bluuebunny/crossref_metadata_2025 huggingface dataset:
IgG4-Related Disease with IgG1-Dominant Membranous Nephropathy: A Rare Case Report
Authors: Duan Yanya , Qu Yue , Zhuang Jing , Abudula Rziwanguli , Zhang Changrong , Tian Xuefei , Jiang Hong
Published: October 2023

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder affecting various organs and tissues. Kidney involvement in IgG4-RD commonly manifests as IgG4-related tubulointerstitial nephritis or IgG4-related membranous nephropathy, with the latter occurring less frequently. The identification of the phospholipase A2 receptor (PLA2R) antigen has improved our understanding of primary membranous nephropathy. Here, we present the case of a 60-year-old Chinese man initially diagnosed with IgG4-related pancreatitis, who achieved clinical remission with glucocorticoid therapy followed by low-dose glucocorticoid maintenance therapy. Two years later, the patient developed nephrotic syndrome. A kidney biopsy revealed membranous nephropathy characterized by glomerular subepithelial deposition of IgG1 and positive PLA2R staining. Rituximab (RTX) treatment resulted in complete clinical remission of nephrotic syndrome, and no recurrence was observed during the 24-month follow-up period. IgG4-RD complicated by membranous nephropathy is a rare pathological feature characterized by glomerular subepithelial IgG1 deposition and positive PLA2R antigen staining. In the present case, RTX treatment was effective in achieving clinical remission. These findings contribute to the evolving understanding of the relationship between IgG4-RD and membranous nephropathy.
Anterior chamber cytokine production and postoperative macular edema in patients with diabetes undergoing FLACS
Authors: Cioana Milena , Patodia Yogesh , Tong Lili , Chiu Hannah H. , Tam Eric S. , Somani Sohel
Published: October 2023

Purpose:

To evaluate the effect of femtosecond laser-assisted cataract surgery (FLACS) and manual cataract surgery (MCS) on proinflammatory cytokine expression in patients with diabetes vs nondiabetic patients.

Setting:

Outpatient surgical center in Vaughan, Ontario, Canada.

Design:

Prospective cohort study.

Methods:

Patients with diabetes and nondiabetic patients undergoing noncomplicated MCS or FLACS were assigned into 4 cohorts: MCS nondiabetic (n = 30), FLACS nondiabetic (n = 42), MCS diabetic (n = 40), and FLACS diabetic (n = 40). Aqueous humor inflammatory mediator concentrations were evaluated at MCS onset and after femtosecond laser treatment. The presence of cystoid macular edema, anterior chamber (AC) inflammation, central retinal thickness, macular volume, and retinal microvascular changes (through optical coherence tomography angiography) were evaluated preoperatively and on postoperative day 1, week 1, month 1 (POM1), and month 3 (POM3).

Results:

Patients with diabetes receiving FLACS had a higher concentration of interleukin (IL)-7, IL-13, and interferon-induced protein-10 than MCS diabetic patients; they also demonstrated higher levels of vascular endothelial growth factor and lower levels of interferon (IFN)-γ, granulocyte colony-stimulating factor, and IFN-α2 compared with MCS nondiabetic patients. Macular volume appeared to be significantly higher in MCS diabetic vs MCS non-diabetic patients at POM1 and between FLACS diabetic vs FLACS nondiabetic patients at POM3. There were no other significant differences between the cohorts for any parameter.

Conclusions:

FLACS use in patients with diabetes demonstrated some differences in AC cytokine expression compared with non-diabetic FLACS or diabetic patients undergoing MCS; however, there was no increase in clinical inflammatory biomarkers. FLACS seems to be a safe technique to use in patients with diabetes.
Anti-inflammatory medication use after cataract surgery: online survey of practice patterns
Authors: Awidi Abdelhalim A. , Chang David F. , Riaz Kamran M. , Li Ximin , LaBorwit Scott , Zebardast Nazlee , Srikumaran Divya , Prescott Christina R. , Daoud Yassine J. , Woreta Fasika A.
Published: October 2023

Purpose:

To determine current prescribing patterns for topical or intraocular/periocular anti-inflammatory medications (AIMs) after routine cataract surgery.

Setting:

kera-netonline members.

Design:

Cross-sectional survey.

Methods:

An online survey was distributed to subscribers ofkera-net, a global online platform sponsored by the Cornea Society. Questions were asked regarding the use of topical or intraocular/periocular AIM after cataract surgery and types of medications prescribed.

Results:

Of 217 surgeon respondents (23% response rate), 171 (79%) practiced in the United States and 171 (79%) were cornea subspecialists. Most of the respondents (n = 196, 97%) prescribed topical corticosteroids after routine cataract surgery. The most frequently prescribed were prednisolone acetate (n = 162, 83%), followed by dexamethasone (n = 26, 13%), difluprednate (n = 24, 12%), and loteprednol etabonate (n = 13, 7%). Corticosteroids comprised (n = 40, 32%) of total intraocular/periocular injections, with triamcinolone acetonide 10 or 40 mg (n = 19, 47.5%) most commonly used. 23 surgeons (58%) who utilized intraocular/periocular corticosteroids also prescribed topical corticosteroids. Topical nonsteroidal anti-inflammatory drugs were prescribed postoperatively by 148 surgeons (73%).

