. Using both stochastic and deterministic simulations and theory based on the statistical physics of disordered systems, this stabilizing effect is shown to be driven by an eco-evolutionary feedback loop which causes the population size to grow as a power law of the variance of the interactions. We show that the stable regime corresponds with the clonal interference regime of population genetics. We conjecture that qualitative aspects of our results generalize to other evolving complex systems.
Impact of diabetes on longevity and disability-free life expectancy among older South African adults: a prospective longitudinal analysis
Authors: Payne Collin F. , Liwin Lilipramawanty K. , Wade Alisha N. , Houle Brian , Du Toit Jacques D. , Flood David , Manne-Goehler Jennifer
Published: August 2022

Objective

We seek to understand the coexisting effects of population aging and a rising burden of diabetes on healthy longevity in South Africa.

Research Design and Methods

We used longitudinal data from the 2015 and 2018 waves of the “Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa” (HAALSI) study to explore life expectancy (LE) and disability-free life expectancy (DFLE) of adults aged 45 and older with and without diabetes in rural South Africa. We estimated LE and DFLE by diabetes status using Markov-based microsimulation.

Results

We find a clear gradient in remaining LE and DFLE based on diabetes status. At age 45, a man without diabetes could expect to live 7.4 [95% CI 3.4 – 11.7] more years than a man with diabetes, and a woman without diabetes could expect to live 3.9 [95% CI: 0.8 – 6.9] more years than a woman with diabetes. Individuals with diabetes lived proportionately more years subject to disability than individuals without diabetes. Additional analyses separating individuals with diabetes based on whether they knew their disease status found that individuals with diabetes diagnosed by a healthcare worker had shorter remaining LE than those who were unaware of their status or those without diabetes.

Conclusions

Our findings highlight the large and important decrements in healthy, disability-free aging for people with diabetes in South Africa. This finding should motivate efforts to strengthen prevention and treatment efforts for diabetes and its complications for older adults in this setting.
Deep Learning for Automatic Segmentation of Vestibular Schwannoma: A Retrospective Study from Multi-Centre Routine MRI
Authors: Kujawa Aaron , Dorent Reuben , Connor Steve , Thomson Suki , Ivory Marina , Vahedi Ali , Guilhem Emily , Wijethilake Navodini , Bradford Robert , Kitchen Neil , Bisdas Sotirios , Ourselin Sebastien , Vercauteren Tom , Shapey Jonathan
Published: August 2022

Automatic segmentation of vestibular schwannoma (VS) from routine clinical MRI has potential to improve clinical workflow, facilitate treatment decisions, and assist patient management. Previous work demonstrated reliable automatic segmentation performance on datasets of standardised MRI images acquired for stereotactic surgery planning. However, diagnostic clinical datasets are generally more diverse and pose a larger challenge to automatic segmentation algorithms, especially when post-operative images are included. In this work, we show for the first time that automatic segmentation of VS on routine MRI datasets is also possible with high accuracy.

We acquired and publicly release a curated multi-centre routine clinical (MC-RC) dataset of 160 patients with a single sporadic VS. For each patient up to three longitudinal MRI exams with contrast-enhanced T1-weighted (ceT1w) (n=124) and T2-weighted (T2w) (n=363) images were included and the VS manually annotated. Segmentations were produced and verified in an iterative process: 1) initial segmentations by a specialized company; 2) review by one of three trained radiologists; and 3) validation by an expert team. Inter- and intra-observer reliability experiments were performed on a subset of the dataset. A state-of-the-art deep learning framework was used to train segmentation models for VS. Model performance was evaluated on a MC-RC hold-out testing set, another public VS datasets, and a partially public dataset.

The generalizability and robustness of the VS deep learning segmentation models increased significantly when trained on the MC-RC dataset. Dice similarity coefficients (DSC) achieved by our model are comparable to those achieved by trained radiologists in the inter-observer experiment. On the MC-RC testing set, median DSCs were 86.2(9.5) for ceT1w, 89.4(7.0) for T2w and 86.4(8.6) for combined ceT1w+T2w input images. On another public dataset acquired for Gamma Knife stereotactic radiosurgery our model achieved median DSCs of 95.3(2.9), 92.8(3.8), and 95.5(3.3), respectively. In contrast, models trained on the Gamma Knife dataset did not generalise well as illustrated by significant underperformance on the MC-RC routine MRI dataset, highlighting the importance of data variability in the development of robust VS segmentation models.

