bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly efficient acousto-optic modulation using nonsuspended thin-film lithium niobate-chalcogenide hybrid waveguides
Authors: Wan Lei , Yang Zhiqiang , Zhou Wenfeng , Wen Meixun , Feng Tianhua , Zeng Siqing , Liu Dong , Li Huan , Pan Jingshun , Zhu Ning , Liu Weiping , Li Zhaohui
Published: May 2022

A highly efficient on-chip acousto-optic modulator is as a key component and occupies an exceptional position in microwave-to-optical conversion. Homogeneous thin-film lithium niobate is preferentially employed to build the suspended configuration for the acoustic resonant cavity, with the aim of improving the modulation efficiency of the device. However, the limited cavity length and complex fabrication recipe of the suspended prototype restrain further breakthroughs in modulation efficiency and impose challenges for waveguide fabrication. In this work, based on a nonsuspended thin-film lithium niobate-chalcogenide glass hybrid Mach–Zehnder interferometer waveguide platform, we propose and demonstrate a built-in push-pull acousto-optic modulator with a half-wave-voltage-length product VπL as low as 0.03 V cm that presents a modulation efficiency comparable to that of a state-of-the-art suspended counterpart. A microwave modulation link is demonstrated using our developed built-in push-pull acousto-optic modulator, which has the advantage of low power consumption. The nontrivial acousto-optic modulation performance benefits from the superior photoelastic property of the chalcogenide membrane and the completely bidirectional participation of the antisymmetric Rayleigh surface acoustic wave mode excited by the impedance-matched interdigital transducer, overcoming the issue of low modulation efficiency induced by the incoordinate energy attenuation of acoustic waves applied to the Mach–Zehnder interferometer with two arms in traditional push-pull acousto-optic modulators.
STAT1 is regulated by TRIM24 and promotes immunosuppression in head and neck squamous carcinoma cells, but enhances T cell antitumour immunity in the tumour microenvironment
Authors: Anderson Kelvin , Ryan Nathan , Nedungadi Divya , Lamenza Felipe , Swingler Michael , Siddiqui Arham , Satoskar Abhay , Upadhaya Puja , Pietrzak Maciej , Oghumu Steve
Published: May 2022

Background

Head and neck squamous cell carcinoma (HNSCC) is a significant problem and is frequently resistant to current treatments. STAT1 is important in anti-tumour immune responses against HNSCC. However, the role of STAT1 expression by tumour cells and its regulation during HNSCC is unclear.

Methods

We determined the effects of STAT1 inhibition on tumour development and immunity in CAL27 and UMSCC22A HNSCC cell lines in vitro and in a HNSCC carcinogen-induced model in vivo.

Results

STAT1 siRNA knockdown in human HNSCC cells impaired their proliferation and expression of the immunosuppressive marker PD-L1. Stat1-deficient mice displayed increased oral lesion incidence and multiplicity during tumour carcinogenesis in vivo. Immunosuppressive markers PD-1 in CD8+ T cells and PD-L1 in monocytic MDSCs and macrophages were reduced in oral tumours and draining lymph nodes of tumour-bearing Stat1-deficient mice. However, STAT1 was required for anti-tumour functions of T cells during HNSCC in vivo. Finally, we identified TRIM24 to be a negative regulator of STAT1 that plays a similar tumorigenic function to STAT1 in vitro and thus may be a potential target when treating HNSCC.

Conclusion

Our findings indicate that STAT1 activity plays an important role in tumorigenicity and immunosuppression during HNSCC development.
Regulation of BDNF transcription by Nrf2 and MeCP2 ameliorates MPTP-induced neurotoxicity
Authors: Cao Qianqian , Zou Qiuming , Zhao Xin , Zhang Yimin , Qu Youge , Wang Nanbu , Murayama Shigeo , Qi Qi , Hashimoto Kenji , Lin Song , Zhang Ji-chun
Published: May 2022

Mounting evidence suggests the key role of brain-derived neurotrophic factor (BDNF) in the dopaminergic neurotoxicity of Parkinson’s disease (PD). Activation of NF-E2-related factor-2 (Nrf2) and inhibition of methyl CpG-binding protein 2 (MeCP2) can regulate BDNF upregulation. However, the regulation of BDNF by Nrf2 and MeCP2 in the PD pathogenesis has not been reported. Here, we revealed that Nrf2/MeCP2 coordinately regulated BDNF transcription, reversing the decreased levels of BDNF expression in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Repeated administration of sulforaphane (SFN, an Nrf2 activator) attenuated dopaminergic neurotoxicity in MPTP-treated mice through activation of BDNF and suppression of MeCP2 expression. Furthermore, intracerebroventricular injection of MeCP2-HDO, a DNA/RNA heteroduplex oligonucleotide (HDO) silencing MeCP2 expression, ameliorated dopaminergic neurotoxicity in MPTP-treated mice via activation of Nrf2 and BDNF expression. Moreover, we found decreased levels of Nrf2 and BDNF, and increased levels of MeCP2 protein expression in the striatum of patients with dementia with Lewy bodies (DLB). Interesting, there were correlations between BDNF and Nrf2 (or MeCP2) expression in the striatum from DLB patients. Therefore, it is likely that the activation of BDNF transcription by activation of Nrf2 and/or suppression of MeCP2 could be a new therapeutic approach for PD.
A novel TP63 variant in a patient with ankyloblepharon-ectodermal defect–cleft lip/palate syndrome and Rapp–Hodgkin syndrome-like ectodermal dysplasia
Authors: Hori Asuka , Migita Ohsuke , Isogawa Nobutaka , Takada Fumio , Hata Kenichiro
Published: May 2022