Conclusions:

Most surgeons prescribed topical AIM after routine cataract surgery. Many surgeons injected intraocular or periocular AIM while prescribing topical AIM. The diversity of practice patterns may reflect the lack of clear evidence-based guidelines.
Impact of obesity on liver function tests: is nonalcoholic fatty liver disease the only player? A review article
Authors: El-Eshmawy Mervat M.
Published: October 2023

Objectives:

Obesity and nonalcoholic fatty liver disease (NAFLD) are common worldwide health problems with a strong relationship in between. NAFLD is currently the most common cause of abnormal liver function tests (LFT) because of obesity pandemic. The question is NAFLD the only player of abnormal LFT in obesity?

Methodology:

This article reviews the most important topics regarding the derangements of LFT in obesity through a PubMed search strategy for all English-language literature.

Results:

The reported abnormal LFT in obesity were increased serum levels of transaminases (alanine aminotransaminase, aspartate aminotransaminase), gamma glutamyl transferase, and alkaline phosphatase and decreased serum levels of bilirubin and albumin. Besides novel potential hepatic markers of NAFLD/NASH such as triglycerides/high-density lipoprotein cholesterol ratio, sex hormone–binding globulin, fibroblast growth factor 21, and markers of hepatocyte apoptosis i.e. cytokeratin 18 and microribonucleic acids (miRNAs). Beyond NAFLD, there are other underlying players for the abnormal LFT in obesity such as oxidative stress, inflammation, and insulin resistance.

Conclusion:

Derangements of LFT in obesity are attributed to NAFLD but also to obesity itself and its related oxidative stress, insulin resistance, and chronic inflammatory state. Abnormal LFT predict more than just liver disease.
Brevilin A ameliorates sepsis-induced cardiomyopathy through inhibiting NLRP3 inflammation
Authors: Liu Ya-Feng , Li Wen-Qiang , Hu Nian-Dan , Ai Bo , Xia Hong-Xia , Guo Xin , Chen Zheng , Xia Hao
Published: October 2023

Background:

Sepsis is a systemic inflammatory disease, and Brevilin A (BA) has a powerful anti-inflammatory effect. However, whether BA has a similar effect on septic cardiomyopathy remains unclear. This study aimed to investigate the effect and mechanism of BA in septic cardiomyopathy.

Methods:

First, a model of septic cardiomyopathy was constructed in vitro and in vivo. The expression of the cardiac injury markers, NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammation factors and its upstream modulator NF-κB was detected by real-time polymerase chain reaction and western blotting. Cardiac function was measured using echocardiography, cell viability was detected using the methyl thiazolyl tetrazolium assay. To further investigate the effects of BA on septic cardiomyopathy, different concentrations of BA were used. The experiment was divided into control group, LPS induced- group, LPS+2.5, 5.0, 10.0 μM BA treatment group of the vitro model, and the Sham, CLP, CLP+10, 20, 30 mg/kg BA treatment groups of the rat vivo model. Lastly, cardiac injury, NLRP3 inflammation, and cardiac function were assessed in each group.

Results:

The mRNA and protein expression of cardiac inflammation and injury genes were significantly increased in the in vitro and in vivo sepsis cardiomyopathy models. When different concentrations of BA were used in sepsis cardiomyopathy in vivo and in vitro, the above-mentioned myocardial inflammation and injury factors were suppressed to varying degrees, cell viability increased, cardiac function improved, and the survival rate of rats also increased.

Conclusion:

BA ameliorated sepsis cardiomyopathy by inhibiting NF-κB/NLRP3 inflammation activation.
Acute spinal cord injury in Africa: exploring the long-term outcomes and future directions of acute spinal cord injury – short communication
Authors: Kassahun Bekele Bezawit , Boluwatife Samuel Fatokun , Soufan Fatima , Kravarioti Dionysia , Nazir Abubakar , Ahmad Nakhleh Hamza , Wojtara Magda , Uwishema Olivier
Published: October 2023

Acute spinal cord injury (ASCI), a key factor behind serious sensory, motor, and autonomic dysfunctions, holds on as a fundamental cause of morbidity, psychological disturbances, and high socioeconomic burden. This study sheds light, particularly on the African countries where it is found that traumatic ASCI, mainly due to road traffic accidents, remains the leading cause, with 130 cases per million in this part of the world. Moreover, limited resources, with the lack of funds and equipment, as well as widespread poverty, restrict the availability of suitable diagnostic, management, and treatment options. The weight of the evidence suggests that there is an ultimate need for well-developed infrastructure embracing a multidisciplinary approach to rehabilitation in Africa. Furthermore, international collaborations, posing a significantly wide background for evidence-based information and resources, are indispensable for ASCI prospects and future studies among the African population. The purpose of this study is to fill a part of the persistent gap in the research era regarding the ASCI in Africa and direct future research toward investigating its different aspects as well as exploring its interventional needs.
Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome following vaccination: analysis of the VAERS database and systematic review
Authors: Srichawla Bahadar S. , Fang Ton , Kipkorir Vincent , Garcia-Dominguez Maria A.
Published: October 2023

Objectives:

This study aimed to analyze the Vaccine Adverse Event Reporting System (VAERS) database and systematically review the literature to provide a comprehensive analysis of reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES) secondary to vaccination.

