bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel frameshift variant ofLMX1Athat leads to autosomal dominant non-syndromic sensorineural hearing loss: functional characterization of the C-terminal domain in LMX1A
Authors: Xiao Min , Zheng Yan , Huang Kuo-Hsiang , Yu Shanhe , Zhang Wenbi , Xi Yanping , Dou Yan , Sun Xiaoxi , Lei Caixia , Yu Huiqian
Published: December 2022

Non-syndromic sensorineural hearing loss (NSHL) is a group of genetically heterogeneous conditions with broad phenotypic heterogeneity. There is, at present, no curative treatment for genetic hearing loss (HL). Early molecular diagnosis of progressive disorders and elucidation of the causes and pathomechanisms are essential for developing therapeutic strategies. Here, we identified a novel rare frameshift variant of LMX1A (c.915dup), which resulted in the C-terminal-altered and -truncated LMX1A (p.Val306Cysfs*32). This C-terminal frameshift mutation co-segregated with autosomal dominant (AD) NSHL in a four-generation Chinese family, suggesting that the LMX1A non-missense mutation is also contributed to ADNSHL. In this family, the affected individuals exhibited the variable auditory phenotypes ranging from profound congenital deafness at birth or to mild/moderate HL in adulthood. We also found that the embryonic cells carrying with the heterozygous variant significantly expressed several upregulated HL-associated genes at transcriptional level. In vitro splicing assay suggested that the LMX1A mRNA with c.915dup did not cause nonsense-mediated decay and was translated into a truncated LMX1A. In addition, electrophoresis mobility shift assay and luciferase assays have shown that the highly conserved C-terminal domain (amino acid 306–382) of the LMX1A was required for regulating the protein–DNA interaction and transactivation in vitro. Furthermore, apoptosis assays suggested that the C-terminal domain of the LMX1A was important for mediating apoptosis in the cochlear hair cells. Our work provided the multiline of the evidence to support that non-missense mutation of LMX1A leads to ADNSHL and the C-terminal domain of LMX1A is important for mediating transcriptional activity and associated with promoting apoptosis in the cells.
A review of the importance of various areas for northern contingent West-Atlantic mackerel spawning
Authors: Van Beveren Elisabeth , Plourde Stéphane , Pepin Pierre , Cogliati Karen , Castonguay Martin
Published: December 2022

The southern Gulf of St. Lawrence (sGSL) is considered to be the dominant spawning area of northern contingent West-Atlantic mackerel (Scomber scombrus). This premise underlies our basic understanding of the stock and its assessment. Because there are however indications of spawning outside the sGSL, we aimed to review the potential importance of various external regions for spawning, based on a weight of evidence approach. Fundamentally, important spawning areas can only exist where there is evidence of a considerable spawning stock biomass being present when environmental conditions are suitable for spawning. This should lead to direct observations of significant egg and larval densities. Based on an ensemble of evidence (migration patterns, environmental conditions, and ichthyoplankton observations), we investigated the dominance of the sGSL for northern contingent mackerel spawning. Elsewhere, such as on the Scotian Shelf, where mackerel starts its spring migration, there is evidence of minor but relatively consistent egg production. Spawning off Newfoundland, where mackerel can migrate to later in the year, appears sporadic and highly variable in intensity. This review should alleviate some of the uncertainty associated with the mackerel stock assessments and be a baseline to further our knowledge on mackerel spatial spawning dynamics.
Emergence of vortices at the edges of planet-driven gaps in protoplanetary discs
Authors: Cimerman Nicolas P , Rafikov Roman R
Published: December 2022

Young planets embedded in protoplanetary discs (PPDs) excite spiral density waves, which propagate shock and deposit angular momentum in the disc. This results in gap opening around the planetary orbit, even for low (sub-thermal) mass planets, provided that the effective viscosity in the disc is low. The edges of these planet-induced gaps are known to be prone to emergence of observable vortices via the Rossby wave instability (RWI). We study time-scales for the development of vortices driven by low-mass planets in inviscid discs. We employ a recently developed semi-analytical theory of vortensity production by the planet-driven shock to predict vortensity evolution near the planet, from which we derive the radial profile of the planet-induced gap as a function of time (this procedure can have multiple other uses, e.g. to study dust trapping, suppression of pebble accretion, etc.). We then analyse the linear stability of the gap edges against the RWI, obtaining the time-scales for the first appearance of unstable modes and (later) fully developed vortices at gap edges. We present useful formulae for these time-scales as functions of planetary and disc parameters and provide their physical justification. We also thoroughly test our semi-analytical framework against high-resolution 2D hydrodynamic simulations, confirming the accuracy of our theoretical predictions. We discuss ways in which our semi-analytical framework can be extended to incorporate additional physics, e.g. planetary accretion, migration, and non-zero disc viscosity. Our results can be used to interpret observations of PPDs and to predict emergence of vortices in simulations.
Transmission strings: a technique for spatially mapping exoplanet atmospheres around their terminators
Authors: Grant David , Wakeford Hannah R
Published: December 2022