Ankyloblepharon-ectodermal defect–cleft lip/palate syndrome and Rapp–Hodgkin syndrome are well-known TP63-related autosomal-dominant genetic disorders with various similar ectodermal dysplasias. In this study, whole-exome sequencing revealed a novel, potentially pathogenic TP63 nonsense variant (NM_001114980.2:c.25 C > T: p.Gln9Ter) in a patient with an atypical clinical phenotype. This variant was detected near translation initiation sites and has an effect only on ΔNp63α, the short isoform protein product of the TP63 gene.
Machine learning sparse tight-binding parameters for defects
Authors: Schattauer Christoph , Todorović Milica , Ghosh Kunal , Rinke Patrick , Libisch Florian
Published: May 2022

We employ machine learning to derive tight-binding parametrizations for the electronic structure of defects. We test several machine learning methods that map the atomic and electronic structure of a defect onto a sparse tight-binding parameterization. Since Multi-layer perceptrons (i.e., feed-forward neural networks) perform best we adopt them for our further investigations. We demonstrate the accuracy of our parameterizations for a range of important electronic structure properties such as band structure, local density of states, transport and level spacing simulations for two common defects in single layer graphene. Our machine learning approach achieves results comparable to maximally localized Wannier functions (i.e., DFT accuracy) without prior knowledge about the electronic structure of the defects while also allowing for a reduced interaction range which substantially reduces calculation time. It is general and can be applied to a wide range of other materials, enabling accurate large-scale simulations of material properties in the presence of different defects.
Delegation to artificial agents fosters prosocial behaviors in the collective risk dilemma
Authors: Fernández Domingos Elias , Terrucha Inês , Suchon Rémi , Grujić Jelena , Burguillo Juan C. , Santos Francisco C. , Lenaerts Tom
Published: May 2022

Home assistant chat-bots, self-driving cars, drones or automated negotiation systems are some of the several examples of autonomous (artificial) agents that have pervaded our society. These agents enable the automation of multiple tasks, saving time and (human) effort. However, their presence in social settings raises the need for a better understanding of their effect on social interactions and how they may be used to enhance cooperation towards the public good, instead of hindering it. To this end, we present an experimental study of human delegation to autonomous agents and hybrid human-agent interactions centered on a non-linear public goods dilemma with uncertain returns in which participants face a collective risk. Our aim is to understand experimentally whether the presence of autonomous agents has a positive or negative impact on social behaviour, equality and cooperation in such a dilemma. Our results show that cooperation and group success increases when participants delegate their actions to an artificial agent that plays on their behalf. Yet, this positive effect is less pronounced when humans interact in hybrid human-agent groups, where we mostly observe that humans in successful hybrid groups make higher contributions earlier in the game. Also, we show that participants wrongly believe that artificial agents will contribute less to the collective effort. In general, our results suggest that delegation to autonomous agents has the potential to work as commitment devices, which prevent both the temptation to deviate to an alternate (less collectively good) course of action, as well as limiting responses based on betrayal aversion.
First purified recombinant CYP75B including transmembrane helix with unexpected high substrate specificity to (2R)-naringenin
Authors: Hausjell Johanna , Weissensteiner Julia , Molitor Christian , Schlangen Karin , Spadiut Oliver , Halbwirth Heidi
Published: May 2022

Anthochlor pigments (chalcones and aurones) play an important role in yellow flower colourization, the formation of UV-honey guides and show numerous health benefits. The B-ring hydroxylation of chalcones is performed by membrane bound cytochrome P450 enzymes. It was assumed that usual flavonoid 3′-hydroxlases (F3′Hs) are responsible for the 3,4- dihydroxy pattern of chalcones, however, we previously showed that a specialized F3′H, namely chalcone 3-hydroxylase (CH3H), is necessary for the hydroxylation of chalcones. In this study, a sequence encoding membrane bound CH3H from Dahlia variabilis was recombinantly expressed in yeast and a purification procedure was developed. The optimized purification procedure led to an overall recovery of 30% recombinant DvCH3H with a purity of more than 84%. The enzyme was biochemically characterized with regard to its kinetic parameters on various substrates, including racemic naringenin, as well as its enantiomers (2S)-, and (2R)-naringenin, apigenin and kaempferol. We report for the first time the characterization of a purified Cytochrome P450 enzyme from the flavonoid biosynthesis pathway, including the transmembrane helix. Further, we show for the first time that recombinant DvCH3H displays a higher affinity for (2R)-naringenin than for (2S)-naringenin, although (2R)-flavanones are not naturally formed by chalcone isomerase.
Copper(II) invigorated EHU-30 for continuous electroreduction of CO2 into value-added chemicals
Authors: Landaluce Nerea , Perfecto-Irigaray Maite , Albo Jonathan , Beobide Garikoitz , Castillo Oscar , Irabien Angel , Luque Antonio , Méndez Alba S. J. , Platero-Prats Ana E. , Pérez-Yáñez Sonia
Published: May 2022