Methods:

The authors analyzed the VAERS database and conducted a systematic review following PRISMA guidelines. The inclusion criteria for VAERS data were a score of ≥3 on the RCVS2 score and/or radiographic findings consistent with the diagnosis of RCVS or PRES. The systematic review was registered with PROSPERO.

Results:

Our combined data set included 29 cases (9 RCVS and 20 PRES). Most cases were women (72.4%) with a mean age of 50.7 years (SD 19.4 years). Most cases were associated with COVID-19 mRNA vaccines (58.6% Moderna, 20.7% Pfizer). Hypertension (37.9%), hyperlipidemia (13.7%), chronic kidney disease (CKD) (10.3%), and end-stage renal disease (6.8%) were common comorbidities. Furthermore, 20.6% (6/29) of cases were on immunosuppression therapy for various reasons. The mean time to symptom onset was 10.49 days after vaccination (SD 18.60), and the mean duration of hospitalization was 7.42 days (SD 5.94). The symptoms reported the most frequently were headache (41.3%), elevated blood pressure (31.0%), and emesis (17.2%). Typical radiographic findings included T2/FLAIR hyperintensities affecting the parieto-occipital lobes, indicative of vasogenic and/or cytotoxic edema.

Conclusions:

This study provides a comprehensive analysis of postvaccine RCVS and PRES. Both disease states were seen most often in those with pre-existing risk factors such as female sex, age over 50, hypertension, renal disease, and immunosuppression. Vaccines and their associated immune response may cause endothelial dysfunction leading to cerebral vasospasm and loss of cerebral autoregulation. However, further research is required to understand the underlying pathophysiological mechanisms. Despite the associations found, the absolute risk of these syndromes remains extremely low compared to the immense benefits of vaccination.
Revolutionary breakthrough: FDA approves Vyjuvek, the first topical gene therapy for dystrophic epidermolysis bullosa
Authors: Khan Afsheen , Riaz Rumaisa , Ashraf Saad , Akilimali Aymar
Published: October 2023

This article provides an updated overview of Vyjuvek, a Food and Drug Administration (FDA) approved medication and its potential in managing dystrophic epidermolysis bullosa (DEB). DEB is a rare genetic disorder characterized by skin fragility, blistering, wounds, and scarring. The underlying cause of DEB is the impaired production of type VII collagen (COL7), leading to weakened anchoring fibrils in the skin. Vyjuvek is the first topical gene therapy for DEB, utilizing a genetically modified HSV-1 (herpes simplex virus 1) vector to express human COL7 and promote wound healing. Clinical trials have shown that Vyjuvek increases the probability of complete wound healing compared to placebo. Although further research is needed, Vyjuvek represents a significant advancement in addressing the unmet medical needs of patients with DEB, offering hope for improved quality of life and long-term complication reduction.
Screening for Social Determinants of Health in Transitional Care Patients and Partnering With the Faith Community to Address Food Insecurity
Authors: Bryant Susan G.
Published: October 2023

Purpose/Objectives:

The purposes of this project were to collect and document social determinants of health (SDOH) data, and to partner with the faith community to address identified food insecurity.

Primary Practice Setting:

The setting for this project was an ambulatory care clinic in Guilford County, North Carolina. The clinic offers care to patients discharged from a regional medical center who have no insurance and/or primary care providers.

Findings/Conclusions:

Clinic staff successfully developed and implemented a screening tool for entering SDOH data into the electronic health record (EHR) charts of clinic patients. Results demonstrated that 52% of clinic patients reported food insecurity. The clinic collaborated with the faith community to provide donated food bags to patients in need.

Implications for Case Management Practice:

SDOH data were largely absent from the EHR before the clinic case manager started this project. Results of the screening tool demonstrated higher rates of food insecurity than expected. The case manager worked with the faith community to address immediate needs of food insecurity. The case manager plans to share SDOH information with the wider community to affect positive change and to encourage other clinics and departments to start collecting SDOH data.
Antibiotic therapy for nonfermenting Gram-negative bacilli infections: future perspectives
Authors: Bassetti Matteo , Castaldo Nadia , Fantin Alberto , Giacobbe Daniele Roberto , Vena Antonio
Published: October 2023

Purpose of review

Serious infections caused by nonfermenting Gram-negative bacteria (NF-GNB) pose a significant challenge for clinicians due to the limited treatment options available, which are frequently associated with issues of toxicity and unfavourable pharmacokinetic profiles. The aim of this review is to provide a brief overview of the existing data concerning the ongoing development of antiinfective agents targeting NF-GNB.

Recent findings

Several agents exhibiting efficacy against NF-GNB are under clinical investigation. Durlobactam-sulbactam and cefepime-taniborbactam emerge as promising therapeutic avenues against carbapenem-resistant Acinetobacter baumanii. Cefepime-zidebactam may serve as a suitable treatment option for urinary tract infections caused by a wide range of NF-GNB. Cefepime-enmetazobactam demonstrates potent in vitro activity against various NF-GNB strains; however, its role as an anti-Pseudomonal agent is inadequately substantiated by available data. Xeruborbactam is a wide β-lactamase inhibitor that can be associated with a range of agents, enhancing in-vitro activity of these against many NF-GNB, including those resistant to newer, broader spectrum options. Lastly, murepavadin appears to be a potential pathogen-specific solution for severe Pseudomonas infections; however, additional investigation is necessary to establish the safety profile of this compound.

