bluuebunny/crossref_metadata_2025 huggingface dataset:
Imbalance between default mode and sensorimotor connectivity is associated with perseverative thinking in obsessive-compulsive disorder
Authors: Stern Emily R. , Eng Goi Khia , De Nadai Alessandro S. , Iosifescu Dan V. , Tobe Russell H. , Collins Katherine A.
Published: January 2022

Obsessive-compulsive disorder (OCD) is highly heterogeneous. Although perseverative negative thinking (PT) is a feature of OCD, little is known about its neural mechanisms or relationship to clinical heterogeneity in the disorder. In a sample of 85 OCD patients, we investigated the relationships between self-reported PT, clinical symptom subtypes, and resting-state functional connectivity measures of local and global connectivity. Results indicated that PT scores were highly variable within the OCD sample, with greater PT relating to higher severity of the “unacceptable thoughts” symptom dimension. PT was positively related to local connectivity in subgenual anterior cingulate cortex (ACC), pregenual ACC, and the temporal poles—areas that are part of, or closely linked to, the default mode network (DMN)—and negatively related to local connectivity in sensorimotor cortex. While the majority of patients showed higher local connectivity strengths in sensorimotor compared to DMN regions, OCD patients with higher PT scores had less of an imbalance between sensorimotor and DMN connectivity than those with lower PT scores, with healthy controls exhibiting an intermediate pattern. Clinically, this imbalance was related to both the “unacceptable thoughts” and “symmetry/not-just-right-experiences” symptom dimensions, but in opposite directions. These effects remained significant after accounting for variance related to psychiatric comorbidity and medication use in the OCD sample, and no significant relationships were found between PT and global connectivity. These data indicate that PT is related to symptom and neural variability in OCD. Future work may wish to target this circuity when developing personalized interventions for patients with these symptoms.
Somatic copy number alteration predicts clinical benefit of lung adenocarcinoma patients treated with cytokine-induced killer plus chemotherapy
Authors: Kou Fan , Wu Lei , Zhu Ye , Li Baihui , Huang Ziqi , Ren Xiubao , Yang Lili
Published: January 2022

Somatic copy number alterations (SCNA), which are widespread in cancer, can predict the efficacy of immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC). However, the usefulness of SCNA for predicting the survival of patients treated with cytokine-induced killer (CIK) cells or chemotherapy (CT) is unknown. This study aimed to explore the correlation between SCNA and clinical outcome in NSCLC patients treated with CIK + CT or CT alone. We performed whole-exome sequencing on 45 NSCLC patients treated with CIK + CT, as well as 305 NSCLC patients treated with CT alone, from The Cancer Genome Atlas, which showed SCNA had a superiority in predicting the progression-free survival (PFS) over tumor mutation burden (TMB) and SCNA + TMB in NSCLC patients treated with CIK + CT, especially in lung adenocarcinoma, while SCNA could not predict the efficacy of CT alone. Additionally, we investigated the association between SCNA and immune cell infiltration by RNA sequencing and immunohistochemistry. The results revealed that SCNA was negatively associated with the expression of dendritic cells. Collectively, this study revealed a negative correlation between SCNA and response to CIK + CT and showed that SCNA is a predictive indicator in LUAD patients treated with CIK + CT.
SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth
Authors: Yu Yu-qiang , Thonn Veronika , Patankar Jay V. , Thoma Oana-Maria , Waldner Maximilian , Zielinska Marta , Bao Li-li , Gonzalez-Acera Miguel , Wallmüller Stefan , Engel Felix B. , Stürzl Michael , Neurath Markus F. , Liebing Eva , Becker Christoph
Published: January 2022

SMYD2 is a histone methyltransferase, which methylates both histone H3K4 as well as a number of non-histone proteins. Dysregulation of SMYD2 has been associated with several diseases including cancer. In the present study, we investigated whether and how SMYD2 might contribute to colorectal cancer. Increased expression levels of SMYD2 were detected in human and murine colon tumor tissues compared to tumor-free tissues. SMYD2 deficiency in colonic tumor cells strongly decreased tumor growth in two independent experimental cancer models. On a molecular level, SMYD2 deficiency sensitized colonic tumor cells to TNF-induced apoptosis and necroptosis without affecting cell proliferation. Moreover, we found that SMYD2 targeted RIPK1 and inhibited the phosphorylation of RIPK1. Finally, in a translational approach, pharmacological inhibition of SMYD2 attenuated colonic tumor growth. Collectively, our data show that SMYD2 is crucial for colon tumor growth and inhibits TNF-induced apoptosis and necroptosis.
Alamandine alleviates hypertension and renal damage via oxidative-stress attenuation in Dahl rats
Authors: Gong Juexiao , Luo Man , Yong Yonghong , Zhong Shan , Li Peng
Published: January 2022

