bluuebunny/crossref_metadata_2025 huggingface dataset:
Semi-classical Lindblad master equation for spin dynamics
Authors: Dubois Jonathan , Saalmann Ulf , Rost Jan M
Published: April 2021

We derive the semi-classical Lindblad master equation in phase space for both canonical and non-canonical Poisson brackets using the Wigner–Moyal formalism and the Moyal star-product. The semi-classical limit for canonical dynamical variables, i.e. canonical Poisson brackets, is the Fokker–Planck equation, as derived before. We generalize this limit and show that it holds also for non-canonical Poisson brackets. Examples are gyro-Poisson brackets, which occur in spin ensembles, systems of recent interest in atomic physics and quantum optics. We show that the equations of motion for the collective spin variables are given by the Bloch equations of nuclear magnetization with relaxation. The Bloch and relaxation vectors are expressed in terms of the microscopic operators: the Hamiltonian and the Lindblad functions in the Wigner–Moyal formalism.
Next generation human brain models: engineered flat brain organoids featuring gyrification
Authors: Rothenbücher Theresa S P , Gürbüz Hakan , Pereira Marta P , Heiskanen Arto , Emneus Jenny , Martinez-Serrano Alberto
Published: April 2021

Brain organoids are considered to be a highly promising in vitro model for the study of the human brain and, despite their various shortcomings, have already been used widely in neurobiological studies. Especially for drug screening applications, a highly reproducible protocol with simple tissue culture steps and consistent output, is required. Here we present an engineering approach that addresses several existing shortcomings of brain organoids. By culturing brain organoids with a polycaprolactone scaffold, we were able to modify their shape into a flat morphology. Engineered flat brain organoids (efBOs) possess advantageous diffusion conditions and thus their tissue is better supplied with oxygen and nutrients, preventing the formation of a necrotic tissue core. Moreover, the efBO protocol is highly simplified and allows to customize the organoid size directly from the start. By seeding cells onto 12 by 12 mm scaffolds, the brain organoid size can be significantly increased. In addition, we were able to observe folding reminiscent of gyrification around day 20, which was self-generated by the tissue. To our knowledge, this is the first study that reports intrinsically caused gyrification of neuronal tissue in vitro. We consider our efBO protocol as a next step towards the generation of a stable and reliable human brain model for drug screening applications and spatial patterning experiments.
Tissue printing for engineering transplantable human parathyroid patch to improve parathyroid engraftment, integration, and hormone secretion in vivo
Authors: Yu Hyeong Won , Kim Byoung Soo , Lee Jae Yeon , Lee Keunchul , Ahn Minjun , Jang Jinah , Cho Dong-Woo , Choi June Young
Published: April 2021

During thyroid surgery, some parathyroid glands fail to maintain their function, therefore, they are unavoidably detached from the patient. For the purpose of re-preservation of the function, they are minced into small segments and transplanted into the fat or muscle layer. Yet, this method of auto-grafting the parathyroid glands is frequently unsuccessful due to its poor interaction and engraftment with the native tissue, eventually leading to the dysfunction of the parathyroid hormone (PTH) secretion. In this study, we suggest a methodology to restore parathyroid activity through the introduction of the ‘tissue printing’ concept. Parathyroid glands of patients with secondary hyperparathyroidism were minced into the fragments smaller than 0.5 × 0.5 mm, which is in common with the traditional surgical method. These parathyroid tissues (PTs) were uniformly mixed with the adipose-derived decellularized extracellular matrix (adECM) bioink that protects the PTs from hostile in vivo environments and promote initial engraftment. PTs-encapsulated adECM bioink (PTs-adECM) was then printed onto the pre-designed polycaprolactone (PCL) mesh to produce patch-type PTs construct, which functions as a mechanical support to further enhance long-term in vivo stability. The engineered patch was transplanted subcutaneously into rats and harvested after 4 weeks. In vivo results showed that the engineered patches were well engrafted and stabilized in their original position for 4 weeks as compared with PTs only. Immunohistochemistry results further revealed that the concentration of PTH was approximately 2.5-fold greater in rats engrafted in the patch. Taken together, we envision that the novel concept ‘tissue printing’ over cell printing could provide a closer step towards clinical applications of 3D bioprinting to solve the unmet need for parathyroid surgery method.
Sustainable application of silvered nickel foam for the highly efficient degradation of rhodamine B
Authors: Meng Yongde
Published: April 2021

The use of organic dyes has led to serious environmental problems resulting from contaminated wastewater; hence, the development of new dye-removal methods is an important objective. Herein, silvered nickel foam (nickel foam loaded with silver nanoparticles) is reported to significantly degrade an organic dye in aqueous solution. 20 mg · l–1 rhodamine B is completely reduced within 20 min with a rate constant of 0.26 min−1 in the presence of nickel foam sparsely loaded with silver. A mechanism for the reduction of rhodamine B is proposed. Moreover, the silvered nickel foam can be recycled at least five times. This research demonstrates that silvered nickel foam is a promising pollution-control candidate material.
An investigation into the microstructural and mechanical properties of the ZrB2/SiC composites prepared by silicon infiltration
Authors: Nilforoushan Mohammad Reza , Kazemzadeh Parya , Babaei Behzad , Tayebi Morteza , Yaghoubi Mohammad
Published: April 2021

