bluuebunny/crossref_metadata_2025 huggingface dataset:
Does medial calcaneal wedge improve static balance and load distribution in young adults with pronated foot?
Authors: Guven Izgi , Yagci Gozde , Erel Suat
Published: August 2023

Background:

Foot orthoses changing the momentum in the subtalar joint are often recommended, especially in activities loading the foot, to bring the pronated foot posture closer to neutral.

Objective(s):

To examine the immediate effect of medial heel wedge on static balance and load distribution in patients with increased pronation in the foot.

Study Design:

Experimental study design.

Methods:

Forty people with right dominant lower extremity participated in the study. For static balance assessment, we assessed ellipse surface, sway length, x-y mean, AP index, and Romberg ratio on 1 foot and measured load distribution as right-left foot and fore-hind foot with and without wedge.

Results:

There was a difference between the parameters of the ellipse surface and the Romberg ratio on the left side in the measurements performed with and without wedge for static balance on the left side (P < 0.05) while there was no difference in the remaining values (P > 0.05). In the load distribution, the change in the right anteroposterior foot was significant, increasing the load on the forefoot with the wedge (P < 0.05) while we observed no difference in the left fore-hind foot load distribution and right-left foot load distribution (P > 0.05).

Conclusion:

Our study showed that for static balance, medial wedge can improve balance on the left side by decreasing sway, and for load distribution, the medial wedge changed the load distribution from back to front on the right side. These small differences in young healthy individuals are a preliminary indication that further studies are needed.
Does the Type of Failure and the Choice of the Second Biologic Influence Response and Persistence on Medication in Rheumatoid Arthritis?
Authors: Bessette Louis , Movahedi Mohammad , Reed George , Kremer Joel M. , Kane Kevin , Keystone Edward
Published: August 2023

Background

The type of failure may predict response to a second biologic. We evaluated the response to a second tumor necrosis factor inhibitor (TNFi) or non-TNFi in patients failing their initial TNFi, either primarily or secondarily.

Methods

Patients with rheumatoid arthritis who were biologic-naive and had a Clinical Disease Activity Index (CDAI) >10, who started their first TNFi for ≥3 months and then switched to a second biologic, were included in the study. Secondary failure was defined as 2 consecutive low-CDAI visits and then switching to a second biologic while they had moderate/severe CDAI. Primary failure was defined if it did not meet the definition of secondary failure, or if they had at least 1 moderate/severe CDAI after 3 months on treatment. We used multivariable logistic regression comparing primary versus secondary failure for achievement of CDAI ≤10 (primary outcome) and minimal clinically important differences (secondary outcome) at 6 months after switch.

Results

Of the 462 patients included, 64.3% and 35.7% stopped the first TNFi because of a primary and secondary failure, respectively. Patients with primary failure had a more severe disease (CDAI mean, 26.39 vs. 21.61; p < 0.001). The likelihood of achieving CDAI ≤10 (odds ratio, 4.367; 95% confidence interval, 2.428–7.856) and minimal clinically important difference (odds ratio, 2.851; 95% confidence interval, 1.619–5.020) was significantly higher for secondary than primary failure regardless of choice of a second agent.

Conclusion

Patients with rheumatoid arthritis with secondary failure to a first TNFi responded better to a second biologic agent, regardless of the choice of biologic.
An Unusual Asymptomatic Case of Unilateral Parotid Gland Agenesis
Authors: Barca Ida , Della Torre Attilio , Cristofaro Maria Giulia
Published: August 2023

Congenital absence of the major salivary glands, especially of the parotid gland, is a very infrequent condition of poorly understood etiology. This condition may be unilateral or bilateral and may occur alone or in association with the absence of other salivary glands or with other developmental craniofacial deformities of maxillofacial first and second branchial arch. Only 24 cases are documented in the literature. The authors present a case of a 79-year-old female who was referred to the Neurosurgery Department for neurocognitive impairment. The brain computed tomography with contrast enhancement incidentally showed a complete absence of the left parotid gland. The medical history and physical and radiographic examinations were indicative of nonsyndromic and nonfamilial asymptomatic unilateral aplasia of the parotid gland.
Unveiling the Significance of Dynamic Arterial Elastance: An Insightful Approach to Assessing Arterial Load in an Endotoxin Shock Model
Authors: Alvarado Sánchez Jorge I. , Caicedo Ruiz Juan D. , Diaztagle Fernández Juan J. , Monge Garcia Manuel I. , Cruz Martínez Luis E.
Published: August 2023

Background

The aim of this study was to investigate the relationship between dynamic arterial elastance (EaDyn) and the pulsatile and steady components of arterial load in an endotoxin shock model using a two-element Windkessel model and to describe the behavior of EaDyn in this model.

Methods

Ten female Yorkshire pigs were administered lipopolysaccharide intravenously to induce endotoxin shock, while three female pigs served as the control group. Measurements of EaDyn (ratio between pulse pressure variation (PPV) and stroke volume variation (SVV)), effective arterial elastance, arterial compliance (Cart), and systemic vascular resistance were taken every 30 minutes in the endotoxin group until shock was induced. In the control group, these variables were measured every 30 minutes for 3 hours. Subsequently, a fluid load was administered to both groups, and measurements were repeated every 30 minutes. After one hour of shock induction, the endotoxin group was divided into two subgroups: one receiving norepinephrine (END-NE) and the other not receiving it (END-F).