The doping of zirconium based EHU-30 and EHU-30-NH2 metal–organic frameworks with copper(II) yielded a homogeneous distribution of the dopant with a copper/zirconium ratio of 0.04–0.05. The doping mechanism is analysed by chemical analysis, microstructural analysis and pair distribution function (PDF) analysis of synchrotron total scattering data in order to get deeper insight into the local structure. According to these data, the Cu(II) atoms are assembled within the secondary building unit by a transmetalation reaction, contrarily to UiO-66 series in which the post-synthetic metalation of the MOF takes place through chemical anchorage. The resulting materials doubled the overall performance of the parent compounds for the CO2 electroreduction, while retained stable the performance during continuous transformation reaction.
Nitrate respiration occurs throughout the depth of mucoid and non-mucoid Pseudomonas aeruginosa submerged agar colony biofilms including the oxic zone
Authors: Schwermer Carsten Ulrich , de Beer Dirk , Stoodley Paul
Published: May 2022

Pseudomonas aeruginosa is an opportunistic pathogen and well characterized biofilm former. P. aeruginosa forms strong oxygen gradients inside biofilms due to rapid oxygen respiration in the top layers and the poor solubility of oxygen coupled with diffusion limited transport. Transcriptomic evidence from in vitro and ex vivo sampling suggests that denitrification is occurring in biofilms in ostensibly oxic environments. It is hypothesized that in the presence of nitrate there is stratification with aerobic respiration occurring in the outer oxic layer and denitrification in the lower anoxic zone. We used submerged agar colony biofilms grown from mucoid (FRD1) and non-mucoid (PAO1) strains to simultaneously measure depth microprofiles of oxygen and nitrous oxide in the same colony with microelectrodes. Oxygen respiration occurred at the top of the colony as expected but denitrification occurred throughout the entire depth, even in the oxic region. Local denitrification rates were highly variable suggesting heterogenous metabolic activity within the colony. We also assessed the short-term influence of tobramycin on aerobic respiration within a PAO1 colony. Although there was an immediate reduction in respiration it was never completely arrested over a 2 h period. On tobramycin removal the oxygen gradient steadily reestablished, demonstrating immediate recovery of metabolic activity.
Efficient capture of circulating tumor cells with low molecular weight folate receptor-specific ligands
Authors: Hu Yingwen , Chen Danyang , Napoleon John V. , Srinivasarao Madduri , Singhal Sunil , Savran Cagri A. , Low Philip S.
Published: May 2022

Retrieval of circulating tumor cells (CTC) has proven valuable for assessing a patient's cancer burden, evaluating response to therapy, and analyzing which drug might treat a cancer best. Although most isolation methods retrieve CTCs based on size, shape, or capture by tumor-specific antibodies, we explore here the use of small molecule tumor-specific ligands linked to magnetic beads for CTC capture. We have designed folic acid-biotin conjugates with different linkers for the capture of folate receptor (FR) + tumor cells spiked into whole blood, and application of the same technology to isolate FR + CTCs from the peripheral blood of both tumor-bearing mice and non-small cell lung patients. We demonstrate that folic acid linked via a rigid linker to a flexible PEG spacer that is in turn tethered to a magnetic bead enables optimal CTC retrieval, reaching nearly 100% capture when 100 cancer cells are spiked into 1 mL of aqueous buffer and ~ 90% capture when the same quantity of cells is diluted into whole blood. In a live animal model, the same methodology is shown to efficiently retrieve CTCs from tumor-bearing mice, yielding cancer cell counts that are proportional to total tumor burden. More importantly, the same method is shown to collect ~ 29 CTCs/8 mL peripheral blood from patients with non-small cell lung cancer. Since the ligand-presentation strategy optimized here should also prove useful in targeting other nanoparticles to other cells, the methods described below should have general applicability in the design of nanoparticles for cell-specific targeting.
The influence of sea ice on the detection of bowhead whale calls
Authors: Jones Joshua M. , Hildebrand John A. , Thayre Bruce J. , Jameson Ellen , Small Robert J. , Wiggins Sean M.
Published: May 2022

Bowhead whales (Balaena mysticetus) face threats from diminishing sea ice and increasing anthropogenic activities in the Arctic. Passive acoustic monitoring is the most effective means for monitoring their distribution and population trends, based on the detection of their calls. Passive acoustic monitoring, however, is influenced by the sound propagation environment and ambient noise levels, which impact call detection probability. Modeling and simulations were used to estimate detection probability for bowhead whale frequency-modulated calls in the 80–180 Hz frequency band with and without sea ice cover and under various noise conditions. Sound transmission loss for bowhead calls is substantially greater during ice-covered conditions than during open-water conditions, making call detection ~ 3 times more likely in open-water. Estimates of daily acoustic detection probability were used to compensate acoustic detections for sound propagation and noise effects in two recording datasets in the northeast Chukchi Sea, on the outer shelf and continental slope, collected between 2012 and 2013. The compensated acoustic density suggests a decrease in whale presence with the retreat of sea ice at these recording sites. These results highlight the importance of accounting for effects of the environment on ambient noise and acoustic propagation when interpreting results of passive acoustic monitoring.
D-galactose-induced aging aggravates obesity-induced bone dyshomeostasis
Authors: Imerb Napatsorn , Thonusin Chanisa , Pratchayasakul Wasana , Arunsak Busarin , Nawara Wichwara , Ongnok Benjamin , Aeimlapa Ratchaneevan , Charoenphandhu Narattaphol , Chattipakorn Nipon , Chattipakorn Siriporn C.
Published: May 2022