Exoplanet transmission spectra, which measure the absorption of light passing through a planet’s atmosphere during transit, are most often assessed globally, resulting in a single spectrum per planetary atmosphere. However, the inherent 3D nature of planetary atmospheres, via thermal, chemical, and dynamical processes, can imprint inhomogeneous structure and properties in the observables. In this work, we devise a technique for spatially mapping the atmospheres of exoplanets in transmission. Our approach relaxes the assumption that transit light curves are created from circular stars occulted by circular planets, and instead we allow for flexibility in the planet’s sky-projected shape. We define the planet’s radius to be a single-valued function of angle around its limb, and we refer to this mathematical object as a transmission string. These transmission strings are parametrized in terms of Fourier series, a choice motivated by these series having adjustable complexity, generating physically practical shapes, while being reducible to the classical circular case. The utility of our technique is primarily intended for high-precision multiwavelength light curves, from which inferences of transmission spectra can be made as a function of angle around a planet’s terminator, enabling analysis of the multidimensional physics at play in exoplanet atmospheres. More generally, the technique can be applied to any transit light curve to derive the shape of the transiting body. The algorithm we develop is available as an open-source package, called harmonica1.
Testing Bayesian reconstruction methods from peculiar velocities
Authors: Valade Aurélien , Libeskind Noam I , Hoffman Yehuda , Pfeifer Simon
Published: December 2022

Reconstructing the large-scale density and velocity fields from surveys of galaxy distances is a major challenge for cosmography. The data are very noisy and sparse. Estimated distances, and thereby peculiar velocities, are strongly affected by the Malmquist-like lognormal bias. Two algorithms have been recently introduced to perform reconstructions from such data: the Bias Gaussian correction coupled with the Wiener filter (BGc/WF) and the Hamlet implementation of the Hamiltonian Monte Carlo forward modelling. The two methods are tested here against mock catalogues that mimic the Cosmicflows-3 data. Specifically the reconstructed cosmography and moments of the velocity field (monopole, dipole) are examined. A comparison is made to the ‘exact’ WF as well, namely, the WF in the unrealistic case of zero observational errors. This is to understand the limits of the WF method. The following is found. In the nearby regime ($d \lesssim 40 \, \mathrm{ \mathit{ h}}^{-1}\, {\rm Mpc}$), the two methods perform roughly equally well. Hamlet shows more contrast in the intermediate regime ($40 \lesssim d \lesssim 120 \, h^{-1}\, {\rm Mpc}$). The main differences between the two appear in the most distant regime ($d \gtrsim 120 \, h^{-1}\, {\rm Mpc}$), close to the edge of the data. Hamlet outperforms the BGc/WF in terms of contrast and tighter correlations of the density and velocity fields. Yet, close to the edge of the data, Hamlet yields a slightly biased reconstruction, which affects the multipoles of the velocity field. Such biases are missing from the BGc/WF reconstruction. In sum, both methods perform well and create reliable reconstructions with significant differences apparent when details are examined.
Common envelope evolution and triple dynamics as potential pathways to form the inner white dwarf + brown dwarf binary of the triple star system Gaia 0007−1605
Authors: Lagos Felipe , Zorotovic Monica , Schreiber Matthias R , Gänsicke B T
Published: December 2022

The recently discovered system Gaia 0007−1605 consisting of a white dwarf (WD) with a close brown dwarf companion and a distant WD tertiary very much resembles the triple system containing the first transiting planet candidate around a WD ever discovered: WD 1856+534. We have previously argued that the inner binary in WD 1856+534 most likely formed through common envelope evolution but triple star dynamics represent an alternative scenario. Here, we analyse different formation scenarios for Gaia 0007−1605. We reconstructed the potential common envelope evolution of the system and found that assuming standard parameters for the energy budget provides a reasonable solution. In agreement with other close white dwarf + brown dwarf binaries, and in contrast to WD 1856+534, no energy sources other than orbital energy during common envelope evolution are required to understand the current configuration of the system. In addition, using analytical prescriptions for triple dynamics, we show that Von Zeipel–Lidov–Kozai oscillations might have triggered tidal migration due to high-eccentricity incursions (e ≳ 0.997). We conclude that the inner binary in Gaia 0007−1605, as its sibling WD 1856+534, formed either through common envelope evolution, triple dynamics, or a combination of both mechanisms.
Cooperative interaction between AAG and UV-DDB in the removal of modified bases
Authors: Jang Sunbok , Kumar Namrata , Schaich Mathew A , Zhong Zhou , van Loon Barbara , Watkins Simon C , Van Houten Bennett
Published: December 2022