In this study, the synthesis of ZrB2/SiC composite was carried out via infiltration of silicon melt into a ZrSiO4/B4C preform, and the effect of different ratios of ZrSiO4/B4C and C/ZrSiO4 was investigated on phase and microstructural properties. For this purpose, stoichiometric ratios of raw materials and 10 wt% phenolic resin were used to induce the porosities in the preform. Then the powder mixture was milled and pressed. To perform pyrolysis reaction, it was placed in a vacuum-controlled atmosphere furnace with argon gas at 650 °C and then the Si infiltration process was performed at 1650 °C for 1 h. The hardness, density, and elastic modulus of the samples were measured. The optimum results were obtained for the composite sample with a ZrSiO4/B4C ratio of 4, which had a density of 5.28 g cm−3, elastic modulus of 423 GPa, and hardness of 33.28 GPa. Moreover, scanning electron microscopy and x-ray diffraction analyses confirmed a uniform distribution of ZrB2 and SiC phases and the absence of undesirable phases in the sample, respectively.
The effects of thermal deformation temperatures on microstructure and mechanical properties of TiBw/Ti60 composites synthesized by SPS
Authors: Zhang Yueting , Wang Bo , Zhang Haobiao , Li Yang
Published: April 2021

In this work, 1vol.%, 3vol.% and 5vol.% TiBw/Ti60 composites were fabricated by spark plasma sintering (SPS) at 1150 °C with Ti60 powder and B powder. Scanning electron microscopy (SEM) confirmed that micro-nano enhancement TiBw can be obtained by SPS and the network structure were formed in the 3vol.% TiBw/Ti60 composites. The tensile properties of composites with different volume fraction at 600 °C show that 3vol.% TiBw/Ti60 composites have optimum comprehensive mechanical properties. The microstructure of thermal deformation of the 3vol.% TiBw/Ti60 composites shows that the matrix grains recrystallized at 1050 °C and the grains were refined. The tensile strength and elongation of the composites increased at first and then decreased with the increase of thermal deformation temperature. Highest values for flexural strength (∼752 MPa) and elongation (∼7.03%) were attained at 1050 °C, respectively. The strengthening mechanism can be mainly attributed to the directional arrangement of reinforcements and the grain refinement of the matrix.
Influence of anthopometric variables on the mechanical properties of human rib cortical bone
Authors: Velázquez-Ameijide Juan , García-Vilana Silvia , Sánchez-Molina David , Martínez-González Eva , Llumà Jordi , Rebollo-Soria M Carmen , Arregui-Dalmases Carlos
Published: April 2021

Objective. The mechanical properties of ribs from a large number of post-mortem human subjects (PMHS) were analyzed to search for variation according to age, sex or BMI in the sample. A large sample of specimens from different donors (N = 64) with a very wide range of ages and anthropometric characteristics was tested. Methods. Uniaxial tensile tests were used for a sample of coupons machined from cortical bone tissue in order to isolate the purely mechanical properties from the geometrically influenced properties of the rib. Each coupon is about 25 mm long and has a thickness of about 0.5 mm. The mechanical properties measured for each specimen/coupon include YM, yield stress, ultimate stress (maximum failure stress), ultimate strain, and resilience (energy to fracture of SED). The study provides new methodological improvements in DIC techniques. Results. This study is notable for using an atypically large sample of number of PMHS. The size of the sample allowed the authors to determine that age has a significant effect on failure stress (p < 0.0001), yield stress (p = 0.0047), ultimate strain (p < 0.0001) and resilience (p < 0.0001) [numbers in parentheses represent the corresponding p − values]. Finally, there is a combined effect, so that for a given age, an increase of BMI leads to a decrease of the maximum strain (i.e. cortical bone is less stiff when both age and BMI are higher).
Tailoring the triboelectric output of poly-L-lactic acid nanotubes through control of polymer crystallinity
Authors: Margaronis Kalliope , Busolo Tommaso , Nair Malavika , Chalklen Thomas , Kar-Narayan Sohini
Published: April 2021

Triboelectric devices capable of harvesting ambient mechanical energy have attracted attention in recent years for powering biomedical devices. Typically, triboelectric energy harvesters rely on contact-generated charges between pairs of materials situated at opposite ends of the triboelectric series. However, very few biocompatible polymeric materials exist at the ‘tribopositive’ end of the triboelectric series. In order to further explore the use of triboelectric energy harvesting devices within the body, it is necessary to develop more biocompatible tribopositive materials and look into ways to improve their triboelectric performance in order to enhance the harvested power output of these devices. Poly-L-lactic acid (PLLA) is a tribopositive biocompatible polymer, frequently used in biomedical applications. Here, we present a way to improve the triboelectric output of nanostructured PLLA through fine control of its crystallinity via a customised template-assisted nanotube (NT) fabrication process. We find that PLLA NTs with higher values of crystallinity (∼41%) give rise to a threefold enhancement of the maximum triboelectric power output as compared to NTs of the same material and geometry but with lower crystallinity (∼13%). Our results thus pave the way for the production of a viable polymeric and biocompatible tribopositive material with improved power generation, for possible use in implantable triboelectric nanogenerators.
Intense terahertz pulses inhibit Ras signaling and other cancer-associated signaling pathways in human skin tissue models
Authors: Hough Cameron M , Purschke David N , Huang Chenxi , Titova Lyubov V , Kovalchuk Olga V , Warkentin Brad J , Hegmann Frank A
Published: April 2021