We aimed to compare the time-course effect of D-galactose (D-gal)-induced aging, obesity, and their combined effects on bone homeostasis. Male Wistar rats were fed with either a normal diet (ND; n = 24) or a high-fat diet (HFD; n = 24) for 12 weeks. All rats were then injected with either vehicle or 150 mg/kg/day of D-gal for 4 or 8 weeks. Blood was collected to measure metabolic, aging, oxidative stress, and bone turnover parameters. Bone oxidative stress and inflammatory markers, as well as bone histomorphometry were also evaluated. Additionally, RAW 264.7 cells were incubated with either D-gal, insulin, or D-gal plus insulin to identify osteoclast differentiation capacity under the stimulation of receptor activator of nuclear factor κB ligand. At week 4, D-gal-induced aging significantly elevated serum malondialdehyde level and decreased trabecular thickness in ND- and HFD-fed rats, when compared to the control group. At week 8, D-gal-induced aging further elevated advanced glycation end products, increased bone inflammation and resorption, and significantly impaired bone microarchitecture in HFD-fed rats. The osteoclast number in vitro were increased in the D-gal, insulin, and combined groups to a similar extent. These findings suggest that aging aggravates bone dyshomeostasis in the obese condition in a time-dependent manner.
A generalization of the standard map and its statistical characterization
Authors: Cetin Kivanc , Tirnakli Ugur , Boghosian Bruce M.
Published: May 2022

From the statistical mechanical point of view, area-preserving maps have great potential and importance. These maps exhibit chaotic and regular behavior separately or together in the available phase space as the control parameter changes. Several works on these maps, e.g., the standard map and the web map, have shown that ergodicity breakdown causes the statistical mechanical framework that describes the dynamics of the system to change. In this paper, for a novel generalization of the standard map, which we define by generalizing the periodic function used in its definition, we verify that a q-Gaussian with $$q\simeq 1.935$$

q
≃
1.935

for the probability distribution of sum of the iterates of the system with initial conditions chosen from the nonergodic stability islands is robust. We also show that the probability distributions become more complicated and unexpected limiting behavior occurs for some parameter regimes.
Evaluating machine learning classifiers for glaucoma referral decision support in primary care settings
Authors: Kaskar Omkar G. , Wells-Gray Elaine , Fleischman David , Grace Landon
Published: May 2022

Several artificial intelligence algorithms have been proposed to help diagnose glaucoma by analyzing the functional and/or structural changes in the eye. These algorithms require carefully curated datasets with access to ocular images. In the current study, we have modeled and evaluated classifiers to predict self-reported glaucoma using a single, easily obtained ocular feature (intraocular pressure (IOP)) and non-ocular features (age, gender, race, body mass index, systolic and diastolic blood pressure, and comorbidities). The classifiers were trained on publicly available data of 3015 subjects without a glaucoma diagnosis at the time of enrollment. 337 subjects subsequently self-reported a glaucoma diagnosis in a span of 1–12 years after enrollment. The classifiers were evaluated on the ability to identify these subjects by only using their features recorded at the time of enrollment. Support vector machine, logistic regression, and adaptive boosting performed similarly on the dataset with F1 scores of 0.31, 0.30, and 0.28, respectively. Logistic regression had the highest sensitivity at 60% with a specificity of 69%. Predictive classifiers using primarily non-ocular features have the potential to be used for identifying suspected glaucoma in non-eye care settings, including primary care. Further research into finding additional features that improve the performance of predictive classifiers is warranted.
Mean-field theory of social laser
Authors: Alodjants Alexander P. , Bazhenov A. Yu. , Khrennikov A. Yu. , Bukhanovsky A. V.
Published: May 2022

In this work we suggest a novel paradigm of social laser (solaser), which can explain such Internet inspired social phenomena as echo chambers, reinforcement and growth of information cascades, enhancement of social actions under strong mass media operation. The solaser is based on a well-known in quantum physics laser model of coherent amplification of the optical field. Social networks are at the core of the solaser model; we define them by means of a network model possessing power–law degree distribution. In the solaser the network environment plays the same role as the gain medium has in a physical laser device. We consider social atoms as decision making agents (humans or even chat bots), which possess two (mental) states and occupy the nodes of a network. The solaser establishes communication between the agents as absorption and spontaneous or stimulated emission of socially actual information within echo chambers, which mimic an optical resonator of a convenient (physical) laser. We have demonstrated that social lasing represents the second order nonequilibrium phase transition, which evokes the release of coherent socially stimulated information field represented with the order parameter. The solaser implies the formation of macroscopic social polarization and results in a huge social impact, which is realized by viral information cascades occurring in the presence of population imbalance (social bias). We have shown that decision making agents follow an adiabatically time dependent mass media pump, which acts in the network community reproducing various reliable scenarios for information cascade evolution. We have also shown that in contrast to physical lasers, due to node degree peculiarities, the coupling strength of decision making agents with the network may be enhanced $$\sqrt{\langle k\rangle }$$