Results

EaDyn showed an association with Cart, while PPV was connected to both pulsatile and steady components, and SVV was solely associated with steady components. Additionally, EaDyn exhibited higher values in the END groups than in the control group when shock was achieved. Furthermore, after the administration of norepinephrine, EaDyn displayed higher values in END-F than in END-NE.

Conclusions

The EaDyn variable helps identify changes in the pulsatile component of arterial load, providing valuable guidance for management strategies aimed at improving cardiac performance.
Isolated Sixth Nerve Palsy and COVID-19: A Recurrent Case in a 7-Month-Old Child and Analysis of Reported Cases
Authors: Baldwin Grace E. , Gaier Eric D. , Hennein Lauren M.
Published: August 2023

Background:

With the SARS-CoV-2 pandemic (COVID-19), data on central and peripheral nervous system involvement, including those causing cranial nerve 6 (CN6) palsy, have been limited to case reports. To extract clinically relevant features of COVID-19–related CN6 palsy, we report on a recurrent pediatric case and analysis of reported cases associated with infection or immunization.

Methods:

A PubMed search revealed 18 cases of isolated CN6 palsy in addition to the index case (n = 19). Clinical characteristics, workup, and temporal associations between systemic symptoms onset or vaccination, symptoms onset, and resolution were compiled and analyzed.

Results:

The median age of CN6 onset was 43 years (interquartile range [IQR]: 28–52). Sixteen cases (84.2%) were associated with COVID-19 illness and 3 (15.8%) were associated with COVID-19 vaccination. Four cases (23.5%) had positive neuroimaging findings. The median latency from first COVID-19 symptoms or vaccination to onset of CN6 palsy was 6 days (IQR: 2.3–16), and the median time from onset to resolution was 30 days (IQR: 14–60). Latency to onset of CN6 palsy was significantly and directly associated with time to resolution (R2 = 0.401, P = 0.010). Patients who had a positive SARS-CoV-2 antibody test had significantly longer days from symptoms to onset (6.0 vs 24.5, P = 0.030), and patients with a positive SARS-CoV-2 polymerase chain reaction test had a significantly shorter time to resolution (17.50 vs 90, P = 0.042).

Conclusions:

Isolated CN6 palsy from COVID-19 is rare, can occur in infants as young as 7 months, and can be recurrent. Longer latency from systemic symptoms onset portends greater recovery times, and this relationship may reflect multiple mechanisms by which COVID-19 (and/or an immune response thereto) causes cranial neuropathies with direct clinical relevance.
Causal lifting and link prediction
Authors: Cotta Leonardo , Bevilacqua Beatrice , Ahmed Nesreen , Ribeiro Bruno
Published: August 2023

Existing causal models for link prediction assume an underlying set of inherent node factors—an innate characteristic defined at the node’s birth—that governs the causal evolution of links in the graph. In some causal tasks, however, link formation is
path-dependent
: the outcome of link interventions depends on existing links. Unfortunately, these existing causal methods are not designed for path-dependent link formation, as the cascading functional dependencies between links (arising from
path dependence
) are either unidentifiable or require an impractical number of control variables. To overcome this, we develop the first causal model capable of dealing with path dependencies in link prediction. In this work, we introduce the concept of causal lifting, an invariance in causal models of independent interest that, on graphs, allows the identification of causal link prediction queries using limited interventional data. Further, we show how structural pairwise embeddings exhibit lower bias and correctly represent the task’s causal structure, as opposed to existing node embeddings, e.g. graph neural network node embeddings and matrix factorization. Finally, we validate our theoretical findings on three scenarios for causal link prediction tasks: knowledge base completion, covariance matrix estimation and consumer-product recommendations.
Optimal intercellular competition in senescence and cancer
Authors: Michaels Thomas C. T. , Mahadevan L.
Published: August 2023

Effective multicellularity requires both cooperation and competition between constituent cells. Cooperation involves sacrificing individual fitness in favour of that of the community, but excessive cooperation makes the community susceptible to senescence and ageing. Competition eliminates unfit senescent cells via natural selection and thus slows down ageing, but excessive competition makes the community susceptible to cheaters, as exemplified by cancer and cancer-like phenomena. These observations suggest that an optimal level of intercellular competition in a multicellular organism maximizes organismal vitality by delaying the inevitability of ageing. We quantify this idea using a statistical mechanical framework that leads to a generalized replicator dynamical system for the population of cells that changes their vitality and cooperation due to somatic mutations that make them susceptible to ageing and/or cancer. By accounting for the cost of cooperation and strength of competition in a minimal setting, we show that our model predicts an optimal value of competition that maximizes vitality and delays the inevitability of senescence or cancer. The results have implications for the design of strategies aimed at delaying ageing in biological, technical and social systems that exhibit similar processes.
Third-party punishers who express emotions are trusted more
Authors: Kupfer Tom R. , Tybur Joshua M.
Published: August 2023

Third party punishment (TPP) is thought to be crucial to the evolution and maintenance of human cooperation. However, this type of punishment is often not rewarded, perhaps because punishers' underlying motives are unclear. We propose that the expression of moral emotions could solve this problem by advertising such motives. In each of three experiments (n= 1711), a third-party punishment game was followed by a trust game. Third parties expressed anger or disgust instead of, or in addition to, financial punishment. Results showed that third parties who expressed these emotions were trusted more than those who didn't express (Experiment 1), and more than those who financially punished (Experiment 2). Moreover, third parties who expressed while financially punishing were trusted more than those who punished without expressing (Experiment 3). Findings suggest that emotion expression might play a role in the evolution and maintenance of cooperation by facilitating TPP.
Lelliottia amnigena recovered from the lung of a harbour porpoise, and comparative analyses with Lelliottia spp.
Authors: Negus David , Foster Geoffrey , Hoyles Lesley
Published: August 2023