Terahertz (THz) radiation has shown unique advantages in biomedical applications for novel diagnostic technologies due to the high sensitivity to molecular structure and chemical concentration. However, emerging evidence shows that intense pulses of THz radiation can induce significant non-thermal biological effects that must be characterized. In human skin exposed to intense THz pulses, relatively large responses characterized by differential gene expression profiles are observed. These data are analyzed by signaling pathway perturbation analysis to predict phenotypic endpoints and dysregulatory effects on cancer-related processes. The activities of several important pathways that drive the initiation, development, and progression of many human cancers are predicted to be suppressed, and this effect is intensity-dependent. Some affected pathways are targets for current and emerging anti-cancer therapies. In particular, the activity of the Ras signaling and Calcium signaling pathways is predicted to be significantly inhibited. These results indicate the possibility of an additional therapeutic mechanism of intense THz pulses, due to the potential for targeted suppression of pro-mitotic activity in diseased tissue.
Advances in scientific literature mining for interpreting materials characterization
Authors: Park Gilchan , Pouchard Line
Published: April 2021

Using synchrotron light sources, such as the National Synchrotron Light Source II at Brookhaven National Laboratory, scientists in fields as diverse as physics, biology, and materials science, identify the atomic structure, chemical composition, or other important properties of varied specimens. x-ray spectroscopy from light sources is particularly valuable for materials research with vast information available about reference spectra in the scientific literature. However, as the technique is applicable to many science domains, searching for information about select x-ray spectroscopy spectra is impeded by the sheer number of publications. Moreover, useful information about the context of an experiment or figures presented in papers can be buried among the details, which takes time to assess. This work presents a scientific literature mining system that supports data acquisition, information extraction, and user interaction for referencing x-ray spectra identification and spectral interpretation. The goal is to provide efficient access to useful spectral data to researchers who may spend only a few days at a synchrotron light source. With this system, users browse a classification tree for papers arranged according to x-ray spectroscopic methods, chemical elements, and x-ray absorption spectroscopy edges. Relevant figures are extracted with sentences from the paper that explain them, known as ‘figure explanatory text.’ Notably, this system focuses on semantic aspects (logical analysis) to find figure explanatory text using deep contextualized word embeddings techniques and contains an interface to obtain labeled data from domain experts that is used to evaluate and improve the model.
A tight structure theorem for sumsets
Authors: Granville Andrew , Walker Aled
Published: April 2021

Let

A
=
{
0
=

a
0

>

a
1

>
⋯
>

a

ℓ
+
1

=
b
}

A = \{0 = a_0 > a_1 > \cdots > a_{\ell + 1} = b\}

be a finite set of non-negative integers. We prove that the sumset

N
A

NA

has a certain easily-described structure, provided that

N
⩾
b
−
ℓ

N \geqslant b-\ell

, as recently conjectured (see A. Granville and G. Shakan [Acta Math. Hungar. 161 (2020), pp. 700–718]). We also classify those sets

A
A

for which this bound cannot be improved.
Conical tessellations associated with Weyl chambers
Authors: Godland Thomas , Kabluchko Zakhar
Published: April 2021

We consider

d
d

-dimensional random vectors

Y
1

,
…
,

Y
n

Y_1,\ldots ,Y_n

that satisfy a mild general position assumption a.s. The hyperplanes
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartLayout 1st Row left-parenthesis upper Y Subscript i Baseline minus upper Y Subscript j Baseline right-parenthesis Superscript up-tack Baseline left-parenthesis 1 less-than-or-equal-to i greater-than j less-than-or-equal-to n right-parenthesis EndLayout">

(

Y
i

−

Y
j

)
⊥

(
1
≤
i
>
j
≤
n
)

\begin{align*} (Y_i-Y_j)^\perp \;\; (1\le i>j\le n) \end{align*}

generate a conical tessellation of the Euclidean

d
d

-space which is closely related to the Weyl chambers of type

A

n
−
1

A_{n-1}

. We determine the number of cones in this tessellation and show that it is a.s. constant. For a random cone chosen uniformly at random from this random tessellation, we compute expectations of several geometric functionals. These include the face numbers, as well as the conic intrinsic volumes and the conical quermassintegrals. Under the additional assumption of exchangeability on

Y
1

,
…
,

Y
n

Y_1,\ldots ,Y_n

, the same is done for the dual random cones which have the same distribution as the positive hull of

Y
1

−

Y
2

,
…
,

Y

n
−
1

−

Y
n

Y_1-Y_2,\ldots , Y_{n-1}-Y_n

conditioned on the event that this positive hull is not equal to

R

d

\mathbb R^d

. All these expectations turn out to be distribution-free.

Similarly, we consider the conical tessellation induced by the hyperplanes
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartLayout 1st Row left-parenthesis upper Y Subscript i Baseline plus upper Y Subscript j Baseline right-parenthesis Superscript up-tack Baseline left-parenthesis 1 less-than-or-equal-to i greater-than j less-than-or-equal-to n right-parenthesis comma left-parenthesis upper Y Subscript i Baseline minus upper Y Subscript j Baseline right-parenthesis Superscript up-tack Baseline left-parenthesis 1 less-than-or-equal-to i greater-than j less-than-or-equal-to n right-parenthesis comma upper Y Subscript i Superscript up-tack Baseline left-parenthesis 1 less-than-or-equal-to i less-than-or-equal-to n right-parenthesis period EndLayout">

(

Y
i

+

Y
j

)
⊥

(
1
≤
i
>
j
≤
n
)
,

(

Y
i

−

Y
j

)
⊥

(
1
≤
i
>
j
≤
n
)
,

Y
i
⊥

(
1
≤
i
≤
n
)
.

\begin{align*} (Y_i+Y_j)^\perp \;\; (1 \le i>j\le n),\quad (Y_i-Y_j)^\perp \;\; (1\le i>j\le n),\quad Y_i^\perp \;\; (1\le i\le n). \end{align*}

This tessellation is closely related to the Weyl chambers of type

B
n

B_n

. We compute the number of cones in this tessellation and the expectations of various geometric functionals for random cones drawn from this random tessellation.