Each of the novel molecules reviewed possesses an interesting range of in-vitro activity against NF-GNB. In addition, some of them have already been proved effective in vivo, underscoring their potential as future treatment options.
68Ga-DOTA-FAPI-04 PET/CT in the Detection of Thoracic SMARCA4-Deficient Undifferentiated Tumor
Authors: Shen Xiuling , Yang Zhi , Li Nan
Published: October 2023

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare malignant disease. We present the case of a 56-year-old woman with thoracic SMARCA4-UT presenting as a mediastinal mass who underwent 68Ga-DOTA-FAPI-04 PET/CT imaging. Intense 68Ga-DOTA-FAPI-04 uptake was observed in the primary tumor and lymph node metastases. After 7 cycles of immune checkpoint inhibitor plus chemotherapy, the patient underwent mediastinal mass resection, and postoperative pathology confirmed a complete pathologic response. This case may provide valuable insights into the diagnosis and monitoring of the treatment response of thoracic SMARCA4-UT.
Unicellular and multicellular developmental variations in algal zygotes produce sporophytes
Authors: Horinouchi Yusuke , Togashi Tatsuya
Published: October 2023

The emergence of sporophytes, that is, diploid multicellular bodies in plants, facilitated plant diversification and the evolution of complexity. Although sporophytes may have evolved in an ancestral alga exhibiting a haplontic life cycle with a unicellular diploid and multicellular haploid (gametophyte) phase, the mechanism by which this novelty originated remains largely unknown. Ulotrichalean marine green algae (Ulvophyceae) are one of the few extant groups with haplontic-like life cycles. In this study, we show that zygotes of the ulotrichalean alga
Monostroma angicava
, which usually develop into unicellular cysts, exhibit a developmental variation producing multicellular reproductive sporophytes. Multicellular development likely occurred stochastically in individual zygotes, but its ratio responded plastically to growth conditions. Sporophytes showed identical morphological development to gametophytes, which should reflect the expression of the same genetic programme directing multicellular development. Considering that sporophytes were evolutionarily derived in Ulotrichales, this implies that sporophytes emerged by co-opting the gametophyte developmental programme to the diploid phase. This study suggests a possible mechanism of sporophyte formation in haplontic life cycles, contributing to the understanding of the evolutionary transition from unicellular to multicellular diploid body plans in green plants.
Locating complex singularities of Burgers’ equation using exponential asymptotics and transseries
Authors: Lustri Christopher J. , Aniceto Inês , VandenHeuvel Daniel J. , McCue Scott W.
Published: October 2023

Burgers’ equation is an important mathematical model used to study gas dynamics and traffic flow, among many other applications. Previous analysis of solutions to Burgers’ equation shows an infinite stream of simple poles born att=0+, emerging rapidly from the singularities of the initial condition, that drive the evolution of the solution fort>0. We build on this work by applying exponential asymptotics and transseries methodology to an ordinary differential equation that governs the small-time behaviour in order to derive asymptotic descriptions of these poles and associated zeros. Our analysis reveals that subdominant exponentials appear in the solution across Stokes curves; these exponentials become the same size as the leading order terms in the asymptotic expansion along anti-Stokes curves, which is where the poles and zeros are located. In this region of the complex plane, we write a transseries approximation consisting of nested series expansions. By reversing the summation order in a process known as transasymptotic summation, we study the solution as the exponentials grow, and approximate the pole and zero location to any required asymptotic accuracy. We present the asymptotic methods in a systematic fashion that should be applicable to other nonlinear differential equations.
Binocular field configuration in owls: the role of foraging ecology
Authors: Potier Simon , Roulin Alexandre , Martin Graham R. , Portugal Steven J. , Bonhomme Vincent , Bouchet Thierry , de Romans Romuald , Meyrier Eva , Kelber Almut
Published: October 2023

The binocular field of vision differs widely in birds depending on ecological traits such as foraging. Owls (Strigiformes) have been considered to have a unique binocular field, but whether it is related to foraging has remained unknown. While taking into account allometry and phylogeny, we hypothesized that both daily activity cycle and diet determine the size and shape of the binocular field in owls. Here, we compared the binocular field configuration of 23 species of owls. While we found no effect of allometry and phylogeny, ecological traits strongly influence the binocular field shape and size. Binocular field shape of owls significantly differed from that of diurnal raptors. Among owls, binocular field shape was relatively conserved, but binocular field size differed among species depending on ecological traits, with larger binocular fields in species living in dense habitat and foraging on invertebrates. Our results suggest that (i) binocular field shape is associated with the time of foraging in the daily cycle (owls versus diurnal raptors) and (ii) that binocular field size differs between closely related owl species even though the general shape is conserved, possibly because the field of view is partially restricted by feathers, in a trade-off with auditory localization.
Stochastic model for cell population dynamics quantifies homeostasis in colonic crypts and its disruption in early tumorigenesis
Authors: Mamis Konstantinos , Zhang Ruibo , Bozic Ivana
Published: October 2023