Strain M1325/93/1 (= GFKo1) of Lelliottia amnigena was isolated from the lung of a harbour porpoise in 1993. The genome sequence and antimicrobial resistance profile (genomic, phenotypic) of the strain were generated, with the genomic data compared with those from closely related bacteria. We demonstrate the recently described chromosomally-encoded AmpC β-lactamase blaLAQ is a core gene of L. amnigena, and suggest new variants of this class of lactamase are encoded by other members of the genus Lelliottia. Although presence of blaLAQ is ubiquitous across the currently sequenced members of L. amnigena, we highlight that strain GFKo1 is sensitive to ampicillin and cephalosporins. These data suggest blaLAQ may act as a useful genetic marker for identification of L. amnigena strains, but its presence may not correlate with expected phenotypic resistances. Further studies are required to determine the regulatory mechanisms of blaLAQ in L. amnigena.
The Relationship between microbial population adenosine triphosphate and quantitative polymerase chain reaction bioburdens in diesel fuel microcosms
Authors: Passman Frederick Jay , Schmidt Jordan , Nicoletti Danika
Published: August 2023

Fluid samples drawn from the fuel, interface, and water phases of fuel over water microcosms were tested for cellular adenosine triphosphate concentration ([cATP]), and quantitative polymerase chain reaction (qPCR) bioburdens. Additionally, surface swab samples from steel corrosion coupon surfaces exposed to each of these three phases were collected and tested for total ATP concentration ([tATP]) and qPCR bioburdens. Relationships between ATP and qPCR bioburdens were examined. Correlation coefficients between the two variables were matrix dependent and ranged from negligible (|r| = 0.2) to strong (|r| = 0.7). When results were categorized into negligible, moderate and heavy bioburdens, parameter agreement was again matrix dependent and ranged from 11% to 89% – with qPCR-bioburden ratings typically being greater than ATP-bioburden ratings.
VP24 matrix proteins of eight filoviruses downregulate innate immune response by inhibiting the interferon-induced pathway
Authors: Khan Hira , Tripathi Lav , Kolehmainen Pekka , Lundberg Rickard , Altan Eda , Heroum Jemna , Julkunen Ilkka , Kakkola Laura , Huttunen Moona
Published: August 2023

Filoviruses encode viral protein 24 (VP24) which effectively inhibit the innate immune responses in infected cells. Here we systematically analysed the effects of nine mammalian filovirus VP24 proteins on interferon (IFN)-induced immune response. We transiently expressed Ebola, Bombali, Bundibugyo, Reston, Sudan and Taï Forest ebolavirus (EBOV, BOMV, BDBV, RESTV, SUDV, TAFV, respectively), Lloviu virus (LLOV), Mengla dianlovirus (MLAV) and Marburgvirus (MARV) VP24 proteins and analysed their ability to inhibit IFN-α-induced activation of myxovirus resistance protein 1 (MxA) and interferon-induced transmembrane protein 3 (IFITM3) promoters. In addition, we analysed the expression of endogenous MxA protein in filovirus VP24-expressing cells. Eight filovirus VP24 proteins, including the VP24s of the recently discovered MLAV, BOMV and LLOV, inhibited IFN-induced MxA and IFITM3 promoter activation. MARV VP24 was the only protein with no inhibitory effect on the activation of either promoter. Endogenous MxA protein expression was impaired in cells transiently expressing VP24s with the exception of MARV VP24. We mutated nuclear localization signal (NLS) of two highly pathogenic filoviruses (EBOV and SUDV) and two putatively non-pathogenic filoviruses (BOMV and RESTV), and showed that the inhibitory effect on IFN-induced expression of MxA was dependent on functional cluster 3 of VP24 nuclear localization signal. Our findings suggest that filovirus VP24 proteins are both genetically and functionally conserved, and that VP24 proteins of most filovirus species are capable of inhibiting IFN-induced antiviral gene expression thereby efficiently downregulating the host innate immune responses.
Inferring personal intake recommendations of phosphorous and potassium for end-stage renal failure patients by simulating with Bayesian hierarchical multivariate model
Authors: Turkia Jari , Schwab Ursula , Hautamäki Ville
Published: August 2023