Alamandine (Ala) is a novel member of the renin–angiotensin-system (RAS) family. The present study aimed to explore the effects of Ala on hypertension and renal damage of Dahl salt-sensitive (SS) rats high-salt diet-induced, and the mechanisms of Ala on renal-damage alleviation. Dahl rats were fed with high-salt diets to induce hypertension and renal damage in vivo, and HK-2 cells were treated with sodium chloride (NaCl) to induce renal injury in vitro. Ala administration alleviated the high-salt diet-induced hypertension, renal dysfunction, and renal fibrosis and apoptosis in Dahl SS rats. The HK-2 cells’ damage, and the increases in the levels of cleaved (c)-caspase3, c-caspase8, and c-poly(ADP-ribose) polymerase (PARP) induced by NaCl were inhibited by Ala. Ala attenuated the NaCl-induced oxidative stress in the kidney and HK-2 cells. DETC, an inhibitor of SOD, reversed the inhibitory effect of Ala on the apoptosis of HK-2 cells induced by NaCl. The NaCl-induced increase in the PKC level was suppressed by Ala in HK-2 cells. Notably, PKC overexpression reversed the moderating effects of Ala on the NaCl-induced apoptosis of HK-2 cells. These results show that Ala alleviates high-salt diet-induced hypertension and renal dysfunction. Ala attenuates the renal damage via inhibiting the PKC/reactive oxygen species (ROS) signaling pathway, thereby suppressing the apoptosis in renal tubular cells.
Feasibility and clinical utility of handheld fundus cameras for retinal imaging
Authors: Das Susmit , Kuht Helen J. , De Silva Ian , Deol Sundeep S. , Osman Lina , Burns Joyce , Sarvananthan Nagini , Sarodia Usman , Kapoor Bharat , Islam Tahir , Sampath Raghavan , Poyser Alicia , Konidaris Vasileios , Anzidei Rossella , Proudlock Frank A. , Thomas Mervyn G.
Published: January 2022

Background/objectives

Handheld fundus cameras are portable and cheaper alternatives to table-top counterparts. To date there have been no studies comparing feasibility and clinical utility of handheld fundus cameras to table-top devices. We compare the feasibility and clinical utility of four handheld fundus cameras/retinal imaging devices (Remidio NMFOP, Volk Pictor Plus, Volk iNview, oDocs visoScope) to a table-top camera (Zeiss VisucamNM/FA).

Subjects/methods

Healthy participants (n = 10, mean age ± SD = 21.0 ± 0.9 years) underwent fundus photography with five devices to assess success/failure rates of image acquisition. Participants with optic disc abnormalities (n = 8, mean age ± SD = 26.8 ± 15.9) and macular abnormalities (n = 10, mean age ± SD = 71.6 ± 15.4) underwent imaging with the top three scoring fundus cameras. Images were randomised and subsequently validated by ophthalmologists masked to the diagnoses and devices used.

Results

Image acquisition success rates (100%) were achieved in non-mydriatic and mydriatic settings for Zeiss, Remidio and Pictor, compared with lower success rates for iNview and oDocs. Image quality and gradeability were significantly higher for Zeiss, Remidio and Pictor (p < 0.0001) compared to iNview and oDocs. For cup:disc ratio estimates, similar levels of bias were seen for Zeiss (−0.09 ± SD:0.15), Remidio (−0.07 ± SD:0.14) and Pictor (−0.05 ± SD:0.16). Diagnostic sensitivities were highest for Zeiss (84.9%; 95% CI, 78.2–91.5%) followed by Pictor (78.1%; 95% CI, 66.6–89.5%) and Remidio (77.5%; 95% CI, 65.9–89.0%).

Conclusions

Remidio and Pictor achieve comparable results to the Zeiss table-top camera. Both devices achieved similar scores in feasibility, image quality, image gradeability and diagnostic sensitivity. This suggests that these devices potentially offer a more cost-effective alternative in certain clinical scenarios.
QTL-seq for the identification of candidate genes for days to flowering and leaf shape in pigeonpea
Authors: Singh Vikas , Sinha Pallavi , Obala Jimmy , Khan Aamir W. , Chitikineni Annapurna , Saxena Rachit K. , Varshney Rajeev K.
Published: January 2022

To identify genomic segments associated with days to flowering (DF) and leaf shape in pigeonpea, QTL-seq approach has been used in the present study. Genome-wide SNP profiling of extreme phenotypic bulks was conducted for both the traits from the segregating population (F2) derived from the cross combination- ICP 5529 × ICP 11605. A total of 126.63 million paired-end (PE) whole-genome resequencing data were generated for five samples, including one parent ICP 5529 (obcordate leaf and late-flowering plant), early and late flowering pools (EF and LF) and obcordate and lanceolate leaf shape pools (OLF and LLS). The QTL-seq identified two significant genomic regions, one on CcLG03 (1.58 Mb region spanned from 19.22 to 20.80 Mb interval) for days to flowering (LF and EF pools) and another on CcLG08 (2.19 Mb region spanned from 6.69 to 8.88 Mb interval) for OLF and LLF pools, respectively. Analysis of genomic regions associated SNPs with days to flowering and leaf shape revealed 5 genic SNPs present in the unique regions. The identified genomic regions for days to flowering were also validated with the genotyping-by-sequencing based classical QTL mapping method. A comparative analysis of the identified seven genes associated with days to flowering on 12 Fabaceae genomes, showed synteny with 9 genomes. A total of 153 genes were identified through the synteny analysis ranging from 13 to 36. This study demonstrates the usefulness of QTL-seq approach in precise identification of candidate gene(s) for days to flowering and leaf shape which can be deployed for pigeonpea improvement.
Postmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation
Authors: Wu Haibo , He Peiqi , Ren Yong , Xiao Shiqi , Wang Wei , Liu Zhenbang , Li Heng , Wang Zhe , Zhang Dingyu , Cai Jun , Zhou Xiangdong , Jiang Dongpo , Fei Xiaochun , Zhao Lei , Zhang Heng , Liu Zhenhua , Chen Rong , Li Weiqing , Wang Chaofu , Zhang Shuyang , Qin Jiwei , Nashan Björn , Sun Cheng
Published: January 2022