The main ingredient in the proofs is a connection between the number of faces of the tessellation and the number of faces of the Weyl chambers of the corresponding type that are intersected non-trivially by a certain linear subspace in general position.
Structural insights into the cause of human RSPH4A primary ciliary dyskinesia
Authors: Zhao Yanhe , Pinskey Justine , Lin Jianfeng , Yin Weining , Sears Patrick R. , Daniels Leigh A. , Zariwala Maimoona A. , Knowles Michael R. , Ostrowski Lawrence E. , Nicastro Daniela
Published: April 2021

A growing number of ciliopathy-associated genes have been identified, but how they cause ciliary dysfunction is often unclear. Using cryo-electron tomography, we characterize the structural defects in patient cilia lacking radial spoke protein RSPH4A, revealing the underlying molecular defects and providing new insight into ciliary disease etiology.
A System for Phenotype Harmonization in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) Program
Authors: Stilp Adrienne M , Emery Leslie S , Broome Jai G , Buth Erin J , Khan Alyna T , Laurie Cecelia A , Wang Fei Fei , Wong Quenna , Chen Dongquan , D’Augustine Catherine M , Heard-Costa Nancy L , Hohensee Chancellor R , Johnson William Craig , Juarez Lucia D , Liu Jingmin , Mutalik Karen M , Raffield Laura M , Wiggins Kerri L , de Vries Paul S , Kelly Tanika N , Kooperberg Charles , Natarajan Pradeep , Peloso Gina M , Peyser Patricia A , Reiner Alex P , Arnett Donna K , Aslibekyan Stella , Barnes Kathleen C , Bielak Lawrence F , Bis Joshua C , Cade Brian E , Chen Ming-Huei , Correa Adolfo , Cupples L Adrienne , de Andrade Mariza , Ellinor Patrick T , Fornage Myriam , Franceschini Nora , Gan Weiniu , Ganesh Santhi K , Graffelman Jan , Grove Megan L , Guo Xiuqing , Hawley Nicola L , Hsu Wan-Ling , Jackson Rebecca D , Jaquish Cashell E , Johnson Andrew D , Kardia Sharon L R , Kelly Shannon , Lee Jiwon , Mathias Rasika A , McGarvey Stephen T , Mitchell Braxton D , Montasser May E , Morrison Alanna C , North Kari E , Nouraie Seyed Mehdi , Oelsner Elizabeth C , Pankratz Nathan , Rich Stephen S , Rotter Jerome I , Smith Jennifer A , Taylor Kent D , Vasan Ramachandran S , Weeks Daniel E , Weiss Scott T , Wilson Carla G , Yanek Lisa R , Psaty Bruce M , Heckbert Susan R , Laurie Cathy C
Published: April 2021

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase statistical power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data-set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data-sharing mechanisms. This system was developed for the National Heart, Lung, and Blood Institute’s Trans-Omics for Precision Medicine (TOPMed) program, which is generating genomic and other -omics data for more than 80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants (recruited in 1948–2012) from up to 17 studies per phenotype. Here we discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include 1) the software code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify, or extend these harmonizations to additional studies, and 2) the results of labeling thousands of phenotype variables with controlled vocabulary terms.
Trajectories of Blood Pressure Control a Year After Randomization and Incident Cardiovascular Outcomes in SPRINT
Authors: German Charles A , Elfassy Tali , Singleton Matthew J , Rodriguez Carlos J , Ambrosius Walter T , Yeboah Joseph
Published: April 2021

BACKGROUND

While studies have assessed the association between blood pressure trajectories and cardiovascular disease (CVD) outcomes using observational data, few have assessed these associations using clinical trial data. We sought to identify systolic blood pressure (SBP) trajectories and to determine if these trajectory patterns carry inherent CVD risk, irrespective of baseline blood pressure.

METHODS

SBP trajectories were identified using latent class group-based modeling among a cohort of Systolic Blood Pressure Intervention Trial (SPRINT) participants by incorporating SBP measures during the first 12 months of the trial postrandomization. Cox models were used to evaluate the association between SBP trajectory with CVD and all-cause mortality.

RESULTS

Four distinct SBP trajectories were identified: “low decline” (41%), “high decline” (6%), “low stable” (48%), and “high stable” (5%). Relative to the “low decline” group, the “low stable” group was associated with a 29% increased risk of CVD (hazard ratio [HR]: 1.29, 95% confidence interval [CI]: 1.06–1.57) and the “high stable” group was associated with a 76% increased risk of all-cause mortality (HR: 1.76, 95% CI: 1.15–2.68). Relative to the “low stable” group, the “high stable” group was associated with a 54% increased risk of all-cause mortality (HR: 1.54, 95% CI: 1.05–2.28).