Most end-stage renal disease (ESRD) patients face a risk of malnutrition, partly due to dietary restrictions on phosphorous and, in some cases, potassium intake. These restrictions aim to regulate plasma phosphate and potassium concentrations and prevent the adverse effects of hyperphosphatemia or hyperkalemia. However, individual responses to nutrition are known to vary, highlighting the need for personalized recommendations rather than relying solely on general guidelines. In this study, our objective was to develop a Bayesian hierarchical multivariate model that estimates the individual effects of nutrients on plasma concentrations and to present a recommendation algorithm that utilizes this model to infer personalized dietary intakes capable of achieving normal ranges for all considered concentrations. Considering the limited research on the reactions of ESRD patients, we collected dietary intake data and corresponding laboratory analyses from a cohort of 37 patients. The collected data were used to estimate the common hierarchical model, from which personalized models of the patients’ diets and individual reactions were extracted. The application of our recommendation algorithm revealed substantial variations in phosphorus and potassium intakes recommended for each patient. These personalized recommendations deviate from the general guidelines, suggesting that a notably richer diet may be proposed for certain patients to mitigate the risk of malnutrition. Furthermore, all the participants underwent either hospital, home, or peritoneal dialysis treatments. We explored the impact of treatment type on nutritional reactions by incorporating it as a nested level in the hierarchical model. Remarkably, this incorporation improved the fit of the nutritional effect model by a notable reduction in the normalized root mean square error (NRMSE) from 0.078 to 0.003. These findings highlight the potential for personalized dietary modifications to optimize nutritional status, enhance patient outcomes, and mitigate the risk of malnutrition in the ESRD population.
Key variants via Alzheimer’s Disease Sequencing Project whole genome sequence data
Authors: Wang Yanbing , Sarnowski Chloé , Lin Honghuang , Pitsillides Achilleas N , Heard-Costa Nancy L , Choi Seung Hoan , Wang Dongyu , Bis Joshua C , Blue Elizabeth E ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Boerwinkle Eric , De Jager Philip L , Fornage Myriam , Wijsman Ellen M , Seshadri Sudha , Dupuis Josée , Peloso Gina M , DeStefano Anita L ,   Alzheimer’s Disease Sequencing Project (ADSP)
Published: August 2023

INTRODUCTION

Genome-wide association studies (GWAS) have identified loci associated with Alzheimer’s disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci.

METHODS

We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases=2,184, N controls=2,383) and targeted analyses in sub-populations using WGS data from the Alzheimer’s Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants.

RESULTS

Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses.

DISCUSSION

This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS.
Encyclopaedia of family A DNA polymerases localized in organelles: Evolutionary contribution of bacteria including the proto-mitochondrion
Authors: Harada Ryo , Hirakawa Yoshihisa , Yabuki Akinori , Kim Eunsoo , Yazaki Euki , Kamikawa Ryoma , Nakano Kentaro , Eliáš Marek , Inagaki Yuji
Published: August 2023

DNA polymerases (DNAPs) synthesize DNA from deoxyribonucleotides in a semi-conservative manner and serve as the core of DNA replication and repair machineries. In eukaryotic cells, there are two genome-containing organelles, mitochondria and plastids, that were derived from an α-proteobacterium and a cyanobacterium, respectively. Except for rare cases of genome-lacking mitochondria and plastids, both organelles must be served by nucleus-encoded DNAPs that localize and work in them to maintain their genomes. The evolution of organellar DNAPs has yet to be fully understood because of two unsettled issues. First, the diversity of organellar DNAPs has not been elucidated in the full spectrum of eukaryotes. Second, it is unclear when the DNAPs that were used originally in the endosymbiotic bacteria giving rise to mitochondria and plastids were discarded, as the organellar DNAPs known to date show no phylogenetic affinity to those of the extant α-proteobacteria or cyanobacteria. In this study, we identified from diverse eukaryotes 134 family A DNAP sequences, which were classified into 10 novel types, and explored their evolutionary origins. The subcellular localizations of selected DNAPs were further examined experimentally. The results presented here suggest that the diversity of organellar DNAPs has been shaped by multiple transfers of the PolIgene from phylogenetically broad bacteria, and their occurrence in eukaryotes was additionally impacted by secondary plastid endosymbioses. Finally, we propose that the last eukaryotic common ancestor may have possessed two mitochondrial DNAPs, POP and a candidate of the direct descendant of the proto-mitochondrial DNAP, rdxPolA, identified in this study.
Chlorpheniramine Maleate Displays Multiple Modes of Antiviral Action Against SARS-CoV-2: A Mechanistic Study
Authors: Elshaier Yaseen A. M. M. , Mostafa Ahmed , Valerio-Pascua Fernando , Tesch Mari L. , Costin Joshua M. , Rahaghi Franck F.
Published: August 2023

Chlorpheniramine Maleate (CPM) has been identified as a potential antiviral compound against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In this study, we investigated the in vitro effects of CPM on key stages of the SARS-CoV-2 replication cycle, including viral adsorption, replication inhibition, and virucidal activity. Our findings demonstrate that CPM exhibits antiviral properties by interfering with viral adsorption, replication, and directly inactivating the virus. Molecular docking analysis revealed interactions between CPM and essential viral proteins, such as the main protease receptor, spike protein receptor, and RNA polymerase. CPM’s interactions were primarily hydrophobic in nature, with an additional hydrogen bond formation in the RNA polymerase active site. These results suggest that CPM has the potential to serve as a multitarget antiviral agent against SARS-CoV-2 and potentially other respiratory viruses. Further investigations are warranted to explore its clinical implications and assess its efficacy in vivo.
3D Printed Ti3C2TxMXene/PCL Scaffolds for Guided Neuronal Growth and Photothermal Stimulation
Authors: Li Jianfeng , Hashemi Payam , Liu Tianyi , Dang Ka My , Brunk Michael G.K. , Mu Xin , Nia Ali Shaygan , Sacher Wesley D. , Feng Xinliang , Poon Joyce K. S.
Published: August 2023