A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy.
Morphodynamic limits to environmental signal propagation across landscapes and into strata
Authors: Toby Stephan C. , Duller Robert A. , De Angelis Silvio , Straub Kyle M.
Published: January 2022

The sedimentary record contains unique information about landscape response to environmental forcing at timescales that far exceed landscape observations over human timescales. However, stochastic processes can overprint and shred evidence of environmental signals, such as sediment flux signals, and so inhibit their transfer to strata. Our community currently lacks a quantitative framework to differentiate between environmental signals and autogenic signals in field-scale analysis of strata. Here we develop a framework and workflow to estimate autogenic thresholds for ancient sediment routing systems. Crucially these thresholds can be approximated using measurements that are readily attainable from field systems, circumventing the low temporal resolution offered by strata. This work demonstrates how short-term system dynamics can be accessed from ancient sediment routing systems to place morphodynamic limits on environmental signal propagation across ancient landscapes and into strata.
Genetic diversity in terrestrial subsurface ecosystems impacted by geological degassing
Authors: Bornemann Till L. V. , Adam Panagiotis S. , Turzynski Victoria , Schreiber Ulrich , Figueroa-Gonzalez Perla Abigail , Rahlff Janina , Köster Daniel , Schmidt Torsten C. , Schunk Ralf , Krauthausen Bernhard , Probst Alexander J.
Published: January 2022

Earth’s mantle releases 38.7 ± 2.9 Tg/yr CO2along with other reduced and oxidized gases to the atmosphere shaping microbial metabolism at volcanic sites across the globe, yet little is known about its impact on microbial life under non-thermal conditions. Here, we perform comparative metagenomics coupled to geochemical measurements of deep subsurface fluids from a cold-water geyser driven by mantle degassing. Key organisms belonging to uncultivatedCandidatusAltiarchaeum show a global biogeographic pattern and site-specific adaptations shaped by gene loss and inter-kingdom horizontal gene transfer. Comparison of the geyser community to 16 other publicly available deep subsurface sites demonstrate a conservation of chemolithoautotrophic metabolism across sites. In silico replication measures suggest a linear relationship of bacterial replication with ecosystems depth with the exception of impacted sites, which show near surface characteristics. Our results suggest that subsurface ecosystems affected by geological degassing are hotspots for microbial life in the deep biosphere.
Structural basis of prokaryotic ubiquitin-like protein engagement and translocation by the mycobacterial Mpa-proteasome complex
Authors: Kavalchuk Mikhail , Jomaa Ahmad , Müller Andreas U. , Weber-Ban Eilika
Published: January 2022

Proteasomes are present in eukaryotes, archaea and Actinobacteria, including the human pathogenMycobacterium tuberculosis, where proteasomal degradation supports persistence inside the host. In mycobacteria and other members of Actinobacteria, prokaryotic ubiquitin-like protein (Pup) serves as a degradation tag post-translationally conjugated to target proteins for their recruitment to the mycobacterial proteasome ATPase (Mpa). Here, we use single-particle cryo-electron microscopy to determine the structure of Mpa in complex with the 20S core particle at an early stage of pupylated substrate recruitment, shedding light on the mechanism of substrate translocation. Two conformational states of Mpa show how substrate is translocated stepwise towards the degradation chamber of the proteasome core particle. We also demonstrate, in vitro and in vivo, the importance of a structural feature in Mpa that allows formation of alternating charge-complementary interactions with the proteasome resulting in radial, rail-guided movements during the ATPase conformational cycle.
Multifactorial engineering of biomimetic membranes for batteries with multiple high-performance parameters
Authors: Wang Mingqiang , Emre Ahmet E. , Kim Ji-Young , Huang Yiting , Liu Li , Cecen Volkan , Huang Yudong , Kotov Nicholas A.
Published: January 2022

Lithium–sulfur (Li–S) batteries have a high specific capacity, but lithium polysulfide (LPS) diffusion and lithium dendrite growth drastically reduce their cycle life. High discharge rates also necessitate their resilience to high temperature. Here we show that biomimetic self-assembled membranes from aramid nanofibers (ANFs) address these challenges. Replicating the fibrous structure of cartilage, multifactorial engineering of ion-selective mechanical, and thermal properties becomes possible. LPS adsorption on ANF surface creates a layer of negative charge on nanoscale pores blocking LPS transport. The batteries using cartilage-like bioinspired ANF membranes exhibited a close-to-theoretical-maximum capacity of 1268 mAh g−1, up to 3500+ cycle life, and up to 3C discharge rates. Essential for safety, the high thermal resilience of ANFs enables operation at temperatures up to 80 °C. The simplicity of synthesis and recyclability of ANFs open the door for engineering high-performance materials for numerous energy technologies.
Manipulation and control of droplets on surfaces in a homogeneous electric field
Authors: Hartmann Johannes , Schür Maximilian T. , Hardt Steffen
Published: January 2022

A method to manipulate and control droplets on a surface is presented. The method is based on inducing electric dipoles inside the droplets using a homogeneous external electric field. It is shown that the repulsive dipole force efficiently suppresses the coalescence of droplets moving on a liquid-infused surface (LIS). Using a combination of experiments, numerical computations and semi-analytical models, the dependence of the repulsion force on the droplet volumes, the distance between the droplets and the electric field strength is revealed. The method allows to suppress coalescence in complex multi-droplet flows and is real-time adaptive. When the electric field strength exceeds a critical value, tip streaming from the droplets sets in. Based on that, it becomes possible to withdraw minute samples from an array of droplets in a parallel process.
NuA4 and H2A.Z control environmental responses and autotrophic growth in Arabidopsis
Authors: Bieluszewski Tomasz , Sura Weronika , Dziegielewski Wojciech , Bieluszewska Anna , Lachance Catherine , Kabza Michał , Szymanska-Lejman Maja , Abram Mateusz , Wlodzimierz Piotr , De Winne Nancy , De Jaeger Geert , Sadowski Jan , Côté Jacques , Ziolkowski Piotr A.
Published: January 2022