UV-DDB is a DNA damage recognition protein recently discovered to participate in the removal of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxoG) by stimulating multiple steps of base excision repair (BER). In this study, we examined whether UV-DDB has a wider role in BER besides oxidized bases and found it has specificity for two known DNA substrates of alkyladenine glycosylase (AAG)/N-methylpurine DNA glycosylase (MPG): 1, N6-ethenoadenine (ϵA) and hypoxanthine. Gel mobility shift assays show that UV-DDB recognizes these two lesions 4–5 times better than non-damaged DNA. Biochemical studies indicated that UV-DDB stimulated AAG activity on both substrates by 4- to 5-fold. Native gels indicated UV-DDB forms a transient complex with AAG to help facilitate release of AAG from the abasic site product. Single molecule experiments confirmed the interaction and showed that UV-DDB can act to displace AAG from abasic sites. Cells when treated with methyl methanesulfonate resulted in foci containing AAG and UV-DDB that developed over the course of several hours after treatment. While colocalization did not reach 100%, foci containing AAG and UV-DDB reached a maximum at three hours post treatment. Together these data indicate that UV-DDB plays an important role in facilitating the repair of AAG substrates.
Fasting influences aquaporin expression, water transport and adipocyte metabolism in the peritoneal membrane
Authors: Costa Ines P D , Hautem Nicolas , Schiano Gugliemo , Uchida Shinichi , Nishino Tomoya , Devuyst Olivier
Published: December 2022

Background

The water channels aquaporin-1 (AQP1) and AQP7 are abundantly expressed in the peritoneal membrane. While AQP1 facilitates water transport during peritoneal dialysis (PD), the role of AQP7, which mediates glycerol transport during fasting, remains unknown.

Methods

We investigated the distribution of AQP7 and AQP1 and used a mouse model of PD to investigate the role of AQP7 in the peritoneal membrane at baseline and after fasting.

Results

Single nucleus RNA-sequencing revealed that AQP7 was mostly detected in mature adipocytes, whereas AQP1 was essentially expressed in endothelial cells. Fasting induced significant decreases in whole body fat, plasma glucose, insulin and triglycerides, as well as higher plasma glycerol and corticosterone levels in mice, paralleled by major decreases in adipocyte size and levels of fatty acid synthase and leptin, and increased levels of hormone-sensitive lipase mRNAs in the peritoneum. Mechanistically, fasting upregulated the expression of AQP1 and AQP7 in the peritoneum, with increased ultrafiltration but no change in small solute transport. Studies based on Aqp1 and Aqp7 knockout mice and RU-486 inhibition demonstrated that the glucocorticoid induction of AQP1 mediates the increase in ultrafiltration whereas AQP7 regulates the size of adipocytes in the peritoneum.

Conclusions

Fasting induces a coordinated regulation of lipolytic and lipogenic factors and aqua(glycero)porins in the peritoneum, driving structural and functional changes. These data yield novel information on the specific roles of aquaporins in the peritoneal membrane and indicate that fasting improves fluid removal in a mouse model of PD.
On shape forming by contractile filaments in the surface of growing tissues
Authors: Fratzl Peter , Fischer F Dieter , Zickler Gerald A , Dunlop John W C
Published: December 2022

Growing tissues are highly dynamic, and flow on sufficiently long timescales due to cell proliferation, migration, and tissue remodeling. As a consequence, growing tissues can often be approximated as viscous fluids. This means that the shape of microtissues growing in vitro is governed by their surface stress state, as in fluid droplets. Recent work showed that cells in the near-surface region of fibroblastic or osteoblastic microtissues contract with highly oriented actin filaments, thus making the surface properties highly anisotropic, in contrast to what is expected for an isotropic fluid. Here, we develop a model that includes mechanical anisotropy of the surface generated by contractile fibers and we show that mechanical equilibrium requires contractile filaments to follow geodesic lines on the surface. Constant pressure in the fluid forces these contractile filaments to be along geodesics with a constant normal curvature. We then take this into account to determine equilibrium shapes of rotationally symmetric bodies subjected to anisotropic surface stress states and derive a family of surfaces of revolution. A comparison with recently published shapes of microtissues shows that this theory accurately predicts both the surface shape and the direction of the actin filaments on the surface.
NEUTROPHIL HETEROGENEITY IN SEPSIS: THE ROLE OF DAMAGE-ASSOCIATED MOLECULAR PATTERNS
Authors: Murao Atsushi , Aziz Monowar , Wang Ping
Published: December 2022

Sepsis is a severe inflammatory disease syndrome caused by the dysregulated host response to infection. Neutrophils act as the first line of defense against pathogens by releasing effector molecules such as reactive oxygen species, myeloperoxidase, and neutrophil extracellular traps. However, uncontrolled activation of neutrophils and extensive release of effector molecules often cause a “friendly fire” to damage organ systems. Although neutrophils are considered a short-lived, terminally differentiated homogeneous population, recent studies have revealed its heterogeneity comprising different subsets or states implicated in sepsis pathophysiology. Besides the well-known N1 and N2 subsets of neutrophils, several new subsets including aged, antigen-presenting, reverse-migrated, intercellular adhesion molecule-1+, low-density, olfactomedin 4+, and Siglec-F+ neutrophils have been reported. These neutrophils potentially contribute to the pathogenesis of sepsis based on their proinflammatory and immunosuppressive functions. Damage-associated molecular patterns (DAMPs) are endogenous molecules to induce inflammation by stimulating pattern recognition receptors on immune cells. Different kinds of DAMPs have been shown to contribute to sepsis pathophysiology, including extracellular cold-inducible RNA-binding protein, high-mobility group box 1, extracellular histones, and heat shock proteins. In this review, we summarize the different subsets of neutrophils and their association with sepsis and discuss the novel roles of DAMPs on neutrophil heterogeneity.
Learning robotic navigation from experience: principles, methods and recent results
Authors: Levine Sergey , Shah Dhruv
Published: December 2022