The MC-RC dataset and all trained deep learning models were made available online.
MitoStores: Chaperone-controlled protein granules store mitochondrial precursors in the cytosol
Authors: Krämer Lena , Dalheimer Niko , Räschle Markus , Storchová Zuzana , Pielage Jan , Boos Felix , Herrmann Johannes M.
Published: August 2022

Hundreds of mitochondrial precursor proteins are synthesized in the cytosol and imported into mitochondria in a post-translational reaction. The early processes associated with mitochondrial protein targeting remain poorly understood. Here we show that in baker’s yeast, the cytosol has the capacity to transiently store matrix-destined precursors in dedicated deposits which we named MitoStores. MitoStores are strongly enhanced when protein import into mitochondria is competitively inhibited by a clogging of mitochondrial import sites, but also formed under physiological conditions when cells grow on non-fermentable carbon sources. MitoStores are enriched for a specific subset of nuclear encoded mitochondrial proteins, in particular those containing N-terminal mitochondrial targeting sequences. MitoStore formation is controlled by the heat shock proteins Hsp42 and Hsp104, potentially to suppress the toxic potential of accumulating mitochondrial precursor proteins. Thus, the cytosolic protein quality control system plays an active role during early stages in mitochondrial protein targeting by the coordinated and localized sequestration of mitochondrial precursor proteins.

The yeast cytosol can deposit precursors of mitochondrial proteins in specific granules called MitoStores. MitoStores are controlled by the cytosolic chaperone system, in particular by Hsp42 and Hsp104. MitoStore formation suppresses the toxicity arising from non-imported mitochondrial precursor proteins.
Fiber Diameter and Architecture Direct Three-Dimensional Assembly of Pericytes into Spheroids
Authors: Sharma Sharan , Hill Jennifer C. , Phillippi Julie A. , Nain Amrinder S.
Published: August 2022

Due to their physiological relevance, multicellular 3D spheroids are actively replacing standard 2D monolayer cultures. How spheroids are formed through the assembly of individual cells in natural fibrous environments that include a mix of diameters and architectures in vivo remains unknown. Here, we demonstrate that the spontaneous assembly of human vasa vasorum-derived pericytes in 3D spheroids depends on the fiber diameter and network architecture. A parallel arrangement of suspended fibers of all tested diameters (200, 500, and 800 nm) leads to the formation of spheroids, while on crosshatch networks, spheroid assembly on larger diameters is absent. The design of fibrous networks of a mix of diameters and architectures leads to the patterning of spheroids in desired locations. Fiber remodeling in parallel arrangements serves as force sensors providing mechanical insights into the assembly dynamics of spheroids and subsequent cell sprouting from spheroids. Translocation and merger of spheroids occur predominantly on parallel fiber networks, while on crosshatch networks, a cellular exchange is observed between spheroids connected with remodeled fibers. Rho kinase inhibition by Y27632 and subsequent wash-off leads to spheroid disintegration and reassembly, thus, highlighting the role of cell contractility in the assembly and integrity of 3D spheroids. Overall, using extracellular mimicking fiber networks of varying diameters and architectures, we report new insights into the 3D dynamics of spheroids which may inform pericyte’s role in vasculogenesis, and (patho)physiological angiogenesis
Exploiting the Nonlinear Structure of the Antithetic Integral Controller to Enhance Dynamic Performance
Authors: Filo Maurice , Kumar Sant , Anastassov Stanislav , Khammash Mustafa
Published: August 2022

The design of biomolecular feedback controllers has been identified as an important goal across a broad range of biological applications spanning synthetic biology, cell therapy, metabolic engineering, etc. This originates from the need to regulate various cellular processes in a robust and timely fashion. Recently, antithetic integral controllers found their way into synthetic biology due to the Robust Perfect Adaptation (RPA) property they endow — the biological analogue of robust steady-state tracking. The antithetic integral motif hinges on a sequestration reaction between two molecules that annihilates their function. Here, we demonstrate that the complex resulting from the nonlinear sequestration reaction can be leveraged as an inhibitor to enhance the dynamic performance while maintaining the RPA property. We establish that this additional inhibition by the sequestration complex gives rise to a filtered Proportional-Integral (PI) controller thus offering more flexibility in shaping the dynamic response and reducing cell-to-cell variability. Furthermore, we explore the effect of various biological inhibitory mechanisms on the overall performance. The various analyses in the paper are carried out using analytical tools and are supported by numerical simulations. Finally, an experimental validation is performed using the cyberloop — a hybrid platform where the controller is implemented in silico to control a genetic circuit in vivo.
Water salinity does not affect acute thermal tolerance (CTmax) in zebrafish (Danio rerio)
Authors: Åsheim Eirik R. , Andreassen Anna H. , Morgan Rachael , Silvestre Mireia , Jutfelt Fredrik
Published: August 2022