Nucleosomal acetyltransferase of H4 (NuA4) is an essential transcriptional coactivator in eukaryotes, but remains poorly characterized in plants. Here, we describe Arabidopsis homologs of the NuA4 scaffold proteins Enhancer of Polycomb-Like 1 (AtEPL1) and Esa1-Associated Factor 1 (AtEAF1). Loss of AtEAF1 results in inhibition of growth and chloroplast development. These effects are stronger in the Atepl1 mutant and are further enhanced by loss of Golden2-Like (GLK) transcription factors, suggesting that NuA4 activates nuclear plastid genes alongside GLK. We demonstrate that AtEPL1 is necessary for nucleosomal acetylation of histones H4 and H2A.Z by NuA4 in vitro. These chromatin marks are diminished genome-wide in Atepl1, while another active chromatin mark, H3K9 acetylation (H3K9ac), is locally enhanced. Expression of many chloroplast-related genes depends on NuA4, as they are downregulated with loss of H4ac and H2A.Zac. Finally, we demonstrate that NuA4 promotes H2A.Z deposition and by doing so prevents spurious activation of stress response genes.
Dynamic targeting enables domain-general inhibitory control over action and thought by the prefrontal cortex
Authors: Apšvalka Dace , Ferreira Catarina S. , Schmitz Taylor W. , Rowe James B. , Anderson Michael C.
Published: January 2022

Over the last two decades, inhibitory control has featured prominently in accounts of how humans and other organisms regulate their behaviour and thought. Previous work on how the brain stops actions and thoughts, however, has emphasised distinct prefrontal regions supporting these functions, suggesting domain-specific mechanisms. Here we show that stopping actions and thoughts recruits common regions in the right dorsolateral and ventrolateral prefrontal cortex to suppress diverse content, via dynamic targeting. Within each region, classifiers trained to distinguish action-stopping from action-execution also identify when people are suppressing their thoughts (and vice versa). Effective connectivity analysis reveals that both prefrontal regions contribute to action and thought stopping by targeting the motor cortex or the hippocampus, depending on the goal, to suppress their task-specific activity. These findings support the existence of a domain-general system that underlies inhibitory control and establish Dynamic Targeting as a mechanism enabling this ability.
Chromosomal microarray analysis of 410 Han Chinese patients with autism spectrum disorder or unexplained intellectual disability and developmental delay
Authors: Liu Yi , Lv Yuqiang , Zarrei Mehdi , Dong Rui , Yang Xiaomeng , Higginbotham Edward J. , Li Yue , Zhao Dongmei , Song Fengling , Yang Yali , Zhang Haiyan , Wang Ying , Scherer Stephen W. , Gai Zhongtao
Published: January 2022

Copy number variants (CNVs) are recognized as a crucial genetic cause of neurodevelopmental disorders (NDDs). Chromosomal microarray analysis (CMA), the first-tier diagnostic test for individuals with NDDs, has been utilized to detect CNVs in clinical practice, but most reports are still from populations of European ancestry. To contribute more worldwide clinical genomics data, we investigated the genetic etiology of 410 Han Chinese patients with NDDs (151 with autism and 259 with unexplained intellectual disability (ID) and developmental delay (DD)) using CMA (Affymetrix) after G-banding karyotyping. Among all the NDD patients, 109 (26.6%) carried clinically relevant CNVs or uniparental disomies (UPDs), and 8 (2.0%) had aneuploidies (6 with trisomy 21 syndrome, 1 with 47,XXY, 1 with 47,XYY). In total, we found 129 clinically relevant CNVs and UPDs, including 32 CNVs in 30 ASD patients, and 92 CNVs and 5 UPDs in 79 ID/DD cases. When excluding the eight patients with aneuploidies, the diagnostic yield of pathogenic and likely pathogenic CNVs and UPDs was 20.9% for all NDDs (84/402), 3.3% in ASD (5/151), and 31.5% in ID/DD (79/251). When aneuploidies were included, the diagnostic yield increased to 22.4% for all NDDs (92/410), and 33.6% for ID/DD (87/259). We identified a de novo CNV in 14.9% (60/402) of subjects with NDDs. Interestingly, a higher diagnostic yield was observed in females (31.3%, 40/128) compared to males (16.1%, 44/274) for all NDDs (P = 4.8 × 10−4), suggesting that a female protective mechanism exists for deleterious CNVs and UPDs.
Toroidal topology of population activity in grid cells
Authors: Gardner Richard J. , Hermansen Erik , Pachitariu Marius , Burak Yoram , Baas Nils A. , Dunn Benjamin A. , Moser May-Britt , Moser Edvard I.
Published: January 2022