Navigation is one of the most heavily studied problems in robotics and is conventionally approached as a geometric mapping and planning problem. However, real-world navigation presents a complex set of physical challenges that defies simple geometric abstractions. Machine learning offers a promising way to go beyond geometry and conventional planning, allowing for navigational systems that make decisions based on actual prior experience. Such systems can reason about traversability in ways that go beyond geometry, accounting for the physical outcomes of their actions and exploiting patterns in real-world environments. They can also improve as more data is collected, potentially providing a powerful network effect. In this article, we present a general toolkit for experiential learning of robotic navigation skills that unifies several recent approaches, describe the underlying design principles, summarize experimental results from several of our recent papers, and discuss open problems and directions for future work.

This article is part of the theme issue ‘New approaches to 3D vision’.
Stereopsis without correspondence
Authors: Read Jenny C. A.
Published: December 2022

Stereopsis has traditionally been considered a complex visual ability, restricted to large-brained animals. The discovery in the 1980s that insects, too, have stereopsis, therefore, challenged theories of stereopsis. How can such simple brains see in three dimensions? A likely answer is that insect stereopsis has evolved to produce simple behaviour, such as orienting towards the closer of two objects or triggering a strike when prey comes within range. Scientific thinking about stereopsis has been unduly anthropomorphic, for example assuming that stereopsis must require binocular fusion or a solution of the stereo correspondence problem. In fact, useful behaviour can be produced with very basic stereoscopic algorithms which make no attempt to achieve fusion or correspondence, or to produce even a coarse map of depth across the visual field. This may explain why some aspects of insect stereopsis seem poorly designed from an engineering point of view: for example, paying no attention to whether interocular contrast or velocities match. Such algorithms demonstrably work well enough in practice for their species, and may prove useful in particular autonomous applications.

This article is part of a discussion meeting issue ‘New approaches to 3D vision’.
Looking at the Ebbinghaus illusion: differences in neurocomputational requirements, not gaze-mediated attention, explain a classic perception-action dissociation
Authors: Whitwell Robert L. , Garach Mehul A. , Goodale Melvyn A. , Sperandio Irene
Published: December 2022

Perceiving and grasping an object present an animal with different sets of computational problems. The solution in primates entails the specialization of separate neural networks for visual processing with different object representations. This explains why the Ebbinghaus illusion minimally affects the grasping hand's in-flight aperture, which normally scales with target size, even though the size of the target disc remains misperceived. An attractive alternative account, however, posits that grasps are refractory to the illusion because participants fixate on the target and fail to attend to the surrounding context. To test this account, we tracked both limb and gaze while participants made forced-choice judgments of relative disc size in the Ebbinghaus illusion or did so in combination with grasping or manually estimating the size of one of the discs. We replicated the classic dissociation: grasp aperture was refractory to the measured illusory effect on perceived size, while judgments and manual estimates of disc size were not. Importantly, the number of display-wide saccades per second and the percentage of total fixation time or fixations directed at the selected disc failed to explain the dissociation. Our findings support the contention that object perception and goal-directed action rely on distinct visual representations.

This article is part of a discussion meeting issue ‘New approaches to 3D vision’.
The protection gap under a social health protection initiative in the COVID-19 pandemic: A case study from Khyber Pakhtunkhwa, Pakistan
Authors: Khan Sheraz Ahmad , Cresswell Kathrin , Sheikh Aziz
Published: December 2022

Background

Sehat Sahulat Programme (SSP) is a Social Health Protection (SHP) initiative by the Government of Khyber Pakhtunkhwa (GoKP), covering inpatient services for 100% of the province’s population. In this paper, we describe SSP’s role in GoKP’s COVID-19 response and draw inferences for similar programmes in Pakistan.

Methodology and methods

We conceptualised SSP as an instrumental case study and collected three complementary data sources. First, we studied GoKP’s official documents to understand SSP’s benefits package. Then we undertook in-depth interviews and collected non-participant observations at the SSP policy and implementation levels. We recruited participants through direct (verbal and email) and indirect (invitation posters) methods.

Use of maximum variation sampling enabled us to understand contrasting views from various stakeholders on SSP’s policy dimensions (i.e., coverage and financing), tensions between the policy directions (i.e., whether or not to cover COVID-19) and how policy decisions were made and implemented. We collected data from March 2021 to December 2021. Thematic analysis was conducted with the help of Nvivo12.

Findings

Throughout 2020, SSP did not cover COVID-19 treatment. The insurer and GoKP officials considered the pandemic a standard exclusion to insurance coverage. One SSP official said: “COVID-19 is not covered and not relevant to us”. GoKP had stopped non-emergency services at all hospitals. When routine services restarted, the insurer did not cover COVID-19 screening tests, which were mandatory prior to hospital admission.