CONCLUSIONS

Our results demonstrate that SBP trajectory patterns are associated with important cardiovascular outcomes, irrespective of baseline blood pressure, which may help better identify individuals at risk and assist with accurate adjudication of antihypertensive therapy to reduce future events.
Terminal Schwann cells at the human neuromuscular junction
Authors: Alhindi Abrar , Boehm Ines , Forsythe Rachael O , Miller Janice , Skipworth Richard J E , Simpson Hamish , Jones Ross A , Gillingwater Thomas H
Published: April 2021

Terminal Schwann cells are non-myelinating glial cells localized to the neuromuscular junction. They play an important role in regulating many aspects of neuromuscular junction form and function, in health and during disease. However, almost all previous studies of mammalian terminal Schwann cells have used rodent models. Despite a growing awareness of differences in the cellular and molecular anatomy of rodent and human neuromuscular junctions, it remains unclear as to whether these differences also extend to the terminal Schwann cells. Here, we have adapted immunohistochemical protocols to facilitate visualization and comparative morphometric analyses of terminal Schwann cells at the human and mouse neuromuscular junction. We labelled terminal Schwann cells in the peroneus brevis muscle in six adult mice and five humans with antibodies against S100 protein. All human neuromuscular junctions were associated with at least one terminal Schwann cell, consistent with findings from other species, with an average of ∼1.7 terminal Schwann cells per neuromuscular junction in both humans and mice. In contrast, human terminal Schwann cells were significantly smaller than those of mice (P ≤ 0.01), in keeping with differences in overall synaptic size. Human terminal Schwann cell cytoplasm extended significantly beyond the synaptic boundaries of the neuromuscular junction, whereas terminal Schwann cells in mice were largely restricted to the synapse. Moreover, there was a significant difference in the location of terminal Schwann cell nuclei (P ≤ 0.01), with human terminal Schwann cells having their nuclear compartment located beyond the perimeter of the synapse more than the mouse. Taken together, these findings demonstrate that terminal Schwann cells at the human neuromuscular junction have notable differences in their morphology and synaptic relationships compared to mice. These fundamental differences need to be considered when translating the findings of both neuromuscular junction biology and pathology from rodents to humans.
Mesenchymal stem cell-based therapy for burn wound healing
Authors: Wang Mingyao , Xu Xinxuan , Lei Xiongxin , Tan Jie , Xie Huiqi
Published: April 2021

Burns, with their high incidence and mortality rates, have a devastating effect on patients. There are still huge challenges in the management of burns. Mesenchymal stem cells (MSCs), which have multidirectional differentiation potential, have aroused interest in exploring the capacity for treating different intractable diseases due to their strong proliferation, tissue repair, immune tolerance and paracrine abilities, among other features. Currently, several animal studies have shown that MSCs play various roles and have beneficial effects in promoting wound healing, inhibiting burn inflammation and preventing the formation of pathological scars during burn healing process. The substances MSCs secrete can act on peripheral cells and promote burn repair. According to preclinical research, MSC-based treatments can effectively improve burn wound healing and reduce pain. However, due to the small number of patients and the lack of controls, treatment plans and evaluation criteria vary widely, thus limiting the value of these clinical studies. Therefore, to better evaluate the safety and effectiveness of MSC-based burn treatments, standardization of the application scheme and evaluation criteria of MSC therapy in burn treatment is required in the future. In addition, the combination of MSC pretreatment and dressing materials are also conducive to improving the therapeutic effect of MSCs on burns. In this article, we review current animal research and clinical trials based on the use of stem cell therapy for treating burns and discuss the main challenges and coping strategies facing future clinical applications.
Extensive Cortical Connectivity of the Human Hippocampal Memory System: Beyond the “What” and “Where” Dual Stream Model
Authors: Huang Chu-Chung , Rolls Edmund T , Hsu Chih-Chin Heather , Feng Jianfeng , Lin Ching-Po
Published: April 2021

The human hippocampus is involved in forming new memories: damage impairs memory. The dual stream model suggests that object “what” representations from ventral stream temporal cortex project to the hippocampus via the perirhinal and then lateral entorhinal cortex, and spatial “where” representations from the dorsal parietal stream via the parahippocampal gyrus and then medial entorhinal cortex. The hippocampus can then associate these inputs to form episodic memories of what happened where. Diffusion tractography was used to reveal the direct connections of hippocampal system areas in humans. This provides evidence that the human hippocampus has extensive direct cortical connections, with connections that bypass the entorhinal cortex to connect with the perirhinal and parahippocampal cortex, with the temporal pole, with the posterior and retrosplenial cingulate cortex, and even with early sensory cortical areas. The connections are less hierarchical and segregated than in the dual stream model. This provides a foundation for a conceptualization for how the hippocampal memory system connects with the cerebral cortex and operates in humans. One implication is that prehippocampal cortical areas such as the parahippocampal TF and TH subregions and perirhinal cortices may implement specialized computations that can benefit from inputs from the dorsal and ventral streams.
Five-year outcome in 18 010 patients from the German Aortic Valve Registry
Authors: Beyersdorf Friedhelm , Bauer Timm , Freemantle Nick , Walther Thomas , Frerker Christian , Herrmann Eva , Bleiziffer Sabine , Möllmann Helge , Landwehr Sandra , Ensminger Stephan , Bekeredjian Raffi , Cremer Jochen , Kuck Karl Heinz , Fujita Buntaro , Gummert Jan , Müller Lisa , Beckmann Andreas , Hamm Christian W ,   for the GARY Executive Board
Published: April 2021

OBJECTIVES

To determine the 5-year outcome in patients treated by isolated transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (sAVR)—a prospective observational cohort study.