The exploration of neural circuitry is essential for understanding the computational mechanisms and physiology of the brain. Despite significant advances in materials and fabrication techniques, controlling neuronal connectivity and response in three dimensions continues to present a formidable challenge. Here, we present a method for engineering the growth of three-dimensional (3D) neural circuits with the capability for optical stimulation. We fabricated bioactive interfaces by melt electrospinning writing (MEW) of 3D printed polycaprolactone (PCL) scaffolds followed by coating with titanium carbide (Ti3C2TxMXene). Beyond enhancing hydrophilicity, cell adhesion, and electrical conductivity, the Ti3C2TxMXene coating enabled optocapacitance-based neuronal stimulation due to illumination-induced local temperature increases. This work presents a strategy for additive manufacturing of neural tissues with optical control for functional tissue engineering and neural circuit computation.
XVir: A Transformer-Based Architecture for Identifying Viral Reads from Cancer Samples
Authors: Consul Shorya , Robertson John , Vikalo Haris
Published: August 2023

It is estimated that approximately 15% of cancers world-wide can be linked to viral infections. The viruses that can cause or increase the risk of cancer include human papillomavirus, hepatitis B and C viruses, Epstein-Barr virus, and human immunodeficiency virus, to name a few. The computational analysis of the massive amounts of tumor DNA data, whose collection is enabled by the recent advancements in sequencing technologies, have allowed studies of the potential association between cancers and viral pathogens. However, the high diversity of oncoviral families makes reliable detection of viral DNA difficult and thus, renders such analysis challenging. In this paper, we introduce XVir, a data pipeline that relies on a transformer-based deep learning architecture to reliably identify viral DNA present in human tumors. In particular, XVir is trained on genomic sequencing reads from viral and human genomes and may be used with tumor sequence information to find evidence of viral DNA in human cancers. Results on semi-experimental data demonstrate that XVir is capable of achieving high detection accuracy, generally outperforming state-of-the-art competing methods while being more compact and less computationally demanding.

CCS CONCEPTS

•Computer systems organization→Embedded systems;Redundancy; Robotics; •Networks→ Network reliability.

ACM Reference Format

Shorya Consul, John Robertson, and Haris Vikalo. 2023. XVir: A Transformer-Based Architecture for Identifying Viral Reads from Cancer Samples. InProceedings of The Eighth International Workshop on Computational Network Biology: Modeling, Analysis, and Control (CNB-MAC ’23). ACM, New York, NY, USA, 8 pages.
Viscosity Prediction of High-Concentration Antibody Solutions with Atomistic Simulations
Authors: Prass Tobias M. , Garidel Patrick , Blech Michaela , Schäfer Lars V.
Published: August 2023

The computational prediction of the viscosity of dense protein solutions is highly desirable, for example in the early development phase of high-concentration biophar-maceutical formulations where the material needed for experimental determination is typically limited. Here, we use large-scale atomistic molecular dynamics (MD) simulations with explicit solvent tode novopredict the dynamic viscosities of solutions of a monoclonal IgG1 antibody (mAb) from the pressure fluctuations using a Green-Kubo approach. The viscosities at simulated mAb concentrations of 200 mg/ml and 250 mg/ml are compared to the experimental values, which we measured with rotational rheometry. The computational viscosity of 24 mPa s at a mAb concentration of 250 mg/ml matches the experimental value of 23 mPa s obtained at a concentration of 213 mg/ml, indicating slightly different effective concentrations (or activities) in the MD simulations and in the experiments. This difference is assigned to a slight underestimation of the effective mAb-mAb interactions in the simulations, leading to a too loose dynamic mAb network that governs the viscosity. Taken together, the present study demonstrates the feasibility of all-atom MD simulations for predicting the properties of dense mAb solutions and provides detailed microscopic insights into the underlying molecular interactions. At the same time, it also shows that there is room for further improvements and highlights challenges, such as the massive sampling required for computing collective properties of dense biomolecular solutions in the high-viscosity regime with reasonable statistical precision.

TOC Graphic
Multi-species benchmark analysis for LC-MS/MS validation and performance evaluation in bottom-up proteomics
Authors: Jumel Tobias , Shevchenko Andrej
Published: August 2023

We present an instrument-independent benchmarking procedure and software (LFQ_bout) for validation and comparative evaluation of the performance of LC-MS/MS and data processing workflows in bottom-up proteomics. It enables back-to-back comparison of common and emerging workflows, e.g. diaPASEF or ScanningSWATH, and evaluates the impact of arbitrary, inadequately documented settings or black-box data processing algorithms. The procedure enhances the overall performance and quantitative accuracy while enabling the detection of major error types.
On the Genetic Origins of Phenotypes in Genome-Wide Association Studies: The SNP Allocation For Estimating Heritability (SAFE-h2) Tool to Explore Additive-only Allelic Effects or Additive and Non-Additive Allelic Effects
Authors: Darbani Behrooz , Nicolaisen Mogens
Published: August 2023

Polygenicity requires the inclusion of all SNPs to ensure accurate estimation of SNP heritability. However, SNPs with large associationp-values should be excluded, as they impose biologically meaningless negative contributions to heritability estimates. This is demonstrated with simulated data and validated using real-world datasets. We introduce SAFE-h2as a solution to this dilemma. SAFE-h2performs heritability profiling and establishes ap-value threshold to filter out SNPs with negative contributions. By examining 74 phenotypes across eight species, SAFE-h2revealed an average negative contribution of 30 units, imposed by SNPs from the upper-bounds ofp-value thresholds. SAFE-h2also provides a safep-value interval to minimize false-positive SNP hits and facilitates capturing intra-locus (Ref-alleleSNPi×Ref-alleleSNPi,Ref- alleleSNPi×Alt-alleleSNPi, andAlt-alleleSNPi×Alt-alleleSNPi) additive and non-additive effects within the framework of linear models. The allelic adjustment algorithm of SAFE-h2revealed considerable uncaptured phenotypic variance when relying on additive effects and improved the SNP heritability estimations up to 56 units for 50 phenotypes in six species.
SQUARNA - an RNA secondary structure prediction method based on a greedy stem formation model
Authors: Bohdan Davyd R. , Nikolaev Grigory I. , Bujnicki Janusz M. , Baulin Eugene F.
Published: August 2023