In 2021, GoKP engaged 10 private SSP hospitals for COVID-19 treatment. The SSP Reserve Fund, rather than insurance pooled money, was used. The Reserve Fund was originally meant to cover high-cost organ transplants. In 2021, SSP had 1,002 COVID-19-related admissions, which represented 0.2% of all hospital admissions (N=544,841).

An advocacy group representative called the COVID-19 care under SSP “too little too late”. In contrast, SSP officials suggested their insurance database and funds flow mechanism could help GoKP in future health emergencies.

Conclusion

The commercially focused interpretation of SHP arrangements led to a protection gap in the context of COVID-19. SSP and similar programmes in other provinces of Pakistan should emphasise the notion of protection and not let commercial interests lead to protection gaps.
scTensor detects many-to-many cell–cell interactions from single cell RNA-sequencing data
Authors: Tsuyuzaki Koki , Ishii Manabu , Nikaido Itoshi
Published: December 2022

Complex biological systems are described as a multitude of cell–cell interactions (CCIs). Recent single-cell RNA-sequencing studies focus on CCIs based on ligand–receptor (L-R) gene co-expression but the analytical methods are not appropriate to detect many-to-many CCIs.

In this work, we proposescTensor, a novel method for extracting representative triadic relationships (or hypergraphs), which include ligand-expression, receptor-expression, and related L-R pairs. Through extensive studies with simulated and empirical datasets, we have shown thatscTensorcan detect some hypergraphs that cannot be detected using conventional CCI detection methods, especially when they include many-to-many relationships.scTensoris implemented as a freely available R/Bioconductor package.
Mad Hatter correctly annotates 98% of small molecule tandem mass spectra searching in PubChem
Authors: Hoffmann Martin A. , Kretschmer Fleming , Ludwig Marcus , Böcker Sebastian
Published: December 2022

Metabolites provide a direct functional signature of cellular state. Untargeted metabolomics usually relies on mass spectrometry, a technology capable of detecting thousands of compounds in a biological sample. Metabolite annotation is executed using tandem mass spectrometry. Spectral library search is far from comprehensive, and numerous compounds remain unannotated. So-calledin silicomethods allow us to overcome the restrictions of spectral libraries, by searching in much larger molecular structure databases. Yet, after more than a decade of method development,in silicomethods still do not reach correct annotation rates that users would wish for. Here, we present a novel computational method called MadHatterfor this task. MadHattercombines CSI:FingerID results with information from the searched structure database via a metascore. Compound information includes the melting point, and the number words in the compound description starting with the letter ‘u’. We then show that MadHatterreaches a stunning 97.6% correct annotations when searching PubChem, one of the largest and most comprehensive molecular structure databases. Finally, we explain what evaluation glitches were necessary for MadHatterto reach this annotation level, what is wrong with similar metascores in general, and why metascores may screw up not only method evaluations but also the analysis of biological experiments.
Quantifying the impacts of an invasive weed on habitat quality and prey availability for tiger snakes (Notechis scutatus) in urban wetlands
Authors: Cornelis Jari , von Takach Brenton , Cooper Christine E. , Vos Jordan , Bateman Philip. W. , Lettoof Damian C.
Published: December 2022

Invasive plants are a threat to natural ecosystems worldwide with urban wetlands being some of the most susceptible and highly modified environments of all. The tiger snake (Notechis scutatus) is a top predator that persists in urban wetlands in south-western Australia, many of which have been degraded by introduced kikuyu grass (Cenchrus clandestinus). To evaluate the potential impact of kikuyu grass on habitat quality for western tiger snakes we quantified the structural features of habitats within wetlands degraded by kikuyu grass and compared them to wetlands with native vegetation, examined tiger snake prey availability, assessed predation risk for juvenile snakes using clay models, and measured the thermal quality of the vegetation. Proliferation of kikuyu grass reduced habitat structural heterogeneity by reducing available bare ground and increasing vegetation density. This homogenisation of habitat structure had little effect on the predation risk for juveniles or the thermal properties of tiger snake shelter sites; however, one key snake prey species, the motorbike frog, had significantly lower abundance in the most impacted habitat. Habitat types with more structural complexity also offered tiger snakes more stable thermal regimes and lower predation risk. These findings indicate that the current extent of kikuyu grass invasion offers overall similar habitat quality for tiger snakes and may contribute to their persistence in urban wetlands, but they, along with their anuran prey, may befit from some increased habitat structural complexity in open areas.
Peripheral nerve conduction speed shows a disease control-dependent and -independent drop in type 1 diabetes mellitus in children
Authors: Oberhauser Sarah S. , l’Allemand Dagmar , Lütschg Jürg , Broser Philip J.
Published: December 2022

Background/Aim

Nerve conduction speed (NCS) abnormalities are considered to be early signs of diabetic peripheral neuropathy. We investigated which determinants impact the NCS and how it is related to markers of metabolic control in children and young adults with diabetes mellitus.

Method

Fifty-four children aged five to 23 years suffering from type I diabetes mellitus were recruited into this study, which was conducted at the Children’s Hospital of Eastern Switzerland in St Gallen from March 2016 to June 2022. The metabolic control parameters were recorded and a nerve conduction study analyzing three motor nerves and one sensory nerve was performed. The data were compared to a control population of healthy children of the same height, and the height-adjusted NCS (dNCS) was analysed.