The medial entorhinal cortex is part of a neural system for mapping the position of an individual within a physical environment1. Grid cells, a key component of this system, fire in a characteristic hexagonal pattern of locations2, and are organized in modules3 that collectively form a population code for the animal’s allocentric position1. The invariance of the correlation structure of this population code across environments4,5 and behavioural states6,7, independent of specific sensory inputs, has pointed to intrinsic, recurrently connected continuous attractor networks (CANs) as a possible substrate of the grid pattern1,8–11. However, whether grid cell networks show continuous attractor dynamics, and how they interface with inputs from the environment, has remained unclear owing to the small samples of cells obtained so far. Here, using simultaneous recordings from many hundreds of grid cells and subsequent topological data analysis, we show that the joint activity of grid cells from an individual module resides on a toroidal manifold, as expected in a two-dimensional CAN. Positions on the torus correspond to positions of the moving animal in the environment. Individual cells are preferentially active at singular positions on the torus. Their positions are maintained between environments and from wakefulness to sleep, as predicted by CAN models for grid cells but not by alternative feedforward models12. This demonstration of network dynamics on a toroidal manifold provides a population-level visualization of CAN dynamics in grid cells.
Mutation bias reflects natural selection in Arabidopsis thaliana
Authors: Monroe J. Grey , Srikant Thanvi , Carbonell-Bejerano Pablo , Becker Claude , Lensink Mariele , Exposito-Alonso Moises , Klein Marie , Hildebrandt Julia , Neumann Manuela , Kliebenstein Daniel , Weng Mao-Lun , Imbert Eric , Ågren Jon , Rutter Matthew T. , Fenster Charles B. , Weigel Detlef
Published: January 2022

Since the first half of the twentieth century, evolutionary theory has been dominated by the idea that mutations occur randomly with respect to their consequences1. Here we test this assumption with large surveys of de novo mutations in the plant Arabidopsis thaliana. In contrast to expectations, we find that mutations occur less often in functionally constrained regions of the genome—mutation frequency is reduced by half inside gene bodies and by two-thirds in essential genes. With independent genomic mutation datasets, including from the largest Arabidopsis mutation accumulation experiment conducted to date, we demonstrate that epigenomic and physical features explain over 90% of variance in the genome-wide pattern of mutation bias surrounding genes. Observed mutation frequencies around genes in turn accurately predict patterns of genetic polymorphisms in natural Arabidopsis accessions (r = 0.96). That mutation bias is the primary force behind patterns of sequence evolution around genes in natural accessions is supported by analyses of allele frequencies. Finally, we find that genes subject to stronger purifying selection have a lower mutation rate. We conclude that epigenome-associated mutation bias2 reduces the occurrence of deleterious mutations in Arabidopsis, challenging the prevailing paradigm that mutation is a directionless force in evolution.
Age of the oldest known Homo sapiens from eastern Africa
Authors: Vidal Céline M. , Lane Christine S. , Asrat Asfawossen , Barfod Dan N. , Mark Darren F. , Tomlinson Emma L. , Tadesse Amdemichael Zafu , Yirgu Gezahegn , Deino Alan , Hutchison William , Mounier Aurélien , Oppenheimer Clive
Published: January 2022

Efforts to date the oldest modern human fossils in eastern Africa, from Omo-Kibish1–3 and Herto4,5 in Ethiopia, have drawn on a variety of chronometric evidence, including 40Ar/39Ar ages of stratigraphically associated tuffs. The ages that are generally reported for these fossils are around 197 thousand years (kyr) for the Kibish Omo I3,6,7, and around 160–155 kyr for the Herto hominins5,8. However, the stratigraphic relationships and tephra correlations that underpin these estimates have been challenged6,8. Here we report geochemical analyses that link the Kamoya’s Hominid Site (KHS) Tuff9, which conclusively overlies the member of the Omo-Kibish Formation that contains Omo I, with a major explosive eruption of Shala volcano in the Main Ethiopian Rift. By dating the proximal deposits of this eruption, we obtain a new minimum age for the Omo fossils of 233 ± 22 kyr. Contrary to previous arguments6,8, we also show that the KHS Tuff does not correlate with another widespread tephra layer, the Waidedo Vitric Tuff, and therefore cannot anchor a minimum age for the Herto fossils. Shifting the age of the oldest known Homo sapiens fossils in eastern Africa to before around 200 thousand years ago is consistent with independent evidence for greater antiquity of the modern human lineage10.
Cefotax-magnetic nanoparticles as an alternative approach to control Methicillin-Resistant Staphylococcus aureus (MRSA) from different sources
Authors: Mohamed Manar Bahaa El Din , Abo El-Ela Fatma I. , Mahmoud Rehab K. , Farghali Ahmed A. , Gamil Shymaa , Aziz Sahar Abdel Aleem Abdel
Published: January 2022

This study aimed to evaluate the efficacy of magnetic nanocomposite of cefotax against MRSA. A total of 190 samples were collected from milk, farm personnel and different environmental components from the dairy farm under the study to isolate S. aureus. Cefotax based magnetic nanoparticles was synthetized by the adsorption method and marked using Fourier-transform infrared spectrum (FT-IR), and X-ray diffraction (XRD), then it was characterized using Scanning and Transmission Electron Microscope (SEM and TEM). The obtained results revealed that number of positive samples of S. aureus isolation were 63 (33.1%), mainly from feed manger followed by milk machine swabs (60.0 and 53.3%, respectively) at X2 = 48.83 and P < 0.001. Obtained isolates were identified biochemically and by using molecular assays (PCR), also mec A gene responsible for resistance to cefotax was detected. Testing the sensitivity of 63 isolates of S. aureus showed variable degree of resistance to different tested antibiotics and significant sensitivity to cefotax based magnetic nanoparticles at P < 0.05. It was concluded that dairy environment might act a potential source for transmission of MRSA between human and animal populations. In addition, cefotax based magnetic nanoparticles verified an extreme antimicrobial efficacy against MRSA.
Mechanical work accounts for most of the energetic cost in human running
Authors: Riddick R. C. , Kuo A. D.
Published: January 2022