Non-coding RNAs play a diverse range of roles in various cellular processes, with their spatial structure being pivotal to their function. The RNA’s secondary structure is a key determinant of its overall fold. Given the scarcity of experimentally determined RNA 3D structures, understanding the secondary structure is vital for discerning the molecule’s function. Currently, there is no universally effective solution for de novo RNA secondary structure prediction. Existing methods are becoming increasingly complex without marked improvements in accuracy, and they often overlook critical elements such as pseudoknots. In this work, we introduce SQUARNA, a novel approach to de novo RNA secondary structure prediction. This method utilizes a simple, greedy stem formation model, addressing many of the limitations inherent in previous tools. Our benchmarks demonstrate that SQUARNA matches the performance of leading methods for single sequence inputs and significantly surpasses existing tools when applied to sequence alignment inputs.
Ancient farmer and steppe pastoralist-related founding lineages contributed to the complex landscape of episodes in the diversification of Chinese paternal lineages
Authors: Wang Mengge , Huang Yuguo , Liu Kaijun , Yuan Haibing , Duan Shuhan , Wang Zhiyong , Wei Lanhai , Yao Hongbing , Sun Qiuxia , Zhong Jie , Tang Renkuan , Chen Jing , Sun Yuntao , Li Xiangping , Su Haoran , Yang Qingxin , Hu Liping , Yun Libing , Yang Junbao , Nie Shengjie , Cai Yan , Yan Jiangwei , Zhou Kun ,   10K_CPGDP Consortium, Wang Chuanchao , Zhu Bofeng , Liu Chao , He Guanglin
Published: August 2023

Ancient DNA advances have reported the complex genetic history of Eurasians, but how the knowledge of ancient subsistence strategy shifts and population movements influenced the fine-scale paternal genetic structure in East Asia has not been assessed. Here, we reported one integrated Y-chromosome genomic database of 15,530 people, including 1753 ancient people and newly-reported 919 individuals genotyped using our recently-developed targeted sequencing YHSeqY3000 panel, to explore Chinese genomic diversity, population evolutionary tracts and their genetic formation mechanism. We identified four major ancient technological innovations and population movements that shaped the landscape of Chinese paternal lineages. First, the expansion of millet farmers and early East Asians from the Yellow River Basin carrying the major O2/D subclades promoted the formation of the Sino-Tibetan people’s major composition and accelerated the Tibetan Plateau’s permanent occupation. Second, rice farmers’ dispersal from the Yangtze River Valley carrying O1 and some sublineages of O2 contributed significantly to Tai-Kadai, Austronesian, Hmong-Mien, Austroasiatic people and southern Han Chinese. Third, Siberian-related paternal lineages of Q and C originated and boomed from Neolithic hunter-gatherers from the Mongolian Plateau and the Amur River Basin and significantly influenced the gene pools of northern Chinese. Fourth, western Eurasian-derived J, G and R lineages initially spread with Yamnaya steppe pastoralists and other proto-Indo-European people and further widely dispersed via the trans-Eurasian cultural communication along the Eurasian Steppe and the ancient Silk Road, remaining genetic trajectories in northwestern Chinese. Our work provided comprehensive modern and ancient genetic evidence to illuminate the impact of population interaction from the ancient farmer or herder-based societies on the genetic diversity patterns of modern people, revised our understandings of ancestral sources of Chinese paternal lineages, underscored the scientific imperative of the large-scale genomic resources of dense spatiotemporal underrepresented sampling populations to understand human evolutionary history.
Evolutionary analysis of mammalian Rem2, a member of the RGK (Rem, Rem2, Rad, and Gem/Kir) family of small GTPases, reveals the role of selection and epistasis in shaping protein functional constraints
Authors: Lucaci Alexander G , Brew William E , Pond Sergei L Kosakovsky , Moore Anna R
Published: August 2023

Rad And Gem-Like GTP-Binding Protein 2 (Rem2), is a member of the RGK family of Ras-like GTPases and has been identified in various mammalian species.Rem2has been implicated in Huntington’s disease and Long QT Syndrome and is highly expressed in the brain and in endocrine cells. In this study, we examined the evolutionary history ofRem2across mammals, focusing on the role of purifying selection and epistasis in shaping its sequence and structure. In our analysis ofRem2sequences across 175 mammalian species, we found evidence for strong purifying selection in 70% of non-invariant codon sites of the protein, characteristic of essential proteins that play critical roles in biological processes and is consistent withRem2’s role in the regulation of neuronal development and function. We inferred epistatic effects in 49 pairs of coevolving codon sites inRem2,some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalianRem2using protein structure prediction of extinct and extant sequences. This analysis revealed the dynamics of how substitutions that change the genetic distance of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and genetic-interactions that have shaped the sequence and structure of the Rem2 protein, we may gain a stronger understanding of its biological and functional constraints.
Absence of chromosome axis proteins recruitment prevents meiotic recombination chromosome-wide in the budding yeastLachancea kluyveri
Authors: Legrand Sylvain , Saifudeen Asma , Bordelet Hélène , Vernerey Julien , Guille Arnaud , Bignaut Amaury , Thierry Agnès , Acquaviva Laurent , Gaudin Maxime , Sanchez Aurore , Johnson Dominic , Friedrich Anne , Schacherer Joseph , Neale Matthew , Borde Valérie , Koszul Romain , Llorente Bertrand
Published: August 2023