METHODS

A total of 18 010 patients were included (n = 8942 TAVI and n = 9068 sAVR) in the German Aortic Valve Registry (GARY) who were treated in 2011 and 2012 at 92 sites in central Germany. Eligible patients with TAVI and sAVR were matched using propensity scores in a nearest-neighbour approach. Patients with repeat procedures or unequivocal indication for one treatment option (e.g. frailty) were excluded (n = 4785 for TAVI and n = 2 for sAVR). This led to 13 223 patients (4157 TAVI and 9066 sAVR) as an unmatched subcohort. The main outcome measure was the 5-year all-cause mortality.

RESULTS

TAVI patients were significantly older (80.9 ± 6.1 vs 68.5 ± 11.1 years, P < 0.001), had a higher Society of Thoracic Surgeons (STS) score (6.3 ± 4.9 vs 2.6 ± 3.0, P < 0.001) and a higher 5-year all-cause mortality (49.8% vs 16.5%, P < 0.0001). There was no major difference in in-hospital stroke, in-hospital myocardial infarction, or temporary and chronic dialysis. In the propensity score-matched group (n = 3640), there were 763 deaths (41.9%) among 1820 TAVI patients compared with 552 (30.3%) among 1820 treated with sAVR during the 5-year follow-up (hazard ratio 1.51, 95% confidence interval 1.35–1.68; P < 0.0001). New pacemaker implantation was performed in 448 patients (24.6%) after TAVI and in 201 (11.0%) after sAVR (P < 0.0001).

CONCLUSIONS

The 5-year follow-up data show that TAVI patients were significantly older and had a higher STS score than sAVR patients. After propensity score matching, TAVI with early-generation prosthesis was associated with significantly higher 5-year all-cause mortality than sAVR.
An automated computational image analysis pipeline for histological grading of cardiac allograft rejection
Authors: Peyster Eliot G , Arabyarmohammadi Sara , Janowczyk Andrew , Azarianpour-Esfahani Sepideh , Sekulic Miroslav , Cassol Clarissa , Blower Luke , Parwani Anil , Lal Priti , Feldman Michael D , Margulies Kenneth B , Madabhushi Anant
Published: April 2021

Aim

Allograft rejection is a serious concern in heart transplant medicine. Though endomyocardial biopsy with histological grading is the diagnostic standard for rejection, poor inter-pathologist agreement creates significant clinical uncertainty. The aim of this investigation is to demonstrate that cellular rejection grades generated via computational histological analysis are on-par with those provided by expert pathologists

Methods and results

The study cohort consisted of 2472 endomyocardial biopsy slides originating from three major US transplant centres. The ‘Computer-Assisted Cardiac Histologic Evaluation (CACHE)-Grader’ pipeline was trained using an interpretable, biologically inspired, ‘hand-crafted’ feature extraction approach. From a menu of 154 quantitative histological features relating the density and orientation of lymphocytes, myocytes, and stroma, a model was developed to reproduce the 4-grade clinical standard for cellular rejection diagnosis. CACHE-grader interpretations were compared with independent pathologists and the ‘grade of record’, testing for non-inferiority (δ = 6%). Study pathologists achieved a 60.7% agreement [95% confidence interval (CI): 55.2–66.0%] with the grade of record, and pair-wise agreement among all human graders was 61.5% (95% CI: 57.0–65.8%). The CACHE-Grader met the threshold for non-inferiority, achieving a 65.9% agreement (95% CI: 63.4–68.3%) with the grade of record and a 62.6% agreement (95% CI: 60.3–64.8%) with all human graders. The CACHE-Grader demonstrated nearly identical performance in internal and external validation sets (66.1% vs. 65.8%), resilience to inter-centre variations in tissue processing/digitization, and superior sensitivity for high-grade rejection (74.4% vs. 39.5%, P < 0.001).

Conclusion

These results show that the CACHE-grader pipeline, derived using intuitive morphological features, can provide expert-quality rejection grading, performing within the range of inter-grader variability seen among human pathologists.
Driving following defibrillator implantation: a nationwide register-linked survey study
Authors: Bjerre Jenny , Rosenkranz Simone Hofman , Schou Morten , Jøns Christian , Philbert Berit Thornvig , Larroudé Charlotte , Nielsen Jens Cosedis , Johansen Jens Brock , Riahi Sam , Melchior Thomas Maria , Torp-Pedersen Christian , Hlatky Mark , Gislason Gunnar , Ruwald Anne-Christine
Published: April 2021

Aims

Patients are restricted from driving following implantable cardioverter defibrillator (ICD) implantation or shock. We sought to investigate how many patients are aware of, and adhere to, the driving restrictions, and what proportion experience an ICD shock or other cardiac symptoms while driving.

Methods and results

We performed a nationwide survey of all living Danish residents 18 years or older who received a first-time ICD between 2013 and 2016 (n = 3913) and linked their responses with nationwide registers. Of 2741 respondents (47% primary prevention, 83% male, median age 67 years), 2513 (92%) held a valid driver’s license at ICD implantation, 175 (7%) of whom had a license for professional driving. Many drivers were unaware of driving restrictions: primary prevention 58%; secondary prevention 36%; post-appropriate shock 28%; professional drivers 55%. Almost all (94%) resumed non-professional driving after ICD implantation, more than one-third during the restricted period; 35% resumed professional driving. During a median follow-up of 2.3 years, 5 (0.2%) reported receiving an ICD shock while driving, one of which resulted in a traffic accident. The estimated risk of harm was 0.0002% per person-year.