Tolerance against acute warming is an essential trait that can determine how organisms cope during heatwaves, yet the mechanisms underlying it remain elusive. Water salinity has previously been shown to modulate thermal tolerance and may therefore provide clues towards these limiting mechanisms. Here we tested whether short (2 hours) and long (10 days) term exposure to different water salinities (0-5 ppt) affected acute thermal tolerance in zebrafish (N=269). We found that water salinity did not affect the thermal tolerance of zebrafish at either time point, indicating that salinity does not affect the mechanism limiting acute thermal tolerance limits in zebrafish. We did, however, observe unexpected behaviour during the CTmax test in a subset of fish in the highest salinity treatment after 10 days (3 ppt), indicating some form of salinity-driven disturbance during warming.
Longitudinal metatranscriptomic sequencing of Southern California wastewater representing 16 million people from August 2020-21 reveals widespread transcription of antibiotic resistance genes
Authors: Rothman Jason A. , Saghir Andrew , Chung Seung-Ah , Boyajian Nicholas , Dinh Thao , Kim Jinwoo , Oval Jordan , Sharavanan Vivek , York Courtney , Zimmer-Faust Amity G. , Langlois Kylie , Steele Joshua A. , Griffith John F. , Whiteson Katrine L.
Published: August 2022

Municipal wastewater provides a representative sample of human fecal waste across a catchment area and contains a wide diversity of microbes. Sequencing wastewater samples provides information about human-associated and medically-important microbial populations, and may be useful to assay disease prevalence and antimicrobial resistance (AMR).

Here, we present a study in which we used untargeted metatranscriptomic sequencing on RNA extracted from 275 sewage influent samples obtained from eight wastewater treatment plants (WTPs) representing approximately 16 million people in Southern California between August 2020 – August 2021. We characterized bacterial and viral transcripts, assessed metabolic pathway activity, and identified over 2,000 AMR genes/variants across all samples. Because we did not deplete ribosomal RNA, we have a unique window into AMR carried as ribosomal mutants. We show that AMR diversity varied between WTPs and that the relative abundance of many individual AMR genes/variants increased over time and may be connected to antibiotic use during the COVID-19 pandemic. Similarly, we detected transcripts mapping to human pathogenic bacteria and viruses suggesting RNA sequencing is a powerful tool for wastewater-based epidemiology and that there are geographical signatures to microbial transcription. We captured the transcription of gene pathways common to bacterial cell processes, including central carbon metabolism, nucleotide synthesis/salvage, and amino acid biosynthesis. We also posit that due to the ubiquity of many viruses and bacteria in wastewater, new biological targets for microbial water quality assessment can be developed.

To the best of our knowledge, our study provides the most complete longitudinal metatranscriptomic analysis of a large population’s wastewater to date and demonstrates our ability to monitor the presence and activity of microbes in complex samples. By sequencing RNA, we can track the relative abundance of expressed AMR genes/variants and metabolic pathways, increasing our understanding of AMR activity across large human populations and sewer sheds.
The association between experience of COVID-19-related discrimination and psychological distress among healthcare workers for six national medical research centers in Japan
Authors: Shrestha Rachana Manandhar , Inoue Yosuke , Yamamoto Shohei , Fukunaga Ami , Sampei Makiko , Okubo Ryo , Morisaki Naho , Ohmagari Norio , Funaki Takanori , Ishizuka Kazue , Yamaguchi Koushi , Sasaki Yohei , Takeda Kazuyoshi , Miyama Takeshi , Kojima Masayo , Nakagawa Takeshi , Nishimura Kunihiro , Ogata Soshiro , Umezawa Jun , Tanaka Shiori , Inoue Manami , Konishi Maki , Miyo Kengo , Mizoue Tetsuya
Published: August 2022

Background

Discrimination has been identified as an important determinant of negative mental health outcomes. This study determined the association between the experience of COVID-19-related discrimination and psychological distress among healthcare workers (HCWs) in Japan.

Methods

This cross-sectional study conducted a health survey among 5,703 HCWs of six national medical and research centers in Japan from October 2020 to March 2021. COVID-19-related discrimination was defined either when participants or their family members were badmouthed or when they felt discriminated against in some way. We used the Kessler Psychological Distress Scale (K6) to assess the presence of severe psychological distress (≥13 points). We used logistic regression models to examine the association between discrimination and psychological distress. We also identified job-related factors associated with discrimination.