Meiotic recombination shows broad variations across species and along chromosomes, and is often suppressed at and around genomic regions determining sexual compatibility such as mating type loci in fungi. Here we show that the absence of Spo11-DSBs and meiotic recombination on Lakl0C-left, the chromosome arm containing the sex locus of theLachancea kluyveribudding yeast, results from the absence of recruitment of the two chromosome axis proteins Red1 and Hop1, essential for proper Spo11-DSBs formation. Furthermore, cytological observation of spread pachytene meiotic chromosomes reveals that Lakl0C-left does not undergo synapsis. However, we show that the behavior of Lakl0C-left is independent of its particularly early replication timing and is not accompanied by any peculiar chromosome structure as detectable by Hi-C in this yet poorly studied yeast. Finally, we observed an accumulation of heterozygous mutations on Lakl0C-left and a sexual dimorphism of the haploid meiotic offspring, supporting a direct effect of this absence of meiotic recombination onL. kluyverigenome evolution and fitness. Because suppression of meiotic recombination on sex chromosomes is widely observed across eukaryotes, the novel mechanism for recombination suppression described here may apply to other species, with the potential to impact sex chromosome evolution.
Metabolic Trade-offs can Reverse the Resource-Diversity Relationship
Authors: Miller Zachary R. , O’Dwyer James P.
Published: August 2023

For species that partition resources, the classic expectation is that increasing resource diversity allows for increased species diversity. On the other hand, for neutral species, such as those competing equally for a single resource, diversity reflects a balance between the rate of introduction of novelty (for example by immigration or speciation) and the rate of extinction. Recent models of microbial metabolism have identified scenarios where metabolic trade-offs among species partitioning multiple resources can produce emergent neutral-like dynamics. In this hybrid scenario, one might expect that both resource diversity and immigration will act to boost species diversity. We show, however, that the reverse may be true: when metabolic trade-offs hold and population sizes are sufficiently large, increasing resource diversity can act to reduce species diversity, sometimes drastically. This reversal is explained by a generic transition between neutral- and niche-like dynamics, driven by the diversity of resources. The inverted resource-diversity relationship that results may be a signature of consumer-resource systems with strong metabolic trade-offs.
CD8 T-cell dysfunction is linked with CAR T-cell failure and can be mitigated by a non-alpha IL-2 agonist, pegenzileukin
Authors: Reville Patrick K , Sheikh Irtiza N , Choi Ahyun , Dai Enyu , Henderson Jared , Li Xubin , Rojas Estela , Le Cuong , Okwuchi Chizitara , Devonish Mikielia , Carrio Roberto , Pate Nathan , Malley Katie , Bangari Dinesh , Givigan Julie-Ann , Shi Chaomei , Liu Bing , Byers Tony , Westin Jason , Ahmed Sairah , Fowler Nathan , Fayad Luis , Lee Hun Ju , Nastoupil Loretta , Sassoon Ingrid , Cucchetti Margot , Wang Rui , Agarwal Maria , Abbadessa Giovanni , Meng Robin , Meibalan Elamaran , Powers Laura , Cao James , Ying Xiaoyou , Balko Kelly , Yu Qunyan , Jiao Jing , Cortez-Retamozo Virna , Sidhu Sukhvinder , Shaffer Donald , Neelapu Sattva , Wang Linghua , Li Xiangming , Green Michael
Published: August 2023

Chimeric antigen receptor (CAR) T-cell therapy has been a breakthrough for relapsed or refractory large B-cell lymphoma (rrLBCL). However, suboptimal CAR T-cell activity can lead to therapeutic failure and dismal outcome. Using single cell RNA-sequencing of rrLBCL tumors, we identify a prominent population of clonally expanded dysfunctional CAR+ CD8 T-cells indicative of ongoing tumor cell engagement, proliferation, and dysfunction at the time of progression from CAR T-cell therapy. Furthermore, we show that rrLBCL patient-derived CAR T-cells are more prone to dysfunction and loss of cytotoxicity compared to healthy donor-derived CAR T-cells. Using both antigen-driven and CAR-driven models of T-cell dysfunction, we show that pegenzileukin, a non-alpha IL2 agonist, can prevent T-cell dysfunction. In bothin vitroandin vivoCAR T-cell models, pegenzileukin improved T-cell expansion and tumor control. This provides pre-clinical rational for use of pegenzileukin in combatting T-cell dysfunction, a central mechanism of CAR T-cell failure.

HIGHLIGHTS

Tumor-infiltrating CD8 CAR T-cells show clonal expansion and dysfunction at the time of progression.

rrLBCL patient-derived CAR T-cells are more prone to dysfunction compared to healthy-donor-derived CAR T-cells.