⟨
k
⟩

times. It leads to a large increase of speed, at which a viral message spreads through a social media. In this case, the mass media pump supports additional reinforcement and acceleration of cascade growth. We have revealed that the solaser model in some approximations possesses clear links with familiar Ising and SIS (susceptible-infected-susceptible) models typically used for evaluating a social impact and information growth, respectively. However, the solaser paradigm can serve as a new platform for modelling temporal social events, which originate from “microscopic” (quantum-like) processes occurring in the society. Our findings open new perspectives for interdisciplinary studies of distributed intelligence agents behavior associated with information exchange and social impact.
Quasinormal modes and shadow of noncommutative black hole
Authors: Campos J. A. V. , Anacleto M. A. , Brito F. A. , Passos E.
Published: May 2022

In this paper we investigate quasinormal modes (QNM) for a scalar field around a noncommutative Schwarzschild black hole. We verify the effect of noncommutativity on quasinormal frequencies by applying two procedures widely used in the literature. The first is the Wentzel–Kramers–Brillouin (WKB) approximation up to sixth order. In the second case we use the continuous fraction method developed by Leaver. Besides, we also show that due to noncommutativity, the shadow radius is reduced when we increase the noncommutative parameter. In addition, we find that the shadow radius is nonzero even at the zero mass limit for finite noncommutative parameter.
Orientation selective DBS of entorhinal cortex and medial septal nucleus modulates activity of rat brain areas involved in memory and cognition
Authors: Wu Lin , Canna Antonietta , Narvaez Omar , Ma Jun , Sang Sheng , Lehto Lauri J. , Sierra Alejandra , Tanila Heikki , Zhang Yuan , Gröhn Olli , Low Walter C. , Filip Pavel , Mangia Silvia , Michaeli Shalom
Published: May 2022

The recently introduced orientation selective deep brain stimulation (OS-DBS) technique freely controls the direction of the electric field’s spatial gradient by using multiple contacts with independent current sources within a multielectrode array. The goal of OS-DBS is to align the electrical field along the axonal track of interest passing through the stimulation site. Here we utilized OS-DBS with a planar 3-channel electrode for stimulating the rat entorhinal cortex (EC) and medial septal nucleus (MSN), two promising areas for DBS treatment of Alzheimer’s disease. The brain responses to OS-DBS were monitored by whole brain functional magnetic resonance imaging (fMRI) at 9.4 T with Multi-Band Sweep Imaging with Fourier Transformation (MB-SWIFT). Varying the in-plane OS-DBS stimulation angle in the EC resulted in activity modulation of multiple downstream brain areas involved in memory and cognition. Contrary to that, no angle dependence of brain activations was observed when stimulating the MSN, consistent with predictions based on the electrode configuration and on the main axonal directions of the targets derived from diffusion MRI tractography and histology. We conclude that tuning the OS-DBS stimulation angle modulates the activation of brain areas relevant to Alzheimer’s disease, thus holding great promise in the DBS treatment of the disease.
X-linked palindromic gene families 4930567H17Rik and Mageb5 are dispensable for male mouse fertility
Authors: Stark-Dykema Evan R. , Dulka Eden A. , Gerlinger Emma R. , Mueller Jacob L.
Published: May 2022

Mammalian sex chromosomes are enriched for large, nearly-identical, palindromic sequences harboring genes expressed predominately in testicular germ cells. Discerning if individual palindrome-associated gene families are essential for male reproduction is difficult due to challenges in disrupting all copies of a gene family. Here we generate precise, independent, deletions to assess the reproductive roles of two X-linked palindromic gene families with spermatid-predominant expression, 4930567H17Rik and Mageb5. Sequence analyses reveals mouse 4930567H17Rik and Mageb5 are orthologs of human HSFX3 and MAGEB5, respectively, where 4930567H17Rik/HSFX3 is harbored in a palindrome in humans and mice, while Mageb5 is not. Additional sequence analyses show 4930567H17Rik and HSFX3 are rapidly diverging in rodents and primates, respectively. Mice lacking either 4930567H17Rik or Mageb5 gene families do not have detectable defects in male fertility, fecundity, spermatogenesis, or in gene regulation, but do show differences in sperm head morphology, suggesting a potential role in sperm function. We conclude that while all palindrome-associated gene families are not essential for male fertility, large palindromes influence the evolution of their associated gene families.
A formal analysis method for composition protocol based on model checking
Authors: Xiao Meihua , Zhao Hanyu , Yang Ke , Ouyang Ri , Song Weiwei
Published: May 2022

Protocol security in a composition protocol environment has always been an open problem in the field of formal analysis and verification of security protocols. As a well-known tool to analyze and verify the logical consistency of concurrent systems, SPIN (Simple Promela Interpreter) has been widely used in the analysis and verification of the security of a single protocol. There is no special research on the verification of protocol security in a composition protocol environment. To solve this problem, firstly, a formal analysis method for composition protocol based on SPIN is proposed, and a formal description of protocol operation semantics is given. Then the attacker model is formalized, and a message specification method based on field detection and component recognition is presented to alleviate the state explosion problem. Finally, the NSB protocol and the NSL protocol are used as examples for compositional analysis. It is demonstrated that the proposed method can effectively verify the security of the protocol in a composition protocol environment and enhance the efficiency of composition protocol verification.
Assessment of mutations on RBD in the Spike protein of SARS-CoV-2 Alpha, Delta and Omicron variants
Authors: da Costa Clauber Henrique Souza , de Freitas Camila Auad Beltrão , Alves Cláudio Nahum , Lameira Jerônimo
Published: May 2022

The severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2) variant Omicron spread more rapid than the other variants of SARS-CoV-2 virus. Mutations on the Spike (S) protein receptor-binding domain (RBD) are critical for the antibody resistance and infectivity of the SARS-CoV-2 variants. In this study, we have used accelerated molecular dynamics (aMD) simulations and free energy calculations to present a systematic analysis of the affinity and conformational dynamics along with the interactions that drive the binding between Spike protein RBD and human angiotensin-converting enzyme 2 (ACE2) receptor. We evaluate the impacts of the key mutation that occur in the RBDs Omicron and other variants in the binding with the human ACE2 receptor. The results show that S protein Omicron has stronger binding to the ACE2 than other variants. The evaluation of the decomposition energy per residue shows the mutations N440K, T478K, Q493R and Q498R observed in Spike protein of SARS-CoV-2 provided a stabilization effect for the interaction between the SARS-CoV-2 RBD and ACE2. Overall, the results demonstrate that faster spreading of SARS-CoV-2 Omicron may be correlated with binding affinity of S protein RBD to ACE2 and mutations of uncharged residues to positively charged residues such as Lys and Arg in key positions in the RBD.
Intra-regional classification of Codonopsis Radix produced in Gansu province (China) by multi-elemental analysis and chemometric tools
Authors: Bai Ruibin , Wang Yanping , Fan Jingmin , Zhang Jingjing , Li Wen , Zhang Yan , Hu Fangdi
Published: May 2022

Multi-elemental analysis is widely used to identify the geographical origins of plants. The purpose of this study was to explore the feasibility of combining chemometrics with multi-element analysis for classification of Codonopsis Radix from different producing regions of Gansu province (China). A total of 117 Codonopsis Radix samples from 7 counties of Gansu province were collected. Inductively coupled plasma mass spectrometry (ICP-MS) was used for the determination of 28 elements (39 K, 24 Mg, 44Ca, 27Al, 137Ba, 57Fe, 23Na, 88Sr, 55Mn, 66Zn, 65Cu, 85Rb, 61Ni, 53Cr, 51 V, 7Li, 208Pb, 59Co, 75As, 133Cs, 71 Ga, 77Se, 205Tl, 114Cd, 238U, 107Ag, 4Be and 202Hg). Among macro elements, 39 K showed the highest level, whereas 23Na was found to have the lowest content value. Micro elements showed the concentrations order of: 88Sr > 55Mn > 66Zn > 85Rb > 65Cu. Among trace elements, 53Cr and 61Ni showed higher content and 4Be was not detected in all samples. Intra-regions differentiation was performed by principal component analysis (PCA), cluster analysis (CA) and supervised learning algorithms such as linear discriminant analysis (LDA), k-nearest neighbors (k-NN), support vector machines (SVM), and random forests (RF). Among them, the RF model performed the best with an accuracy rate of 78.79%. Multi-elemental analysis combined with RF was a reliable method to identify the origins of Codonopsis Radix in Gansu province.
Automatic worm detection to solve overlapping problems using a convolutional neural network
Authors: Mori Shinichiro , Tachibana Yasuhiko , Suzuki Michiyo , Harada Yoshinobu
Published: May 2022

The nematode Caenorhabditis elegans is a powerful experimental model to investigate vital functions of higher organisms. We recently established a novel method, named "pond assay for the sensory systems (PASS)”, that dramatically improves both the evaluation accuracy of sensory response of worms and the efficiency of experiments. This method uses many worms in numbers that are impractical to count manually. Although several automated detection systems have been introduced, detection of overlapped worms remains difficult. To overcome this problem, we developed an automated worm detection system based on a deep neural network (DNN). Our DNN was based on a “YOLOv4″ one-stage detector with one-class classification (OCC) and multi-class classification (MCC). The OCC defined a single class for worms, while the MCC defined four classes for the number of overlapped worms. For the training data, a total of 2000 model sub-images were prepared by manually drawing square worm bounding boxes from 150 images. To make simulated images, a total of 10–80 model images for each class were randomly selected and randomly placed on a simulated microscope field. A total of 19,000 training datasets and 1000 validation datasets with a ground-truth bounding-box were prepared. We evaluated detection accuracy using 150 images, which were different from the training data. Evaluation metrics were detection error, precision, recall, and average precision (AP). Precision values were 0.91 for both OCC and MCC. However, the recall value for MCC (= 0.93) was higher than that for OCC (= 0.79). The number of detection errors for OCC increased with increasing the ground truth; however, that for MCC was independent of the ground truth. AP values were 0.78 and 0.90 for the OCC and the MCC, respectively. Our worm detection system with MCC provided better detection accuracy for large numbers of worms with overlapping positions than that with the OCC.
Alterations of the gut microbial community structure and function with aging in the spontaneously hypertensive stroke prone rat
Authors: Shi Huanan , Nelson James W. , Phillips Sharon , Petrosino Joseph F. , Bryan Robert M. , Durgan David J.
Published: May 2022