Results

Of the participants, 484 (8.4%) reported COVID-19-related discrimination and 486 (8.5%) had severe psychological distress. HCWs who were female vs. male (odds ratio [OR]=1.41, 95% confidence interval [CI]=1.28-1.55), had high vs. low viral exposure (OR=2.31, 95%CI=1.81-2.93), and worked for more than 10 hours/day vs. <8 hours/day (OR=1.42, 95%CI=1.35-1.49) were more likely to have experienced COVID-19-related discrimination. The OR (95%CI) of severe psychological distress was 1.83 (1.29-2.59) among those who experienced discrimination. The analysis was stratified by sociodemographic and job-related factors and the associations trended in the same direction across subgroups.

Conclusion

Experience of COVID-19-related discrimination was associated with severe psychological distress among HCWs. During the pandemic, effective measures should be taken to prevent the development of negative mental health outcomes in HCWs who experience discrimination.
Intermediate Filaments Associate with Aggresome-like Structures in ProteostressedC. elegansNeurons and Influence Large Vesicle Extrusions as Exophers
Authors: Arnold Meghan Lee , Cooper Jason , Androwski Rebecca , Ardeshna Sohil , Melentijevic Ilija , Smart Joelle , Guasp Ryan J. , Nguyen Ken C.Q. , Bai Ge , Hall David H. , Grant Barth D. , Driscoll Monica
Published: August 2022

Under conditions of proteostasis disequilibrium, neurons can enhance intracellular and extracellular protective mechanisms to guard against neurotoxicity. In mammals, an intracellular response to severe proteostasis imbalance that results from proteosome inhibition is the formation of juxtanuclear intermediate filament-surrounded, aggregate-filled aggresomes, which sequester threatening aggregates for later disposal via lysosomal degradation. Highly proteo-stressed neurons can also engage the assistance of neighboring cells in aggregate removal by loading threatening materials into large exopher vesicles that are transferred to neighboring cells for remote degradation of contents, a process that has been suggested to be analogous to the process that enables aggregate spreading in the human brain in neurodegenerative disease. InC. elegansthese large extruded vesicles are called exophers.

Here we document that players involved in aggresome biology are required for the elimination of potentially deleterious materials in neuronal exophers. We show that in proteostressedC. eleganstouch receptor neurons, intermediate filament proteins IFD-1 and IFD-2 can assemble into juxtanuclear structures with multiple molecular and cellular characteristics of mammalian aggresomes. IFD-concentrating structures depend upon orthologs of mammalian adapter proteins, dynein motors, and microtubule integrity for aggregate collection into juxtanuclear compartments where they associate with ubiquitinated and neurotoxic polyglutamine expansion proteins. Strikingly, disruption of aggresome-decoration genes encoding IFDs or disruption of the BAG/14-3-3/Hsc70 adapter that promote aggregate loading of aggresome-like organelles, lowers exopher production via a cell autonomous mechanism. Although aggresome-like structures are not mandatory exopher cargo, IFD compartments can be extruded from neurons in exophers, revealing a previously unreported strategy to eliminate neuronal aggresome-like organelles via transfer to neighboring cells. Human IF neurofilament light chain hNFL can partially substitute forC. elegansIFD-2 proteins in promoting exopher production, indicating conservation of the capacity of intermediate filaments to influence neuronal aggregate extrusions across phyla. In sum, we identify a requirement for specific intermediate filaments, counterparts of human biomarkers of neuronal injury and disease and major components of Parkinson’s disease Lewy bodies, inC. elegansneuronal aggresome-like organelle formation and large vesicle exopher extrusion from stressed neurons.
CAMSAP-driven microtubule release from γ-TuRC and its regulation by nucleation-promoting factors
Authors: Rai Dipti , Hua Shasha , Monster Jooske L. , Stucchi Riccardo , Stecker Kelly , Zhang Yaqian , Katrukha Eugene A. , Altelaar Maarten , Wieczorek Michal , Jiang Kai , Akhmanova Anna
Published: August 2022