Conclusion

In this nationwide study, many ICD patients were unaware of driving restrictions, and more than one third resumed driving during a driving restriction period. However, the rate of reported ICD shocks while driving was very low.
Autonomic modulation and cardiac arrhythmias: old insights and novel strategies
Authors: Chatterjee Neal A , Singh Jagmeet P
Published: April 2021

The autonomic nervous system (ANS) plays a critical role in both health and states of cardiovascular disease. There has been a long-recognized role of the ANS in the pathogenesis of both atrial and ventricular arrhythmias (VAs). This historical understanding has been expanded in the context of evolving insights into the anatomy and physiology of the ANS, including dysfunction of the ANS in cardiovascular disease such as heart failure and myocardial infarction. An expanding armamentarium of therapeutic strategies—both invasive and non-invasive—have brought the potential of ANS modulation to contemporary clinical practice. Here, we summarize the integrative neuro-cardiac anatomy underlying the ANS, review the physiological rationale for autonomic modulation in atrial and VAs, highlight strategies for autonomic modulation, and finally frame future challenges and opportunities for ANS therapeutics.
Inhibitory effect of black cumin (Nigella sativa) seed essential oil on Fusobacterium nucleatum L-methionine-γ-lyase (L-methioninase) activity
Authors: Ishikawa Masao , Murata Takatoshi , Okamoto Masaaki , Miyanohara Mayu , Yamashita Mamiko , Hanada Nobuhiro , Senpuku Hidenobu , Shibuya Koji
Published: April 2021

The enzyme L-methionine-γ-lyase is commonly found in a wide range of bacteria and catalyzes the α-elimination and γ-elimination of L-methionine to produce methyl mercaptan, α-ketobutyrate and ammonia. Black cumin seed essential oil (BC oil) reportedly exhibits deodorizing activity against methyl mercaptan. Therefore, we hypothesized that BC oil may also suppress methyl mercaptan production. In this study, we aimed to evaluate the inhibitory effect of BC oil on L-methionine-γ-lyase activity in Fusobacterium nucleatum. Recombinant L-methionine-γ-lyase was incubated under appropriate conditions with BC oil and its constituent thymoquinone. To analyze L-methionine-γ-lyase activity, α-ketobutyric acid and ammonia concentrations were determined. The concentrations of α-ketobutyric acid and ammonia were significantly decreased by 10 µg mL−1 of BC oil (P < 0.01) and 16.4 µg/mL of thymoquinone (P < 0.05). An enzyme kinetic assay showed a mixed inhibition pattern between L-methionine-γ-lyase and thymoquinone. In conclusion, BC oil not only had a deodorizing effect against methyl mercaptan but also an inhibitory effect on methyl mercaptan production through the suppression of L-methionine-γ-lyase activity. Thymoquinone may be mainly responsible for these effects of BC oil. Thus, application of natural BC oil may be adapted not only for medical use but also in other areas of life.
Grad-seq identifies KhpB as a global RNA-binding protein inClostridioides difficilethat regulates toxin production
Authors: Lamm-Schmidt Vanessa , Fuchs Manuela , Sulzer Johannes , Gerovac Milan , Hör Jens , Dersch Petra , Vogel Jörg , Faber Franziska
Published: April 2021

Much of our current knowledge about cellular RNA–protein complexes in bacteria is derived from analyses in gram-negative model organisms, with the discovery of RNA-binding proteins (RBPs) generally lagging behind in Gram-positive species. Here, we have applied Grad-seq analysis of native RNA–protein complexes to a major Gram-positive human pathogen, Clostridioides difficile, whose RNA biology remains largely unexplored. Our analysis resolves in-gradient distributions for ∼88% of all annotated transcripts and ∼50% of all proteins, thereby providing a comprehensive resource for the discovery of RNA–protein and protein–protein complexes in C. difficile and related microbes. The sedimentation profiles together with pulldown approaches identify KhpB, previously identified in Streptococcus pneumoniae, as an uncharacterized, pervasive RBP in C. difficile. Global RIP-seq analysis establishes a large suite of mRNA and small RNA targets of KhpB, similar to the scope of the Hfq targetome in C. difficile. The KhpB-bound transcripts include several functionally related mRNAs encoding virulence-associated metabolic pathways and toxin A whose transcript levels are observed to be increased in a khpB deletion strain. Moreover, the production of toxin protein is also increased upon khpB deletion. In summary, this study expands our knowledge of cellular RNA protein interactions in C. difficile and supports the emerging view that KhpB homologues constitute a new class of globally acting RBPs in Gram-positive bacteria.
Using dedications to Charles VI to convey political messages: Honorat Bovet, Philippe de Mézières, Christine de Pizan and Pierre Salmon
Authors: Bourassa Kristin
Published: April 2021