The metabolic cost of human running is not well explained, in part because the amount of work performed actively by muscles is largely unknown. Series elastic tissues such as tendon can save energy by performing work passively, but there are few direct measurements of the active versus passive contributions to work in running. There are, however, indirect biomechanical measures that can help estimate the relative contributions to overall metabolic cost. We developed a simple cost estimate for muscle work in humans running (N = 8) at moderate speeds (2.2–4.6 m/s) based on measured joint mechanics and passive dissipation from soft tissue deformations. We found that even if 50% of the work observed at the lower extremity joints is performed passively, active muscle work still accounts for 76% of the net energetic cost. Up to 24% of this cost compensates for the energy lost in soft tissue deformations. The estimated cost of active work may be adjusted based on assumptions of multi-articular energy transfer, elasticity, and muscle efficiency, but even conservative assumptions yield active work costs of at least 60%. Passive elasticity can reduce the active work of running, but muscle work still explains most of the overall energetic cost.
Usefulness of circulating tumor DNA by targeting human papilloma virus-derived sequences as a biomarker in p16-positive oropharyngeal cancer
Authors: Akashi Ken , Sakai Toshihiko , Fukuoka Osamu , Saito Yuki , Yoshida Masafumi , Ando Mizuo , Ito Takeshi , Murakami Yoshinori , Yamasoba Tatsuya
Published: January 2022

In head and neck cancer, early detection of recurrence after treatment is important. The contemporary development of therapeutic agents have improved the prognosis after recurrence; however, no biomarker has been established for evaluating therapeutic effects or detecting recurrence. Recently, circulating tumor DNA (ctDNA), which comprises DNA derived from tumor cells and exists in the form of cell-free DNA in the blood, has attracted attention as a minimally invasive and repeatable biomarker for detecting cancer. We validated the usefulness of ctDNA of human papilloma virus (HPV)-derived sequences as a biomarker in HPV-related p16-positive oropharyngeal cancer by assessing 25 patients with p16-positive oropharyngeal cancer. Blood samples were collected from each patient at multiple time points during the treatment, and the plasma was preserved. The ctDNA was extracted from the plasma and analyzed using digital polymerase chain reaction. HPV-derived ctDNA was detected in 14 (56%) of the 25 patients. In all the patients, the samples were found to be ctDNA-negative after initial treatment. Cancer recurrence was observed in 2 of the 14 patients; HPV-derived ctDNA was detected at the time of recurrence. Our results indicate that HPV-derived ctDNA can be a prospective biomarker for predicting the recurrence of p16-positive oropharyngeal cancer.
Thermally controlled microfluidic back pressure regulator
Authors: Svensson Karolina , Södergren Simon , Hjort Klas
Published: January 2022

By using the temperature dependence of viscosity, we introduce a novel type of microfluidic lab-on-a-chip back pressure regulator (BPR) that can be integrated into a micro-total-analysis-system. A BPR is an important component used to gain pressure control and maintain elevated pressures in e.g. chemical extractions, synthesis, and analyses. Such applications have been limited in microfluidics, since the back pressure regularly has been attained by passive restrictors or external large-scale BPRs. Herein, an active microfluidic BPR is presented, consisting of a glass chip with integrated thin-film heaters and thermal sensors. It has no moving parts but a fluid restrictor where the flow resistance is controlled by the change of viscosity with temperature. Performance was evaluated by regulating the upstream pressure of methanol or water using a PID controller. The developed BPR has the smallest reported dead volume of 3 nL and the thermal actuation has time constants of a few seconds. The pressure regulation were reproducible with a precision in the millibar range, limited by the pressure sensor. The time constant of the pressure changes was evaluated and its dependence of the total upstream volume and the compressibility of the liquids is introduced.
Association of red blood cell and platelet transfusions with persistent inflammation, immunosuppression, and catabolism syndrome in critically ill patients
Authors: Suzuki Ginga , Ichibayashi Ryo , Masuyama Yuka , Yamamoto Saki , Serizawa Hibiki , Nakamichi Yoshimi , Watanabe Masayuki , Honda Mitsuru
Published: January 2022

The objective of this single-center retrospective cohort study was to investigate the relationship between blood transfusion and persistent inflammation, immunosuppression, and catabolism syndrome (PIICS). The study was conducted at the Critical Care Center at Toho University Omori Medical Center, Japan. We included 391 patients in the PIICS group (hospitalization for > 15 days, C-reactive protein > 3.0 mg/dL or albumin < 3.0 mg/dL or lymph < 800/μL on day 14) and 762 patients in the non-PIICS group (hospitalization for > 15 days and not meeting the PIICS criteria). We performed univariate and multivariate logistic regression analyses using PIICS as the objective variable and red blood cell (RBC) or fresh frozen plasma or platelet (PLT) transfusion and other confounding factors as explanatory variables. In addition, we conducted a sensitivity analysis using propensity score matching analysis. The multivariate and propensity score analyses showed that RBC and PLT transfusions were significantly associated with PIICS. This is the first study to report an association between RBC and PLT transfusions and PIICS. Our findings have contributed to better understanding the risk factors of PIICS and suggest that physicians should consider the risk of PIICS occurrence when administering blood transfusions in intensive care unit (ICU) patients.
A multi-omics study of circulating phospholipid markers of blood pressure
Authors: Liu Jun , de Vries Paul S. , Del Greco M. Fabiola , Johansson Åsa , Schraut Katharina E. , Hayward Caroline , van Dijk Ko Willems , Franco Oscar. H. , Hicks Andrew A. , Vitart Veronique , Rudan Igor , Campbell Harry , Polašek Ozren , Pramstaller Peter P. , Wilson James F. , Gyllensten Ulf , van Duijn Cornelia M. , Dehghan Abbas , Demirkan Ayşe
Published: January 2022