γ-tubulin ring complex (γ-TuRC) is the major microtubule-nucleating factor. After nucleation, microtubules can be released from γ-TuRC and stabilized by other proteins, such as CAMSAPs, but the biochemical cross-talk between minus-end regulation pathways is poorly understood. Here, we reconstituted this process in vitro using purified components. We found that all CAMSAP proteins could bind to the minus-ends of γ-TuRC-attached microtubules. CAMSAP2 and CAMSAP3, which decorate and stabilize growing minus ends, but not the minus-end tracking protein CAMSAP1 induced microtubule release from γ-TuRC. CDK5RAP2, a γ-TuRC-interactor, and CLASP2, a regulator of microtubule growth, stimulated γ-TuRC-dependent microtubule nucleation, but only CDK5RAP2 inhibited CAMSAP-driven microtubule detachment by suppressing CAMSAP binding to γ-TuRC-anchored minus ends. CDK5RAP2 also improved γ-TuRC selectivity for 13-rather than 14-protofilament microtubules in microtubule-capping assays. Our results support a model whereby CAMSAPs exploit an imperfect attachment between γ-TuRC and the nucleated microtubule to promote minus-end elongation and release, whereas CDK5RAP2 improves the fit between γ-TuRC and 13-protofilament microtubules and enhances nucleation.
Design of extended metal-binding β-sandwiches from de novo immunoglobulin domains
Authors: Roel-Touris Jorge , Nadal Marta , Marcos Enrique
Published: August 2022

The antigen binding sites of antibodies, and derivatives such as scFvs, consist of an immunoglobulin structural framework that anchors hypervariable loops, and that is arranged as a dimer of β-sandwiches (from the heavy and light chains) packing face-to-face. Yet, the naturally occurring dimer orientation of antibodies is not well suited for engineering rigid single-chain formats of increased stability and solubility, which are two key limitations of engineered antibodies. In this work, we computationally designed an extended 12-stranded β-sandwich as a rigid single-chain dimer of de novo immunoglobulin domains interacting through an alternative edge-to-edge arrangement. The extended β-sandwich was found to be hyperstable and structurally accurate as confirmed through X-ray crystallography. We functionalized this design by inserting a long EF-hand calcium-binding motif into the β-hairpin bridge between both domains, showing high metal-binding affinity while remaining soluble and stable in solution. Finally, we propose a few designs with two EF-hand motifs in either or the same side of the scaffold with high-confidence structure predictions; altogether suggesting the robustness and versatility of our scaffold to harbor long functional loops. Our extended β-sandwiches are structurally divergent to natural antibodies and open new avenues for incorporating multiple loop binding sites either for increased or bispecific activities.
Mitochondrial uncouplers impair human sperm motility without altering ATP content
Authors: Skinner Will M. , Petersen Natalie T. , Unger Bret , Tang Shaogeng , Tabarsi Emiliano , Lamm Julianna , Jalalian Liza , Smith James , Bertholet Ambre M. , Xu Ke , Kirichok Yuriy , Lishko Polina V.
Published: August 2022

Sperm motility is necessary for successful fertilization, but there remains controversy about whether human sperm motility is primarily powered by glycolysis or oxidative phosphorylation. To evaluate the plausibility of reducing human sperm mitochondrial ATP production as an avenue for contraceptive development, we treated human sperm with small-molecule mitochondrial uncouplers, which reduce mitochondrial membrane potential by inducing passive proton flow, and evaluated the effects on a variety of physiological processes that are critical for fertilization. We also sought to clarify the subcellular localization of Adenosine Nucleotide Translocator 4 (ANT4), a gamete-specific protein that has been suggested as a contraceptive target. We determined that ANT4 is mitochondrially localized, that induced mitochondrial uncoupling can be partially mediated by the ANT family, and that two uncouplers, Niclosamide Ethanolamine and BAM15, significantly decreased sperm progressive motility. However, these uncouplers did not reduce sperm ATP content or impair other physiological processes, implying that human sperm can rely on glycolysis for ATP production in the absence of functional mitochondria. Thus, since certain mitochondrial uncouplers impair motility through ATP-independent mechanisms, they could be useful ingredients in on-demand, vaginally-applied contraceptives. However, systemically delivered contraceptives that target sperm mitochondria to reduce their ATP production would need to be paired with sperm-specific glycolysis inhibitors.

Significance Statement

Development of novel contraceptives is critical, since half of all pregnancies are still unplanned, even in developed countries. This high unplanned pregnancy rate contributes to a wide variety of social, environmental, and ecological problems. Impairing human sperm is a way to develop male and unisex contraceptives, but much remains unknown about these unique cells. Here we settle a long-running debate about human sperm metabolism, finding that human sperm can maintain their ATP levels without mitochondrial oxidative phosphorylation. This finding will help focus future contraceptive development efforts. We also identify the potential use of an FDA-approved compound (Niclosamide) as a motility-impairing ingredient in spermicides and correct the misunderstood subcellular localization of an existing contraceptive target, Adenosine Nucleotide Translocator 4.