bluuebunny/crossref_metadata_2025 huggingface dataset:
Photo and copper dual catalysis for allene syntheses from propargylic derivatives via one-electron process
Authors: Liu Qi , Zheng Jian , Zhang Xue , Ma Shengming
Published: June 2022

Different from the traditional two-electron oxidative addition-transmetalation-reductive elimination coupling strategy, visible light has been successfully integrated into transition metal-catalyzed coupling reaction of propargylic alcohol derivatives highly selectively forming allenenitriles: specifically speaking, visible light-mediated Cu-catalyzed cyanation of propargylic oxalates has been realized for the general, efficient, and exclusive syntheses of di-, tri, and tetra-substituted allenenitriles bearing various synthetically versatile functional groups. A set of mechanistic studies, including fluorescence quenching experiments, cyclic voltammetric measurements, radical trapping experiments, control experiments with different photocatalyst, and DFT calculation studies have proven that the current reaction proceeds via visible light-induced redox-neutral reductive quenching radical mechanism, which is a completely different approach as compared to the traditional transition metal-catalyzed two-electron oxidative addition processes.
Deciphering quantum fingerprints in electric conductance
Authors: Daimon Shunsuke , Tsunekawa Kakeru , Kawakami Shinji , Kikkawa Takashi , Ramos Rafael , Oyanagi Koichi , Ohtsuki Tomi , Saitoh Eiji
Published: June 2022

When the electric conductance of a nano-sized metal is measured at low temperatures, it often exhibits complex but reproducible patterns as a function of external magnetic fields called quantum fingerprints in electric conductance. Such complex patterns are due to quantum–mechanical interference of conduction electrons; when thermal disturbance is feeble and coherence of the electrons extends all over the sample, the quantum interference pattern reflects microscopic structures, such as crystalline defects and the shape of the sample, giving rise to complicated interference. Although the interference pattern carries such microscopic information, it looks so random that it has not been analysed. Here we show that machine learning allows us to decipher quantum fingerprints; fingerprint patterns in magneto-conductance are shown to be transcribed into spatial images of electron wave function intensities (WIs) in a sample by using generative machine learning. The output WIs reveal quantum interference states of conduction electrons, as well as sample shapes. The present result augments the human ability to identify quantum states, and it should allow microscopy of quantum nanostructures in materials by making use of quantum fingerprints.
Control of CRK-RAC1 activity by the miR-1/206/133 miRNA family is essential for neuromuscular junction function
Authors: Klockner Ina , Schutt Christian , Gerhardt Theresa , Boettger Thomas , Braun Thomas
Published: June 2022

Formation and maintenance of neuromuscular junctions (NMJs) are essential for skeletal muscle function, allowing voluntary movements and maintenance of the muscle tone, thereby preventing atrophy. Generation of NMJs depends on the interaction of motor neurons with skeletal muscle fibers, which initiates a cascade of regulatory events that is essential for patterning of acetylcholine receptor (AChR) clusters at specific sites of the sarcolemma. Here, we show that muscle-specific miRNAs of themiR-1/206/133family are crucial regulators of a signaling cascade comprising DOK7-CRK-RAC1, which is critical for stabilization and anchoring of postsynaptic AChRs during NMJ development and maintenance. We describe that posttranscriptional repression of CRK bymiR-1/206/133is essential for balanced activation of RAC1. Failure to adjust RAC1 activity severely compromises NMJ function, causing respiratory failure in neonates and neuromuscular symptoms in adult mice. We conclude thatmiR-1/206/133serve a specific function for NMJs but are dispensable for skeletal muscle development.
RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition
Authors: Fang Lishan , Ford-Roshon Dane , Russo Max , O’Brien Casey , Xiong Xiaozhe , Gurjao Carino , Grandclaudon Maximilien , Raghavan Srivatsan , Corsello Steven M. , Carr Steven A. , Udeshi Namrata D. , Berstler James , Sicinska Ewa , Ng Kimmie , Giannakis Marios
Published: June 2022