High-throughput techniques allow us to measure a wide-range of phospholipids which can provide insight into the mechanisms of hypertension. We aimed to conduct an in-depth multi-omics study of various phospholipids with systolic blood pressure (SBP) and diastolic blood pressure (DBP). The associations of blood pressure and 151 plasma phospholipids measured by electrospray ionization tandem mass spectrometry were performed by linear regression in five European cohorts (n = 2786 in discovery and n = 1185 in replication). We further explored the blood pressure-related phospholipids in Erasmus Rucphen Family (ERF) study by associating them with multiple cardiometabolic traits (linear regression) and predicting incident hypertension (Cox regression). Mendelian Randomization (MR) and phenome-wide association study (Phewas) were also explored to further investigate these association results. We identified six phosphatidylethanolamines (PE 38:3, PE 38:4, PE 38:6, PE 40:4, PE 40:5 and PE 40:6) and two phosphatidylcholines (PC 32:1 and PC 40:5) which together predicted incident hypertension with an area under the ROC curve (AUC) of 0.61. The identified eight phospholipids are strongly associated with triglycerides, obesity related traits (e.g. waist, waist-hip ratio, total fat percentage, body mass index, lipid-lowering medication, and leptin), diabetes related traits (e.g. glucose, insulin resistance and insulin) and prevalent type 2 diabetes. The genetic determinants of these phospholipids also associated with many lipoproteins, heart rate, pulse rate and blood cell counts. No significant association was identified by bi-directional MR approach. We identified eight blood pressure-related circulating phospholipids that have a predictive value for incident hypertension. Our cross-omics analyses show that phospholipid metabolites in the circulation may yield insight into blood pressure regulation and raise a number of testable hypothesis for future research.
Effectiveness of Lymphatic Contrast Enhanced Ultrasound in the diagnosis of Cervical Lymph node metastasis from papillary thyroid carcinoma
Authors: Wei Ying , Niu Yun , Zhao Zhen-long , Cao Xiao-jing , Peng Li-li , Li Yan , Yu Ming-an
Published: January 2022

Cervical lymph node metastasis (CLNM) is common in patients with papillary thyroid carcinoma (PTC), which is responsible for tumor staging and surgical strategy. The accurate preoperative identification of CLNM is essential. In this study, twenty consecutive patients with PTC received a parenchyma injection of Sonazoid followed by contrast enhanced ultrasound (CEUS) to identify CLNM. The specific lymphatic CEUS (LCEUS) signs for diagnosing CLNM were summarized, which were further compared with the resected specimens to get the pathological basis. After the injection of contrast agent, lymphatic vessel and lymph node (LN) could be exclusively displayed as hyperperfusion on LCEUS. The dynamic perfusion process of contrast agent in CLNM over time can be clearly visualized. Perfusion defect and interruption of bright ring were the two characteristic LCEUS signs in diagnosing CLNM. After comparing with pathology, perfusion defect was correlated to the metastatic foci in medulla and interruption of bright ring was correlated to the tumor seeding in marginal sinus (all p values < 0.001). The diagnostic efficacies of these two signs were high (perfusion defect vs. interruption of bright ring: AUC, 0.899, 95% CI 0.752–1.000 vs. 0.904, 0.803–1.000). LCEUS has advantages in identifying CLNM from PTC. The typical LCEUS signs of CLNM correlated with pathology.
Survival and mortality of preterm neonates in a neonatal intensive care unit in Northern Ethiopia: a retrospective cohort study
Authors: Gebreheat Gdiom , Teame Hirut
Published: January 2022

The purpose of this study was to assess the predictors of preterm neonatal survival in a neonatal intensive care unit (NICU). A cohort study was conducted retrospectively on 1017 preterm neonates using medical records from January 2014 through December 2018. The Kaplan–Meier model was used to estimate mean survival time and cumulative survival probability. Furthermore, Multivariable Cox regression analysis was run to identify predictors of preterm neonatal mortality using an adjusted hazard ratio (AHR) at P < 0.05 and 95% confidence interval (CI). During the follow-up period in the NICU, the mean survival time of the preterm neonates was 47 (95% CI (43.19–48.95)) days. Compound presentation (AHR = 2.29, 95% CI (1.23–4.24)), perinatal asphyxia (AHR = 2.83, 95% CI (1.75–4.58)), respiratory distress syndrome (AHR = 3.01, 95% CI (1.80–5.01)), 1-min APGAR score (AHR = 0.78, 95% CI (0.62–0.98)), and birth weight (AHR = 0.32, 95% CI (0.17–0.58)) were found to be significant predictors of time to preterm neonatal mortality. In conclusion, the survival probability of preterm neonates showed a considerable decrement in the first week of life. Fetal presentation, gestational age, birth weight, 1-min APGAR score, perinatal asphyxia and respiratory distress syndrome found as independent predictors of preterm neonatal mortality.
Training calibration-based counterfactual explainers for deep learning models in medical image analysis
Authors: Thiagarajan Jayaraman J. , Thopalli Kowshik , Rajan Deepta , Turaga Pavan
Published: January 2022