The dedication of four French-language advice books to Charles VI of France (r. 1380–1422), two just after the king’s declaration of personal rule and two during the period dominated by his mental illness, was a strategic choice by the books’ authors. Honorat Bovet, Philippe de Mézières, Christine de Pizan and Pierre Salmon used these dedications to convey political messages not only to the king but also to his powerful male relatives. The dedications, the way the manuscripts represented Charles both textually and visually and the way the texts urged Charles’ relatives to support Charles and each other, all place the king at the centre of the political conversation. Casting both themselves and the king’s relatives as important contributors to French political life, the writers used the role of Charles as imagined reader of the books to urge his male relatives to prioritize the needs of king and kingdom above their own.
Modelling the impact of climate change on the occurrence of frost damage in Sitka spruce (Picea sitchensis) in Great Britain
Authors: Atucha-Zamkova A A , Steele K A , Smith A R
Published: April 2021

Climate change is predicted to increase temperature and seasonal temperature variance in Great Britain (GB). Sitka spruce (Picea sitchensis (Bong.) Carr) is the most important tree species used in commercial plantations throughout Europe and GB. Frosts that occur outside the winter dormancy period can negatively affect trees, since they happen after dehardening. Damage can be especially severe at bud burst, before emerging needles mature and form protective barriers. Here, we modelled the impact of climate change on frost sensitivity in Sitka spruce with temperature data from five climate projections. The UKCP09 climate model HadRm3 uses emission scenario SRESA1B for the years 2020–2099. The global and downscaled versions of the UKCP18 HadGem3 model use the emissions scenario RCP 8.5. The global model CMCC-CM uses the RCP 4.5 and RCP 8.5 emissions scenarios. The predictions based on these models were compared with results from gridded historical data for the period 1960–2015. Three indicators that assessed the frost sensitivity of Sitka spruce were explored: the total number of frosts between the onset of dehardening and the end of summer, which use three different temperature thresholds (Index 10°C, 1–3°C, 1–5°C); the total number of frosts after bud burst (Index 2); the number of days with minimum temperatures below the resistance level (backlashes) during the hardening–dehardening period (September–August) (Index 3). The indices were validated with historical data for frost damage across GB, and Index 1–3°C, Index 1–5°C and Index 3 were shown to be significantly correlated. The frequency of all frosts and backlashes is expected to decrease with climate change, especially under higher emissions scenarios. Post-bud burst frosts have been historically very rare in GB and remain so with climate change. Downscaled regional climate models detect geographic variability within GB and improve prediction of overall trends in frost damage in comparison to global climate change models for GB.
Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae
Authors: Ollodart Anja R , Yeh Chiann-Ling C , Miller Aaron W , Shirts Brian H , Gordon Adam S , Dunham Maitreya J
Published: April 2021

Despite the fundamental importance of mutation rate as a driving force in evolution and disease risk, common methods to assay mutation rate are time-consuming and tedious. Established methods such as fluctuation tests and mutation accumulation experiments are low-throughput and often require significant optimization to ensure accuracy. We established a new method to determine the mutation rate of many strains simultaneously by tracking mutation events in a chemostat continuous culture device and applying deep sequencing to link mutations to alleles of a DNA-repair gene. We applied this method to assay the mutation rate of hundreds of Saccharomyces cerevisiae strains carrying mutations in the gene encoding Msh2, a DNA repair enzyme in the mismatch repair pathway. Loss-of-function mutations in MSH2 are associated with hereditary nonpolyposis colorectal cancer, an inherited disorder that increases risk for many different cancers. However, the vast majority of MSH2 variants found in human populations have insufficient evidence to be classified as either pathogenic or benign. We first benchmarked our method against Luria–Delbrück fluctuation tests using a collection of published MSH2 missense variants. Our pooled screen successfully identified previously characterized nonfunctional alleles as high mutators. We then created an additional 185 human missense variants in the yeast ortholog, including both characterized and uncharacterized alleles curated from ClinVar and other clinical testing data. In a set of alleles of known pathogenicity, our assay recapitulated ClinVar’s classification; we then estimated pathogenicity for 157 variants classified as uncertain or conflicting reports of significance. This method is capable of studying the mutation rate of many microbial species and can be applied to problems ranging from the generation of high-fidelity polymerases to measuring the frequency of antibiotic resistance emergence.
Assessing Age-Friendly Community Progress: What Have We Learned?
Authors: Black Kathy , Oh Patricia
Published: April 2021

Background and Objectives

The Global Network of Age-Friendly Cities and Communities has grown steadily over the past decade across the United States. The age-friendly model calls for a 5-year process of continuous improvement across the stages of engagement, planning, action, and measurement, culminating in an evaluation of age-friendly progress. However, surprisingly, little is known regarding American age-friendly communities’ accomplishments to date.

Research Design and Methods

We utilized content analysis to assess the progress reported by American age-friendly communities (n = 30) that joined by end of year 2015 using the Age-Friendly Community Evidence-based Tool with expanded program evaluation measures including health equity as defined by the World Health Organization. We employed deductive analytic techniques to assess reported community performance in 11 thematic areas across the range of structures and processes that characterize age-friendly efforts.

Results

We found strong evidence in the areas of leadership and governance, harnessed resources, application of the age-friendly framework, and in multisector collaboration as well as reported provisions. All of the communities reported health equity aims, particularly in promoting accessible physical environments and social inclusion efforts. Our analysis further revealed relatively moderate evidence of older adult involvement and weak performance in the monitoring and reporting of evaluative findings as well as overall summation and dissemination plans.

Discussion and Implications

We conclude by synthesizing the overall performance reported by the age-friendly communities, highlighting both strengths and weaknesses. We also offer suggestions to enhance evaluative efforts and advance the dissemination of age-friendly community progress.