Gut dysbiosis, a pathological imbalance of bacteria, has been shown to contribute to the development of hypertension (HT), systemic- and neuro-inflammation, and blood–brain barrier (BBB) disruption in spontaneously hypertensive stroke prone rats (SHRSP). However, to date individual species that contribute to HT in the SHRSP model have not been identified. One potential reason, is that nearly all studies of the SHRSP gut microbiota have analyzed samples from rats with established HT. The goal of this study was to examine the SHRSP gut microbiota before, during, and after the onset of hypertension, and in normotensive WKY control rats over the same age range. We hypothesized that we could identify key microbes involved in the development of HT by comparing WKY and SHRSP microbiota during the pre-hypertensive state and longitudinally. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and fecal microbiota analyzed by16S rRNA gene sequencing. SHRSP showed significant elevations in SBP, as compared to WKY, beginning at 8 weeks of age (p < 0.05 at each time point). Bacterial community structure was significantly different between WKY and SHRSP as early as 4 weeks of age, and remained different throughout the study (p = 0.001–0.01). At the phylum level we observed significantly reduced Firmicutes and Deferribacterota, and elevated Bacteroidota, Verrucomicrobiota, and Proteobacteria, in pre-hypertensive SHRSP, as compared to WKY. At the genus level we identified 18 bacteria whose relative abundance was significantly different in SHRSP versus WKY at the pre-hypertensive ages of 4 or 6 weeks. In an attempt to further refine bacterial candidates that might contribute to the SHRSP phenotype, we compared the functional capacity of WKY versus SHRSP microbial communities. We identified significant differences in amino acid metabolism. Using untargeted metabolomics we found significant reductions in metabolites of the tryptophan-kynurenine pathway and increased indole metabolites in SHRSP versus WKY plasma. Overall, we provide further evidence that gut dysbiosis contributes to hypertension in the SHRSP model, and suggest for the first time the potential involvement of tryptophan metabolizing microbes.
Proof of concept for multiplex amplicon sequencing for mutation identification using the MinION nanopore sequencer
Authors: Whitford Whitney , Hawkins Victoria , Moodley Kriebashne S. , Grant Matthew J. , Lehnert Klaus , Snell Russell G. , Jacobsen Jessie C.
Published: May 2022

Rapid, cost-effective identification of genetic variants in small candidate genomic regions remains a challenge, particularly for less well equipped or lower throughput laboratories. The application of Oxford Nanopore Technologies’ MinION sequencer has the potential to fulfil this requirement. We demonstrate a proof of concept for a multiplexing assay that pools PCR amplicons for MinION sequencing to enable sequencing of multiple templates from multiple individuals, which could be applied to gene-targeted diagnostics. A combined strategy of barcoding and sample pooling was developed for simultaneous multiplex MinION sequencing of 100 PCR amplicons. The amplicons are family-specific, spanning a total of 30 loci in DNA isolated from 82 human neurodevelopmental cases and family members. The target regions were chosen for further interrogation because a potentially disease-causative variant had been identified in affected individuals following Illumina exome sequencing. The pooled MinION sequences were deconvoluted by aligning to custom references using the minimap2 aligner software. Our multiplexing approach produced an interpretable and expected sequence from 29 of the 30 targeted genetic loci. The sequence variant which was not correctly resolved in the MinION sequence was adjacent to a five nucleotide homopolymer. It is already known that homopolymers present a resolution problem with the MinION approach. Interestingly despite equimolar quantities of PCR amplicon pooled for sequencing, significant variation in the depth of coverage (127×–19,626×; mean = 8321×, std err = 452.99) was observed. We observed independent relationships between depth of coverage and target length, and depth of coverage and GC content. These relationships demonstrate biases of the MinION sequencer for longer templates and those with lower GC content. We demonstrate an efficient approach for variant discovery or confirmation from short DNA templates using the MinION sequencing device. With less than 130 × depth of coverage required for accurate genotyping, the methodology described here allows for rapid highly multiplexed targeted sequencing of large numbers of samples in a minimally equipped laboratory with a potential cost as much 200 × less than that from Sanger sequencing.
Development of an intraoperative breast cancer margin assessment method using quantitative fluorescence measurements
Authors: Ueo Hiroki , Minoura Itsushi , Ueo Hiroaki , Gamachi Ayako , Kai Yuichiro , Kubota Yoko , Doi Takako , Yamaguchi Miki , Yamashita Toshinari , Tsuda Hitoshi , Moriya Takuya , Yamaguchi Rin , Kozuka Yuji , Sasaki Takeshi , Masuda Takaaki , Urano Yasuteru , Mori Masaki , Mimori Koshi
Published: May 2022