The questions of how healthy colonic crypts maintain their size, and how homeostasis is disrupted by driver mutations, are central to understanding colorectal tumorigenesis. We propose a three-type stochastic branching process, which accounts for stem, transit-amplifying (TA) and fully differentiated (FD) cells, to model the dynamics of cell populations residing in colonic crypts. Our model is simple in its formulation, allowing us to estimate all but one of the model parameters from the literature. Fitting the single remaining parameter, we find that model results agree well with data from healthy human colonic crypts, capturing the considerable variance in population sizes observed experimentally. Importantly, our model predicts a steady-state population in healthy colonic crypts for relevant parameter values. We show that
APC
and
KRAS
mutations, the most significant early alterations leading to colorectal cancer, result in increased steady-state populations in mutated crypts, in agreement with experimental results. Finally, our model predicts a simple condition for unbounded growth of cells in a crypt, corresponding to colorectal malignancy. This is predicted to occur when the division rate of TA cells exceeds their differentiation rate, with implications for therapeutic cancer prevention strategies.
Lineage replacement and evolution captured by 3 years of the United Kingdom Coronavirus (COVID-19) Infection Survey
Authors: Lythgoe Katrina A. , Golubchik Tanya , Hall Matthew , House Thomas , Cahuantzi Roberto , MacIntyre-Cockett George , Fryer Helen , Thomson Laura , Nurtay Anel , Ghafani Mahan , Buck David , Green Angie , Trebes Amy , Piazza Paolo , Lonie Lorne J. , Studley Ruth , Rourke Emma , Smith Darren , Bashton Matthew , Nelson Andrew , Crown Matthew , McCann Clare , Young Gregory R. , Andre Nunes dos Santos Rui , Richards Zack , Tariq Adnan ,   Wellcome Sanger Institute COVID-19 Surveillance Team,   COVID-19 Infection Survey Group, The COVID-19 Genomics UK (COG-UK) Consortium, Fraser Christophe , Diamond Ian , Barrett Jeff , Walker Ann Sarah , Bonsall David
Published: October 2023

The Office for National Statistics Coronavirus (COVID-19) Infection Survey (ONS-CIS) is the largest surveillance study of SARS-CoV-2 positivity in the community, and collected data on the United Kingdom (UK) epidemic from April 2020 until March 2023 before being paused. Here, we report on the epidemiological and evolutionary dynamics of SARS-CoV-2 determined by analysing the sequenced samples collected by the ONS-CIS during this period. We observed a series of sweeps or partial sweeps, with each sweeping lineage having a distinct growth advantage compared to their predecessors, although this was also accompanied by a gradual fall in average viral burdens from June 2021 to March 2023. The sweeps also generated an alternating pattern in which most samples had either S-gene target failure (SGTF) or non-SGTF over time. Evolution was characterized by steadily increasing divergence and diversity within lineages, but with step increases in divergence associated with each sweeping major lineage. This led to a faster overall rate of evolution when measured at the between-lineage level compared to within lineages, and fluctuating levels of diversity. These observations highlight the value of viral sequencing integrated into community surveillance studies to monitor the viral epidemiology and evolution of SARS-CoV-2, and potentially other pathogens.
Effects of genotype and host environment on the cuticular hydrocarbon profiles of
Lysiphlebus
parasitoids and aggression by aphid-tending ants
Authors: Hertaeg Corinne , Vorburger Christoph , De Moraes Consuelo M. , Mescher Mark C.
Published: October 2023

Parasitoids in the genus
Lysiphlebus
specialize on ant-tended aphids and have previously been reported to mimic the cuticular hydrocarbon (CHC) profiles of their aphid hosts to avoid detection by ants. However, the precise mechanisms that mediate reduced ant aggression toward
Lysiphlebus
spp. are not known, nor is it clear whether such mechanisms are broadly effective or specialized on particular aphid hosts. Here we explore the effects of wasp genotype and host environment on
Lysiphlebus
CHC profiles and ant aggression. Rearing asexual
Lysiphlebus
lines in different host aphid environments revealed effects of both wasp line and aphid host on wasp CHCs. However, variation in genotype and host affected different features of the CHC profile, with wasp genotype explaining most variation in linear and long-chain methyl alkanes, while aphid host environment primarily influenced short-chain methyl alkanes
.
Subsequent behavioural experiments revealed no effects of host environment on ant aggression, but strong evidence for genotypic effects. The influence of genotypic variation on experienced ant aggression and relevant chemical traits is particularly relevant in light of recent evidence for genetic divergence among
Lysiphlebus
parasitoids collected from different aphid hosts.
Differential clinical characteristics across traditional Chinese medicine (TCM) syndromes in patients with sickle cell disease
Authors: Wang Ying , Wang David D , Pucka Andrew Q , O’Brien Andrew RW , Harte Steven E , Harris Richard E
Published: October 2023

Background

Pain is a common, debilitating, and poorly understood complication of sickle cell disease (SCD). The need for clinical pain management of SCD is largely unmet and relies on opioids as the main therapeutic option, which leads to a decreased quality of life (QoL). According to the literature, acupuncture has shown certain therapeutic effects for pain management in SCD. However, these clinical studies lack the guidance of Traditional Chinese Medicine (TCM) Syndrome Differentiation principles for treatment.