Pegenzileukin, a non-alpha IL2 agonist, rescues antigen– and CAR-driven CD8 T-cell dysfunction and improves CAR T-cell responses in vivo.
Cis-regulatory polymorphism atfizecdysone oxidase contributes to polygenic adaptation to malnutrition inDrosophila
Authors: Cavigliasso Fanny , Savitskiy Mikhail , Koval Alexey , Erkosar Berra , Savary Loriane , Gallart-Ayala Hector , Ivanisevic Julijana , Katanaev Vladimir L. , Kawecki Tadeusz J.
Published: August 2023

We investigate the contribution of a candidate gene,fiz(fezzik), to complex polygenic adaptation to juvenile malnutrition inDrosophila melanogaster. We show that experimental populations adapted during >250 generations of experimental evolution to a nutritionally poor larval diet (Selected populations) evolved several-fold lowerfizexpression compared to unselected Control populations. This divergence infizexpression is mediated by a cis-regulatory polymorphism. This polymorphism, which was originally present in a sample from a natural population in Switzerland, is distinct from a second cis-regulatory SNP previously identified in non-AfricanD. melanogasterpopulations, implying that two independent cis-regulatory variants promoting highfizexpression segregate in non-African populations. Enzymatic analyses of Fiz protein expressed inE. colidemonstrate that it has ecdysone oxidase activity acting on both ecdysone and 20-hydroxyecdysone. Four of fivefizparalogs annotated to ecdysteroid metabolism also show reduced expression in Selected larvae, suggesting that malnutrition-driven selection favored general downregulation of ecdysone oxidases. Finally, as an independent test of the role offizin poor diet adaptation, we show thatfizknockdown by RNAi results in faster larval growth on the poor diet, but at the cost of greatly reduced survival. These results imply that downregulation offizin Selected populations was favored because of its role in suppressing growth in response to nutrient shortage. However,fizdownregulation is only adaptive in combination with other changes evolved by Selected populations, such as in nutrient acquisition and metabolism, which ensure that the organism can actually sustain the faster growth promoted byfizdownregulation.
Machine learning-based investigation of regulated cell death for predicting prognosis and immunotherapy response in glioma patients
Authors: Zhang Wei , Liu Hongyi , Dang Ruiyue , Dai Luohuan , Liu Hongwei , Adegboro Abraham Ayodeji , Zhang Yihao , jiang Nian , Li Xuejun
Published: August 2023

Background

Glioblastoma is a highly aggressive and malignant type of brain cancer that originates from glial cells in the brain, with a median survival time of 15 months and a 5-year survival rate of less than 5%. Regulated cell death (RCD) is the autonomous and orderly cell death under genetic control, controlled by precise signaling pathways and molecularly defined effector mechanisms, modulated by pharmacological or genetic interventions, and plays a key role in maintaining homeostasis of the internal environment. The comprehensive and systemic landscape of the RCD in glioma is not fully investigated and explored.

Method

After collecting 18 RCD-related signatures from the opening literatures, we comprehensively explored the RCD landscape, integrating the multi-omics data, including large-scale bulk data, single-cell level data, glioma cell lines, and proteome level data. We also provided a machine learning framework for screening the potentially therapeutic candidates.

Result

Here, we explored RCD-related phenotypes, investigated the profile of the RCD, and developed a RCD gene pair scoring system, named RCD.GP signature. Using the machine learning framework consisting of Lasso, RSF, XgBoost, Enet, CoxBoost and Boruta, we identified seven RCD genes as potential therapeutic targets in glioma and verified the SLC43A3 by q-PCR in glioma grades and glioma cell lines.

Conclusion

Our study provided comprehensive insights into the RCD roles in glioma, developed a robust RCD gene pair signature for predicting the prognosis of glioma patients, constructed a machine learning framework for screening the core candidates and identified the SLC43A3 as an oncogenic role and a prediction biomarker in glioblastoma.
Preliminary cross-sectional investigations into the human glymphatic system using multiple novel non-contrast MRI methods
Authors: Levendovszky Swati Rane , Flores Jaqueline , Peskind Elaine R. , Václavů Lena , van Osch Matthias J.P. , Iliff Jeffrey
Published: August 2023

We discuss two potential non-invasive MRI methods to cross-sectionally study two distinct facets of the glymphatic system and its association with sleep and aging.

We apply diffusion-based intravoxel incoherent motion (IVIM) imaging to evaluate pseudodiffusion coefficient,D*, or cerebrospinal fluid (CSF) movement across large spaces like the subarachnoid space (SAS). We also performed perfusion-based multi-echo, Hadamard encoded multi-delay arterial spin labeling (ASL) to evaluate whole brain cortical cerebral blood flow (CBF) and transendothelial exchange (Tex) of water from the vasculature into the perivascular space and parenchyma. Both methods were used in young adults (N=9, 6F, 23±3 years old) in the setting of sleep and sleep deprivation. To study aging, 10 older adults, (6F, 67±3 years old) were imaged after a night of normal sleep only and compared with the young adults.D*in SAS was significantly (p<0.05) lesser after sleep deprivation (0.014±0.001 mm2/s) than after normal sleep (0.016±0.001 mm2/s), but was unchanged with aging. Cortical CBF and Texon the other hand, were unchanged after sleep deprivation but were significantly lower in older adults (37±3 ml/100g/min, 476±66 ms) than young adults (42±2 ml/100g/min, 624±66 ms). IVIM was thus, sensitive to sleep physiology and multi-echo, multi-delay ASL was sensitive to aging.