Breast-conserving surgery has become the preferred treatment method for breast cancer. Surgical margin assessment is performed during surgery, as it can reduce local recurrence in the preserved breast. Development of reliable and lower-cost ex vivo cancer detection methods would offer several benefits for patient care. Here, a practical and quantitative evaluation method for the ex vivo fluorescent diagnosis of breast lesions was developed and confirmed through a three-step clinical study. Gamma-glutamyl-hydroxymethyl rhodamine green (gGlu-HMRG) has been reported to generate fluorescence in breast lesions. Using this probe, we constructed a reliable and reproducible procedure for the quantitative evaluation of fluorescence levels. We evaluated the reliability of the method by considering reproducibility, temperature sensitivity, and the effects of other clinicopathological factors. The results suggest that the fluorescence increase of gGlu-HMRG is a good indicator of the malignancy of breast lesions. However, the distributions overlapped. A 5 min reaction with this probe could be used to distinguish at least part of the normal breast tissue. This method did not affect the final pathological examination. In summary, our results indicate that the methods developed in this study may serve as a feasible intraoperative negative-margin assessment tool during breast-conserving surgery.
Contributing factors for acute stress in healthcare workers caring for COVID-19 patients in Argentina, Chile, Colombia, and Ecuador
Authors: Martin-Delgado Jimmy , Poblete Rodrigo , Serpa Piedad , Mula Aurora , Carrillo Irene , Fernández Cesar , Vicente Ripoll María Asunción , Loudet Cecilia , Jorro Facundo , Garcia Elorrio Ezequiel , Guilabert Mercedes , Mira José Joaquín
Published: May 2022

This study analyzed the frequency and intensity of acute stress among health professionals caring for COVID-19 patients in four Latin American Spanish-speaking countries during the outbreak. A cross-sectional study involved a non-probability sample of healthcare professionals in four Latin American countries. Participants from each country were invited using a platform and mobile application designed for this study. Hospital and primary care workers from different services caring for COVID-19 patients were included. The EASE Scale (SARS-CoV-2 Emotional Overload Scale, in Spanish named Escala Auto-aplicada de Sobrecarga Emocional) was a previously validated measure of acute stress. EASE scores were described overall by age, sex, work area, and experience of being ill with COVID-19. Using the Mann–Whitney U test, the EASE scores were compared according to the most critical moments of the pandemic. Univariate and multivariate analysis was performed to investigate associations between these factors and the outcome ‘acute stress’. Finally, the Kruskal–Wallis was used to compare EASE scores and the experience of being ill. A total of 1372 professionals responded to all the items in the EASE scale: 375 (27.3%) Argentines, 365 (26.6%) Colombians, 345 (25.1%) Chileans, 209 (15.2%) Ecuadorians, and 78 (5.7%) from other countries. 27% of providers suffered middle-higher acute stress due to the outbreak. Worse results were observed in moments of peak incidence of cases (14.3 ± 5.3 vs. 6.9 ± 1.7, p < 0.05). Higher scores were found in professionals in COVID-19 critical care (13 ± 1.2) than those in non-COVID-19 areas (10.7 ± 1.9) (p = 0.03). Distress was higher among professionals who were COVID-19 patients (11.7 ± 1) or had doubts about their potential infection (12 ± 1.2) compared to those not infected (9.5 ± 0.7) (p = 0.001). Around one-third of the professionals experienced acute stress, increasing in intensity as the incidence of COVID-19 increased and as they became infected or in doubt whether they were infected. EASE scale could be a valuable asset for monitoring acute stress levels among health professionals in Latin America.

ClinicalTrials: NCT04486404.
Building digital twins of the human immune system: toward a roadmap
Authors: Laubenbacher R. , Niarakis A. , Helikar T. , An G. , Shapiro B. , Malik-Sheriff R. S. , Sego T. J. , Knapp A. , Macklin P. , Glazier J. A.
Published: May 2022

Digital twins, customized simulation models pioneered in industry, are beginning to be deployed in medicine and healthcare, with some major successes, for instance in cardiovascular diagnostics and in insulin pump control. Personalized computational models are also assisting in applications ranging from drug development to treatment optimization. More advanced medical digital twins will be essential to making precision medicine a reality. Because the immune system plays an important role in such a wide range of diseases and health conditions, from fighting pathogens to autoimmune disorders, digital twins of the immune system will have an especially high impact. However, their development presents major challenges, stemming from the inherent complexity of the immune system and the difficulty of measuring many aspects of a patient’s immune state in vivo. This perspective outlines a roadmap for meeting these challenges and building a prototype of an immune digital twin. It is structured as a four-stage process that proceeds from a specification of a concrete use case to model constructions, personalization, and continued improvement.
Terrestrial and marine influence on atmospheric bacterial diversity over the north Atlantic and Pacific Oceans
Authors: Lang-Yona Naama , Flores J. Michel , Haviv Rotem , Alberti Adriana , Poulain Julie , Belser Caroline , Trainic Miri , Gat Daniella , Ruscheweyh Hans-Joachim , Wincker Patrick , Sunagawa Shinichi , Rudich Yinon , Koren Ilan , Vardi Assaf
Published: May 2022

The diversity of microbes and their transmission between ocean and atmosphere are poorly understood despite the implications for microbial global dispersion and biogeochemical processes. Here, we survey the genetic diversity of airborne and surface ocean bacterial communities sampled during springtime transects across the northwest Pacific and subtropical north Atlantic as part of the Tara Pacific Expedition. We find that microbial community composition is more variable in the atmosphere than in the surface ocean. Bacterial communities were more similar between the two surface oceans than between the ocean and the overlying atmosphere. Likewise, Pacific and Atlantic atmospheric microbial communities were more similar to each other than to those in the ocean beneath. Atmospheric community composition over the Atlantic was dominated by terrestrial and specifically, dust-associated bacteria, whereas over the Pacific there was a higher prevalence and differential abundance of marine bacteria. Our findings highlight regional differences in long-range microbial exchange and dispersal between land, ocean, and atmosphere.