Aim

To characterize differences in clinical presentation amongst TCM-diagnosed syndromes in SCD patients.

Method

52 patients with SCD and 28 age- and sex-matched healthy controls (HCs) were enrolled in an ongoing trial of acupuncture. Each participant completed a series of questionnaires on pain, physical function, fatigue, sleep, anxiety, depression, and QoL and underwent cold- and pressure-based quantitative sensory testing at baseline. Data on prescription opioid use over the 12 months prior to study enrollment was used to calculate mean daily morphine milligram equivalents (MME). Differences among the three TCM syndromes were analyzed by one-way ANOVA followed by Tukey post hoc testing. Two-sample t-tests were used to compare SCD and HC groups.

Results

TCM diagnosis criteria classified SCD patients into one of three TCM syndromes: a) Equal; b) Deficiency; and c) Stagnation. The Stagnation group exhibited higher pain interference, physical dysfunction, nociplastic pain, fatigue, anxiety, depression, MME consumption, and lower sleep quality and QoL compared to the Equal group. Few differences were observed between HCs and the Equal SCD group across outcomes. Deficiency and Stagnation groups were differentiated with observed- and patient-reported clinical manifestations.

Conclusion

These findings suggest that TCM-diagnosed syndromes in SCD can be differentially characterized using validated objective and patient-reported outcomes. Because characteristics of pain and co-morbidities in each SCD patient are unique, targeting specific TCM “syndromes” may facilitate treatment effectiveness with a syndrome-based personalized treatment plan that conforms to TCM principles. These findings lay the foundation for the development of tailored acupuncture interventions based on TCM syndromes for managing pain in SCD. Larger samples are required to further refine and validate TCM diagnostic criteria for SCD.
Continuous Tracking using Deep Learning-based Decoding for Non-invasive Brain-Computer Interface
Authors: Forenzo Dylan , Zhu Hao , Shanahan Jenn , Lim Jaehyun , He Bin
Published: October 2023

Brain-computer interfaces (BCI) using electroencephalography (EEG) provide a non-invasive method for users to interact with external devices without the need for muscle activation. While noninvasive BCIs have the potential to improve the quality of lives of healthy and motor impaired individuals, they currently have limited applications due to inconsistent performance and low degrees of freedom. In this study, we use deep learning (DL)-based decoders for online Continuous Pursuit (CP), a complex BCI task requiring the user to track an object in two-dimensional space. We developed a labeling system to use CP data for supervised learning, trained DL-based decoders based on two architectures, including a newly proposed adaptation of the PointNet architecture, and evaluated the performance over several online sessions. We rigorously evaluated the DL-based decoders in a total of 28 human participants, and found that the DL-based models improved throughout the sessions as more training data became available and significantly outperformed a traditional BCI decoder by the last session. We also performed additional experiments to test an implementation of transfer learning by pre-training models on data from other subjects, and mid-session training to reduce inter-session variability. The results from these experiments showed that pre-training did not significantly improve performance, but updating the models mid-session may have some benefit. Overall, these findings support the use of DL-based decoders for improving BCI performance in complex tasks like CP, which can expand the potential applications of BCI devices and help improve the quality of lives of healthy and motor-impaired individuals.

Significance Statement

Brain-computer Interfaces (BCI) have the potential to replace or restore motor functions for patients and can benefit the general population by providing a direct link of the brain with robotics or other devices. In this work, we developed a paradigm using deep learning (DL)-based decoders for continuous control of a BCI system and demonstrated its capabilities through extensive online experiments. We also investigate how DL performance is affected by varying amounts of training data and collected more than 150 hours of BCI data that can be used to train new models. The results of this study provide valuable information for developing future DL-based BCI decoders which can improve performance and help bring BCIs closer to practical applications and wide-spread use.
diplo-locus: A lightweight toolkit for inference and simulation of time-series genetic data under general diploid selection
Authors: Cheng Xiaoheng , Steinruücken Matthias
Published: October 2023

Whole-genome time-series allele frequency data are becoming more prevalent as ancient DNA (aDNA) sequences and data from evolve-and-resequence (E&R) experiments are generated at a rapid pace. Such data presents unprecedented opportunities to elucidate the dynamics of genetic variation under selection. However, despite many methods to infer parameters of selection models from allele frequency trajectories available in the literature, few provide user-friendly implementations for large-scale empirical applications. Here, we presentdiplo-locus, an open-source Python package that provides functionality to simulate and perform inference from time-series data under the Wright-Fisher diffusion with general diploid selection. The package includes Python modules as well as command-line tools and is available at:https://github.com/steinrue/diplo_locus.
Detecting significantly recurrent genomic connections from simple and complex rearrangements in the cancer genome
Authors: Zhang Shu , Kumar Kiran H. , Shapira Ofer , Yao Xiaotong , Wala Jeremiah , Dubois Frank , Gold Rose , Haber James E. , Cherniack Andrew , Imielinski Marcin , Dalin Simona , Beroukhim Rameen
Published: October 2023