The rapid adoption of artificial intelligence methods in healthcare is coupled with the critical need for techniques to rigorously introspect models and thereby ensure that they behave reliably. This has led to the design of explainable AI techniques that uncover the relationships between discernible data signatures and model predictions. In this context, counterfactual explanations that synthesize small, interpretable changes to a given query while producing desired changes in model predictions have become popular. This under-constrained, inverse problem is vulnerable to introducing irrelevant feature manipulations, particularly when the model’s predictions are not well-calibrated. Hence, in this paper, we propose the TraCE (training calibration-based explainers) technique, which utilizes a novel uncertainty-based interval calibration strategy for reliably synthesizing counterfactuals. Given the wide-spread adoption of machine-learned solutions in radiology, our study focuses on deep models used for identifying anomalies in chest X-ray images. Using rigorous empirical studies, we demonstrate the superiority of TraCE explanations over several state-of-the-art baseline approaches, in terms of several widely adopted evaluation metrics. Our findings show that TraCE can be used to obtain a holistic understanding of deep models by enabling progressive exploration of decision boundaries, to detect shortcuts, and to infer relationships between patient attributes and disease severity.
A specific hybridisation internalisation probe (SHIP) enables precise live-cell and super-resolution imaging of internalized cargo
Authors: Hernández-Pérez Sara , Mattila Pieta K.
Published: January 2022

Facilitated by the advancements in microscopy, our understanding of the complexity of intracellular vesicle traffic has dramatically increased in recent years. However, distinguishing between plasma membrane-bound or internalised ligands remains a major challenge for the studies of cargo sorting to endosomal compartments, especially in small and round cells such as lymphocytes. The specific hybridization internalisation probe (SHIP) assay, developed for flow cytometry studies, employs a ssDNA fluorescence internalisation probe and a complementary ssDNA quenching probe to unambiguously detect the internalized receptors/cargo. Here, we adopted the SHIP assay to study the trafficking of receptor/ligand complexes using B lymphocytes and B cell receptor-mediated antigen internalization as a model system. Our study demonstrates the potential of the SHIP assay for improving the imaging of internalized receptor/ligand complexes and establishes the compatibility of this assay with multiple imaging modalities, including live-cell imaging and super-resolution microscopy.
Regulation of adult neurogenesis by the endocannabinoid-producing enzyme diacylglycerol lipase alpha (DAGLa)
Authors: Schuele Lena-Louise , Schuermann Britta , Bilkei-Gorzo Andras , Gorgzadeh Sara , Zimmer Andreas , Leidmaa Este
Published: January 2022

The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). This is demonstrated by the disruption of adult neurogenesis under two experimental conditions: (1) NSPC-specific deletion of cannabinoid receptors and (2) constitutive deletion of the enzyme diacylglycerol lipase alpha (DAGLa) which produces the endocannabinoid 2-arachidonoylglycerol (2-AG). However, the specific cell types producing 2-AG relevant to neurogenesis remain unknown. Here we sought to identify the cellular source of endocannabinoids in the subgranular zone of the dentate gyrus (DG) in hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete Dagla either in neurons, or in astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice bearing a deletion of Dagla in neurons (Syn-Dagla KO), although neurons are the main source for the endocannabinoids in the brain. In contrast, a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) resulted in a strongly impaired neurogenesis with a 50% decrease in proliferation of newborn cells. These results identify Dagla in NSPCs in the DG or in astrocytes as a prominent regulator of adult hippocampal neurogenesis. We also show a reduction of Daglb expression in GLAST-CreERT2-Dagla KO mice, which may have contributed to the neurogenesis phenotype.
A novel subgenotype C6 Enterovirus A71 originating from the recombination between subgenotypes C4 and C2 strains in mainland China
Authors: Liu Yongjuan , Zhou Jingyi , Ji Guangquan , Gao Yupeng , Zhang Chunyan , Zhang Ting , Huo Juan , Liang Wenxue , Yang Jin , Shi Yingying , Zhao Shaolin
Published: January 2022

Recombination plays important roles in the genetic diversity and evolution of Enterovirus A71 (EV-A71). The phylogenetics of EV-A71 in mainland China found that one strain DL71 formed a new subgenotype C6 with unknown origin. This study investigated the detailed genetic characteristics of the new variant. DL71 formed a distinct cluster within genotype C based on the genome and individual genes (5′UTR, VP4, VP1, 2A, 2B, 2C, 3D, and 3′UTR). The average genetic distances of the genome and individual genes (VP3, 2A, 2B, 2C, 3A, 3C, and 3D) between DL71 and reference strains were greater than 0.1. Nine recombination events involving smaller fragments along DL71 genome were detected. The strains Fuyang-0805a (C4) and Tainan/5746/98 (C2) were identified as the parental strains of DL71. In the non-recombination regions, DL71 had higher identities with Fuyang-0805a than Tainan/5746/98, and located in the cluster with C4 strains. However, in the recombination regions, DL71 had higher identities with Tainan/5746/98 than Fuyang-0805a, and located in the cluster with C2 strains. Thus, DL71 was a novel multiple inter-subgenotype recombinant derived from the dominant subgenotype C4 and the sporadic subgenotype C2 strains. Monitoring the emergence of new variants by the whole-genome sequencing remains essential for preventing disease outbreaks and developing new vaccines.