Results

For all four nerves under investigation, a statistically significant drop in the NCS of approximately 5 m/s independent of metabolic control was found, the peroneal nerve being the most sensitive. The NCS of the peroneal nerve correlated significantly negatively with the long-term haemoglobin with bound glucose (HbA1c) and highly significantly negatively with the standard deviation of mean glucose (SD), but there was only a trend with the HbA1c and the time in range (TIR) at the time of neurography.

Interpretation

All patients with diabetes mellitus showed a reduced NCS, partly independent of metabolic control. This may be due to a lack of the C-peptide, which regulates critical axonal membrane enzymes. High glucose variability clearly increases the risk of neuropathy, together with but also independently of the mean plasma glucose level.
Improved functional mapping with GSA-MiXeR implicates biologically specific gene-sets and estimates enrichment magnitude
Authors: Frei Oleksandr , Hindley Guy , Shadrin Alexey A. , van der Meer Dennis , Akdeniz Bayram C. , Cheng Weiqiu , O’Connell Kevin S. , Bahrami Shahram , Parker Nadine , Smeland Olav B. , Holland Dominic ,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, de Leeuw Christiaan , Posthuma Danielle , Andreassen Ole A. , Dale Anders M.
Published: December 2022

While genome-wide association studies (GWAS) are increasingly successful in discovering genomic loci associated with complex human traits and disorders, the biological interpretation of these findings remains challenging. We developed the GSA-MiXeR analytical tool for gene-set analysis (GSA), which fits a model for gene-set heritability enrichments for complex traits, accounting for linkage disequilibrium across variants, and allowing the quantification of partitioned heritability and fold enrichment for small gene-sets. We validate the method using extensive simulations and sensitivity analyses. When applied to height and schizophrenia, GSA-MiXeR implicates gene-sets with greater biological specificity compared to standard GSA approaches, including insulin-like growth factor for height, as well as calcium channel function, GABAergic and dopaminergic signaling for schizophrenia. Such biologically relevant gene-sets, often with less than ten genes, are more likely to provide new insights into the pathobiology of complex diseases and highlight potential drug targets.
The effect of minimum unit pricing for alcohol on prescriptions for treatment of alcohol dependence: a controlled Interrupted Time Series analysis
Authors: Manca Francesco , Zhang Lisong , Fitzgerald Niamh , Mackay Daniel , McAuley Andrew , Sharp Clare , Lewsey Jim
Published: December 2022

In 2018, Scotland introduced a minimum unit price (MUP) for alcohol to reduce alcohol-related harms. We aimed to study the association between MUP introduction and the volume of prescriptions to treat alcohol dependence, and volume of new patients receiving such prescriptions. We also examined whether effects varied across different socioeconomic groups. A controlled interrupted time series was used to examine variations of our two outcomes. The same prescriptions in England and prescriptions for methadone in Scotland were used as controls. There was no evidence of an association between MUP implementation and the volume of prescriptions for alcohol dependence (immediate change: 2.74%, 95% CI: -0.068 0.014; slope change: 0% 95%CI: -0.001 0.000). A small, significant increase in slope in number of new patients receiving prescriptions was observed (0.2% 95%CI: 0.001 0.003). However, no significant results were confirmed after robustness checks. We found also no variation across different socioeconomic groups.
SpLitteR: Diploid genome assembly using TELL-Seq linked-reads and assembly graphs
Authors: Tolstoganov Ivan , Chen Zhoutao , Pevzner Pavel A. , Korobeynikov Anton
Published: December 2022

Background

Recent advances in long-read sequencing technologies enabled accurate and contiguousde novoassemblies of large genomes and metagenomes. However, even long and accurate high-fidelity (HiFi) reads do not resolve repeats that are longer than the read lengths. This limitation negatively affects the contiguity of diploid genome assemblies since two haplomes share many long identical regions. To generate the telomere-to-telomere assemblies of diploid genomes, biologists now construct their HiFi-based phased assemblies and use additional experimental technologies to transform them into more contiguous diploid assemblies. The barcoded linked-reads, generated using an inexpensive TELL-Seq technology, provide an attractive way to bridge unresolved repeats in phased assemblies of diploid genomes.

Results

We developed SpLitteR tool for diploid genome assembly using linked-reads and assembly graphs and benchmarked it against state-of-the-art linked-read scaffolders ARKS and SLR-superscaffolder using human HG002 genome and sheep gut microbiome datasets. The benchmark showed that SpLitteR scaffolding results in 1.5-fold increase in NGA50 compared to baseline LJA assembly and other scaffolders while introducing no additional misassemblies on the human dataset.