The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.
Paramagnetic encoding of molecules
Authors: Kretschmer Jan , David Tomáš , Dračínský Martin , Socha Ondřej , Jirak Daniel , Vít Martin , Jurok Radek , Kuchař Martin , Císařová Ivana , Polasek Miloslav
Published: June 2022

Contactless digital tags are increasingly penetrating into many areas of human activities. Digitalization of our environment requires an ever growing number of objects to be identified and tracked with machine-readable labels. Molecules offer immense potential to serve for this purpose, but our ability to write, read, and communicate molecular code with current technology remains limited. Here we show that magnetic patterns can be synthetically encoded into stable molecular scaffolds with paramagnetic lanthanide ions to write digital code into molecules and their mixtures. Owing to the directional character of magnetic susceptibility tensors, each sequence of lanthanides built into one molecule produces a unique magnetic outcome. Multiplexing of the encoded molecules provides a high number of codes that grows double-exponentially with the number of available paramagnetic ions. The codes are readable by nuclear magnetic resonance in the radiofrequency (RF) spectrum, analogously to the macroscopic technology of RF identification. A prototype molecular system capable of 16-bit (65,535 codes) encoding is presented. Future optimized systems can conceivably provide 64-bit (~10^19 codes) or higher encoding to cover the labelling needs in drug discovery, anti-counterfeiting and other areas.
Efficient aqueous remote loading of peptides in poly(lactic-co-glycolic acid)
Authors: Giles Morgan B. , Hong Justin K. Y. , Liu Yayuan , Tang Jie , Li Tinghui , Beig Avital , Schwendeman Anna , Schwendeman Steven P.
Published: June 2022

Poly(lactic-co-glycolic acid) (PLGA) long-acting release depots are effective for extending the duration of action of peptide drugs. We describe efficient organic-solvent-free remote encapsulation based on the capacity of common uncapped PLGA to bind and absorb into the polymer phase net positively charged peptides from aqueous solution after short exposure at modest temperature. Leuprolide encapsulated by this approach in low-molecular-weight PLGA 75/25 microspheres slowly and continuously released peptide for over 56 days in vitro and suppressed testosterone production in rats in an equivalent manner as the 1-month Lupron Depot®. The technique is generalizable to encapsulate a number of net cationic peptides of various size, including octreotide, with competitive loading and encapsulation efficiencies to traditional methods. In certain cases, in vitro and in vivo performance of remote-loaded PLGA microspheres exceeded that relative to marketed products. Remote absorption encapsulation further removes the need for a critical organic solvent removal step after encapsulation, allowing for simple and cost-effective sterilization of the drug-free microspheres before encapsulation of the peptide.
Short- and long-read metagenomics expand individualized structural variations in gut microbiomes
Authors: Chen Liang , Zhao Na , Cao Jiabao , Liu Xiaolin , Xu Jiayue , Ma Yue , Yu Ying , Zhang Xuan , Zhang Wenhui , Guan Xiangyu , Yu Xiaotong , Liu Zhipeng , Fan Yanqun , Wang Yang , Liang Fan , Wang Depeng , Zhao Linhua , Song Moshi , Wang Jun
Published: June 2022

In-depth profiling of genetic variations in the gut microbiome is highly desired for understanding its functionality and impacts on host health and disease. Here, by harnessing the long read advantage provided by Oxford Nanopore Technology (ONT), we characterize fine-scale genetic variations of structural variations (SVs) in hundreds of gut microbiomes from healthy humans. ONT long reads dramatically improve the quality of metagenomic assemblies, enable reliable detection of a large, expanded set of structural variation types (notably including large insertions and inversions). We find SVs are highly distinct between individuals and stable within an individual, representing gut microbiome fingerprints that shape strain-level differentiations in function within species, complicating the associations to metabolites and host phenotypes such as blood glucose. In summary, our study strongly emphasizes that incorporating ONT reads into metagenomic analyses expands the detection scope of genetic variations, enables profiling strain-level variations in gut microbiome, and their intricate correlations with metabolome.
Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals
Authors: Bozhanova Nina G. , Flyak Andrew I. , Brown Benjamin P. , Ruiz Stormy E. , Salas Jordan , Rho Semi , Bombardi Robin G. , Myers Luke , Soto Cinque , Bailey Justin R. , Crowe James E. , Bjorkman Pamela J. , Meiler Jens
Published: June 2022