The detection of somatic genetic alterations that recur across cancer genomes more than expected by chance has been a major goal of cancer genomics, as these alterations are enriched for “driver” events that promote cancer. Multiple methods have been developed to detect driver point mutations and copy-number variants, but methods to detect driver rearrangements have largely not been pursued. Unlike point mutations and copy-number alterations, which can be assigned to a single genomic locus, rearrangements connect two distant genomic loci, and possibly more in the case of complex or clustered events. Here, we explore genomic features that predict the rate at which any pair of loci will be connected by rearrangements and describe two methods to detect rearrangements that recur more often than this background rate. The first, SVSig-2D, detects pairs of loci that are directly connected by a single rearrangement; the second, SVSig-2Dc also detects loci that are recurrently connected indirectly through two or more rearrangements. When applied to a pan-cancer dataset of over 2,500 cancers, these methods identified 80 significantly recurrent simple rearrangements and 29 complex rearrangements, including both known and novel events. Intriguingly, though both recurrent simple and complex rearrangements tended to be tissue-specific, this was less true for the complex events. The detection of recurrent rearrangements with methods such as these will be an essential component of cancer genomics in the whole-genome sequencing era.
High genetic diversification in a symbiotic marine annelid is driven by microgeography and glaciation
Authors: Sato Yui , Wilkins Laetitia G.E. , Gruhl Alexander , Gruber-Vodicka Harald , Dubilier Nicole
Published: October 2023

Marine invertebrates with limited dispersal abilities exhibit high levels of genetic divergence among populations. However, the spatial extent of genetic differentiation in these species remains poorly understood because identifying natural barriers to gene flow can be challenging in the marine environment. In this study, we investigated the population genetic structure of the interstitial annelidOlavius algarvensis, a species that lays eggs in its immediate surroundings and does not have an active dispersal phase. We analyzed the mitochondrial and nuclear genome sequences of hundreds to thousands of individuals from eleven sites in the Mediterranean, spanning microgeographic scales of < 5 km to macrogeographic scales of 800 km. Comparisons of single nucleotide polymorphisms (SNPs) in mitochondrial genomes revealed a complex history of introgression events, with as many as six mitochondrial lineages co-occurring in individuals from the same site. In contrast, SNP analyses of nuclear genomes revealed clear genetic differentiation at micro- and macrographic scales, characterised by a significant isolation by distance pattern (IBD). IBD patterns further indicated the presence of a historical physical barrier to gene flow on the east coast of the island of Elba corresponding to the historical shoreline around Elba during the Last Glacial Maximum in the Late Pleistocene, and highlighting the influence of geological forces in shaping population genetic structuring in the species today. Overall, our results provide strong empirical evidence for the high genomic diversification across spatial scales in marine interstitial fauna.
Sleep stages antagonistically modulate reactivation drift
Authors: Bollmann Lars , Baracskay Peter , Stella Federico , Csicsvari Jozsef
Published: October 2023

Hippocampal reactivation of waking neuronal assemblies in sleep is a key initial step of systems consolidation. Nevertheless, it is unclear whether reactivated assemblies are static or whether they reorganize gradually over prolonged sleep. Here, we tracked reactivated CA1 assembly patterns over ∼20 hours of sleep/rest periods and related them to assemblies seen before or after in a spatial learning paradigm. We found that reactivated assembly patterns were gradually transformed and started to resemble those seen in the subsequent recall session. Periods of rapid eye movement (REM) sleep and non-REM (NREM) had antagonistic roles: while NREM accelerated the assembly drift, REM countered it. Moreover, only a subset of rate-changing pyramidal cells contributed to the drift, while stable firing rate cells maintained unaltered reactivation patterns. Our data suggest that prolonged sleep promotes the spontaneous reorganization of spatial assemblies, which can contribute to daily cognitive map changes or encoding new learning situations.
Devising reliable and accurate epigenetic predictors: choosing the optimal computational solution
Authors: Vavourakis Charlotte D. , Herzog Chiara M. , Widschwendter Martin
Published: October 2023

Illumina DNA methylation arrays are frequently used for the discovery of methylation signatures associated with aging and disease. One of the major hurdles to overcome when training trait prediction models is the high dimensionality of the data, with the number of features (CpGs) greatly exceeding the typical number of samples assessed. In addition, most large-scale DNA methylation-based studies do not include replicate measurements for a given sample, making it impossible to estimate the degree of measurement uncertainty or the reliability of the prediction models. A recent study proposed that training penalized regression models on derived principal components (PCs) rather than on the original features (CpGs) results in more reliable age predictions, as estimated from technical replication. Moreover, the same method could be applied for predicting other phenotypes more reliably. Here, we aimed at validating the proposed PC method. We found that although dimension reduction with PCA consistently led to small improvements in the reliability of age prediction models, it severely compromised their accuracy. PC-based models needed far larger training set sizes to be similarly accurate as CpG-based models, whereas reliability did not depend on the sample size of the training set data for either approach. Finally, the PC version of a novel multiclass predictor for breast, ovarian and endometrial cancer we trained using weighted ensembles of deep-learning models also had a markedly lower predictive accuracy compared to a CpG version, suggesting limited applicability of the proposed PC method for predicting phenotypes beyond age.
Breast cancer cells can recognize and respond to different levels of progestins to achieve different phenotypic outputs
Authors: Dolan Emma L. , Safi Rachid , Chang Chingyi , Eaton Hilary E. , Krishnan Shweta , Safi Roya , Watkinson Paige , Long Henry , Xie Yingtian , Brown Myles , Murphy Susan K. , McDonnell Donald P.
Published: October 2023