Conclusion

We developed the SpLitteR tool for haplotype phasing and scaffolding in an assembly graph using barcoded linked-reads. We benchmarked SpLitteR on assembly graphs produced by various long-read assemblers and have shown how TELL-Seq reads facilitate phasing and scaffolding in these graphs. This benchmarking demonstrates that SpLitteR improves upon the state-of-the-art linked-read scaffolders in the accuracy and contiguity metrics. SpLitteR is implemented in C++ as a part of the freely available SPAdes package and is available athttps://github.com/ablab/spades/releases/tag/splitter-preprint.
Rejuvenation of Senescent Cells, in vitro and in vivo, by Low-frequency Ultrasound without Senolysis
Authors: Kureel Sanjay , Maroto Rosario , Powell Simon , Aniqua Maisha , Margadant Felix , Blair Brandon , Rasmussen Blake B. , Sheetz Michael
Published: December 2022

The presence of an appreciable number of senescent cells causes age-related pathologies as their removal by genetic or pharmacological means, as well as possibly by exercise, improves outcome in animal models. An alternative to depleting such cells would be to rejuvenate them to promote their return to a replicative state. Means to do so have not been explored, but here we report that treatment of non-growing senescent cells with low-frequency ultrasound (LFU) rejuvenates the cells. Notably, we find 15 characteristics of senescent cells that are reversed by LFU, including decreased cell and organelle motility. Mechanistically, LFU causes Ca2+entry that precedes dramatic increases in autophagy and an inhibition of mTORC1 signaling and the movement of Sirtuin1 from the nucleus to cytoplasm. Also, there is inhibition of SASP secretion, as well as β-galactosidase expression, telomere length is increased, while nuclear 5mc, H3K9me3, γH2AX, nuclear p53, ROS and mitoROS levels are all restored to normal levels. Repeated LFU treatments enables expansion of primary cells and stem cells beyond normal replicative limits without altering their phenotype. The rejuvenation process is enhanced by co-treatment with rapamycin or Rho kinase inhibition but is inhibited by blocking Sirtuin1 or Piezo1 activity. We further optimized the LFU treatment parameters to increase mouse lifespan and healthspan. These results suggest that mechanically-induced pressure waves alone can reverse senescence and aging effects at the cellular and organismal level, providing a non-pharmacological way to treat the effects of aging.

One-Sentence Summary

Low frequency ultrasound is sufficient to rejuvenate senescent cells by activating autophagy in aged mice to improve healthspan.
Herbarium Specimen Sequencing Allows Precise Datation ofXanthomonas citripv.citriDiversification History
Authors: Campos PE , Pruvost O , Boyer K , Chiroleu F , Cao TT , Gaudeul M , Baider C , Utteridge TMA , Dominick S , Becker N , Rieux A , Gagnevin L
Published: December 2022

Over the past decade, the field of ancient genomics has triggered considerable progress in the study of various pathogens, including those affecting crops. In this context, herbarium collections have been an important source of dated, identified and preserved DNA, whose use in comparative genomics and phylogeography may shed light into the emergence and evolutionary history of plant pathogens. In this study, we reconstructed 13 historical genomes of the bacterial crop pathogenXanthomonas citripv.citri(Xci) from infected citrus herbarium specimens using a shotgun-based deep sequencing strategy. Following authentication of the historical genomes based on ancient DNA damage patterns, we compared them to a large set of modern genomes to reconstruct their phylogenetic relationships, pathogeny-associated genes content and estimate several evolutionary parameters, using Bayesian tip-dating calibration and phylogeography inferences. Our results reveal thatXcioriginated in Southern Asia ~11,500 years ago and diversified during the beginning of the 13thcentury, afterCitrusdiversification and before spreading to the rest of the world. This updated scenario linksXcispecialization to Neolithic climatic change and the development of agriculture, and its diversification to the human-driven expansion of citriculture through the early East-West trade and later colonization. The analysis of data obtained from such historical specimens is challenging and must undergo adapted treatment before being compared to modern samples. Nevertheless, we confirm here that herbarium collections are a precious tool to improve the knowledge of the evolutionary history of plant pathogens.
Persistent gene flow suggests an absence of reproductive isolation in an African antelope speciation model
Authors: Wang Xi , Pedersen Casper-Emil Tingskov , Athanasiadis Georgios , Garcia-Erill Genis , Hanghøj Kristian , Bertola Laura D. , Rasmussen Malthe Sebro , Schubert Mikkel , Liu Xiaodong , Li Zilong , Lin Long , Jørsboe Emil , Nursyifa Casia , Liu Shanlin , Muwanika Vincent , Masembe Charles , Chen Lei , Wang Wen , Moltke Ida , Siegismund Hans R. , Albrechtsen Anders , Heller Rasmus
Published: December 2022

African antelope diversity is a globally unique vestige of a much richer world-wide Pleistocene megafauna. Despite this, the evolutionary processes leading to the prolific radiation of African antelopes are not well understood. Here, we sequenced 145 whole genomes from both subspecies of the waterbuck, an African antelope believed to be in the process of speciation. We investigated genetic structure and population divergence and found evidence of a mid-Pleistocene separation on either side of the eastern Great Rift Valley, consistent with vicariance caused by a rain shadow along the so-called ‘Kingdon’s Line’. However, we also found pervasive evidence of not only isolated and recent, but also widespread historical gene flow across the Rift Valley barrier. By inferring the genome-wide landscape of variation among subspecies, we found 14 genomic regions of elevated differentiation, including a locus that may be related to each subspecies’ distinctive coat pigmentation pattern. We investigated these regions as candidate speciation islands.

However, we observed no significant reduction in gene flow in these regions, nor any indications of selection against hybrids. Altogether, these results suggest a pattern whereby climatically driven vicariance is the most important process driving the African antelope radiation, and suggest that reproductive isolation may not set in until very late in the divergence process.
Assessing timing of fledging in a cavity-nesting passerine using temperature data loggers
Authors: Dubiec Anna , Mazgajski Tomasz D.
Published: December 2022

In altricial birds, the length of the nestling period, i.e. time from hatching until fledging (young leaving the nest) varies within and between species. In general, however, variation in the time of fledging and factors mediating such variation remain largely unexplored. To assess the time of nestlings leaving the nest, daily observer visits to the nest are usually done in the predicted fledging period. However, this might initiate premature fledging of young and/or increase the predation risk. The application of iButtons – coin-sized temperature data loggers, which are increasingly used in ornithological studies – may help to overcome these obstacles. We tested whether nest temperatures recorded with iButtons might be used to identify the date and hour of young fledging, i.e. when the last nestling in the brood left the nest, in a small cavity-nesting passerine – the Great Tit (Parus major). We installed iButtons in 38 nests when nestlings were 14-15 days old (hatching day = day 0) and verified the presence of nestlings during daily inspections starting on day 17 post-hatching or later. We found that the day of fledging could be accurately determined based on the difference between the temperature of the nest cup and the outside. The age of nestlings ranged between 17 and 22 days at fledging, with nearly 58% of broods fledging at the age of 20 and 21 days. The majority (81.6%) of broods fledged within 6 h after sunrise. We discuss the advantages and disadvantages of using iButtons to identify fledging time in altricial birds.
A Deep Learning Approach for Histology-Based Nuclei Segmentation and Tumor Microenvironment Characterization
Authors: Rong Ruichen , Sheng Hudanyun , Jin Kevin W. , Wu Fangjiang , Luo Danni , Wen Zhuoyu , Tang Chen , Yang Donghan M. , Jia Liwei , Amgad Mohamed , Cooper Lee A.D. , Xie Yang , Zhan Xiaowei , Wang Shidan , Xiao Guanghua
Published: December 2022

Microscopic examination of pathology slides is essential to disease diagnosis and biomedical research; however, traditional manual examination of tissue slides is laborious and subjective. Tumor whole-slide image (WSI) scanning is becoming part of routine clinical procedure and produces massive data that capture tumor histological details at high resolution. Furthermore, the rapid development of deep learning algorithms has significantly increased the efficiency and accuracy of pathology image analysis. In light of this progress, digital pathology is fast becoming a powerful tool to assist pathologists.

Studying tumor tissue and its surrounding microenvironment provides critical insight into tumor initiation, progression, metastasis, and potential therapeutic targets. Nuclei segmentation and classification are critical to pathology image analysis, especially in characterizing and quantifying the tumor microenvironment (TME). Computational algorithms have been developed for nuclei segmentation and TME quantification within image patches; however, existing algorithms are computationally intensive and time-consuming for WSI analysis.

In this study, we present Histology-based Detection using Yolo (HD-Yolo), a new method that significantly accelerates nuclei segmentation and TME quantification. We demonstrate that HD-Yolo outperforms existing methods for WSI analysis in nuclei detection and classification accuracy, as well as computation time.
Gross anatomy of the Pacific hagfish,Eptatretus burgeri, with special reference to the coelomic viscera
Authors: Muramatsu Banri , Suzuki Daichi G. , Suzuki Masakazu , Higashiyama Hiroki
Published: December 2022

Hagfish (Myxinoidea) are a deep-sea taxon of cyclostomes, the extant jawless vertebrates. Many researchers have examined the anatomy and embryology of hagfish to shed light on the early evolution of vertebrates; however, the diversity within hagfish is often overlooked. Hagfish have two lineages, Myxininae and Eptatretinae. Usually, textbook illustrations of hagfish anatomy reflect the morphology of the former lineage, especiallyMyxine glutinosa, with its single pair of external branchial pores. Here, we instead report the gross anatomy of an Eptatretinae,Eptatretus burgeri, which has six pairs of branchial pores, especially focusing on the coelomic organs. Dissections were performed on fixed and unfixed specimens to provide a guide for those doing organ- or tissue-specific molecular experiments. Our dissections revealed that the ventral aorta is Y-branched inE. burgeri, which differs from the unbranched morphology ofMyxine. Otherwise, there were no differences in the morphology of the lingual apparatus or heart in the pharyngeal domain. The thyroid follicles were scattered around the ventral aorta, as has been reported for adult lampreys. The hepatobiliary system more closely resembled those of jawed vertebrates than those of adult lampreys, with the liver having two lobes and a bile duct connecting the gallbladder to each lobe. Overall, the visceral morphology ofE. burgeridoes not differ significantly from that of the knownMyxineat the level of gross anatomy, except for the number of branchial pores.