The steroid hormone progesterone, acting through its nuclear progesterone receptor (PR), has complex physiologic activities with different levels of hormones manifesting distinct and sometimes opposing phenotypic responses in target tissues. However, most of what is currently known about the transcriptional activity of PR comes from studies performed using progestins at levels that are in the high physiologic range (≥10nM), relevant only in the luteal phase of the reproductive cycle and pregnancy in humans. These studies do not consider the non-linearity of responses to progestins that exist in physiology and are not informative as to the mechanisms by which low levels of progestins, as occurs during menopause, exert their biological activities. Thus, we undertook to define the mechanisms which enable cells to recognize and respond to different levels of progestins. Using a PR expressing cell model of luminal breast cancer (T47D cells) we demonstrated that low concentration progestins (0.1-0.3nM) drive proliferation while high dose progestins (≥10nM) inhibit proliferation. Using both unbiased and targeted approaches, we found that low dose progestins facilitate cell cycle entry by enhanced expression of CCND1 and SGK1, which are both required to initiate a signaling cascade that leads to increased phospho-Rb and E2F1 transcriptional activity. CCND1 cooperates with CDK4/6 to phosphorylate Rb, while SGK1 phosphorylates p21, thereby excluding it from the nucleus and inhibiting its anti-proliferative function. Expression ofCCND1andSGK1mRNAs are primary responses to low dose progestin treatment. However, these responses occur at very low levels of receptor occupancy and in the absence of receptor phosphorylation events that have been shown to be required for nuclear translocation and transcriptional activity. These findings challenge the assumption of linearity in response to progestin dose. Further, they suggest that concentrations of progestins found in post-menopausal women (0.1-0.3nM) have the potential to exert proliferative responses in PR expressing cancers.
Five amino acid mismatches in the zinc-finger domains of CELLULOSE SYNTHASE 5 and CELLULOSE SYNTHASE 6 modulate their incorporation into cellulose synthase complexes inArabidopsis
Authors: Park Sungjin , Ding Shi-You
Published: October 2023

Main conclusionDifferent capacities for the homodimerization of CESA5 and CESA6 are modulated by five amino acid mismatches in their zinc-finger domains and motivate discriminative incorporation of these CESAs into CSCs

Cellulose synthase 5 (CESA5) and CESA6 are known to share substantial functional overlap. In the zinc-finger domain of CESA5, there are five amino acid (AA) mismatches when compared to CESA6. These mismatches in CESA5 were replaced with their CESA6 counterparts one by one until all were replaced, generating nine engineered CESA5s. Each N-terminal enhanced yellow fluorescent protein-tagged engineered CESA5 was introduced toprc1-1, acesa6null mutant, and resulting mutants were subjected to phenotypic analyses. We found that five single AA-replaced CESA5 proteins partially rescue theprc1-1mutant phenotypes to different extents. Multi-AA replaced CESA5s further rescued the mutant phenotypes in an additive manner, culminating in full recovery by CESA5G43R+S49T+S54P+S80A+Y88F. Investigations in cellulose content, cellulose synthase complex (CSC) motility, and cellulose microfibril organization in the same mutants support the results of the phenotypic analyses. Bimolecular fluorescence complementation assays demonstrated that the level of homodimerization in every engineered CESA5 is substantially higher than CESA5. The mean fluorescence intensity of CSCs carrying each engineered CESA5 fluctuates with the degree to which theprc1-1mutant phenotypes are rescued by introducing a corresponding engineered CESA5, indicating that these mismatches modulate the incorporation of both CESAs into CSCs by controlling their ability to homodimerize.
Dietary restriction extends lifespan across different temperatures in the fly
Authors: Phillips Eleanor J , Simons Mirre J P
Published: October 2023

Dietary restriction (DR) has been consistently shown to extend lifespan across a range of taxa. However, it has recently been reported that DR does not extend lifespan at certain, namely lower, temperatures in flies (Drosophila melanogaster). Similar to the interpretation of other findings that appear to question DR’s universality, this finding has been interpreted as being an artefact of benign laboratory conditions. Here we re-test this hypothesis, now using a strain that shows robust lifespan extension at 25°C (across three prior experiments), and using a range of 5 diets across two temperatures, 18°C and 21°C. We found the DR longevity response to be robust, extending lifespan irrespective of temperature. We measured fecundity as a positive control for the DR phenotype, and found, as predicted, that DR reduces egg laying. It will be important for results that question DR as a phenotype to not be overinterpreted readily, as with a substantially larger sample size and a larger range of diets we were unable to replicate this prior work. Differences in experimental setup, genetic lines used and variation in the diet-lifespan reaction norm we suggest are responsible for this discrepancy. In addition, starting with a strain and conditions that show a lifespan extension by DR, as we do here, and then changing environment and/or genotype promises a more robust test of DR modulating factors.