Despite recent success in hepatitis C virus (HCV) treatment using antivirals, an HCV vaccine is still needed to prevent reinfections in treated patients, to avert the emergence of drug-resistant strains, and to provide protection for people with no access to the antiviral therapeutics. The early production of broadly neutralizing antibodies (bNAbs) associates with HCV clearance. Several potent bNAbs bind a conserved HCV glycoprotein E2 epitope using an unusual heavy chain complementarity determining region 3 (HCDR3) containing an intra-loop disulfide bond. Isolation of additional structurally-homologous bNAbs would facilitate the recognition of key determinants of such bNAbs and guide rational vaccine design. Here we report the identification of new antibodies containing an HCDR3 disulfide bond motif using computational screening with the Rosetta software. Using the newly-discovered and already-known members of this antibody family, we review the required HCDR3 amino acid composition and propose determinants for the bent versus straight HCDR3 loop conformation observed in these antibodies.
Structural basis of substrate recognition and translocation by human very long-chain fatty acid transporter ABCD1
Authors: Chen Zhi-Peng , Xu Da , Wang Liang , Mao Yao-Xu , Li Yang , Cheng Meng-Ting , Zhou Cong-Zhao , Hou Wen-Tao , Chen Yuxing
Published: June 2022

Human ABC transporter ABCD1 transports very long-chain fatty acids from cytosol to peroxisome for β-oxidation, dysfunction of which usually causes the X-linked adrenoleukodystrophy (X-ALD). Here, we report three cryogenic electron microscopy structures of ABCD1: the apo-form, substrate- and ATP-bound forms. Distinct from what was seen in the previously reported ABC transporters, the two symmetric molecules of behenoyl coenzyme A (C22:0-CoA) cooperatively bind to the transmembrane domains (TMDs). For each C22:0-CoA, the hydrophilic 3’-phospho-ADP moiety of CoA portion inserts into one TMD, with the succeeding pantothenate and cysteamine moiety crossing the inter-domain cavity, whereas the hydrophobic fatty acyl chain extends to the opposite TMD. Structural analysis combined with biochemical assays illustrates snapshots of ABCD1-mediated substrate transport cycle. It advances our understanding on the selective oxidation of fatty acids and molecular pathology of X-ALD.
The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria
Authors: Uyoga S. , Watson J. A. , Wanjiku P. , Rop J. C. , Makale J. , Macharia A. W. , Kariuki S. N. , Nyutu G. M. , Shebe M. , Mosobo M. , Mturi N. , Rockett K. A. , Woodrow C. J. , Dondorp A. M. , Maitland K. , White N. J. , Williams T. N.
Published: June 2022

Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 (PfHRP2) have diagnostic and prognostic value in severe malaria. We investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of PfHRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma PfHRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4.
Genome-wide mapping of individual replication fork velocities using nanopore sequencing
Authors: Theulot Bertrand , Lacroix Laurent , Arbona Jean-Michel , Millot Gael A. , Jean Etienne , Cruaud Corinne , Pellet Jade , Proux Florence , Hennion Magali , Engelen Stefan , Lemainque Arnaud , Audit Benjamin , Hyrien Olivier , Le Tallec Benoît
Published: June 2022

Little is known about replication fork velocity variations along eukaryotic genomes, since reference techniques to determine fork speed either provide no sequence information or suffer from low throughput. Here we present NanoForkSpeed, a nanopore sequencing-based method to map and extract the velocity of individual forks detected as tracks of the thymidine analogue bromodeoxyuridine incorporated during a brief pulse-labelling of asynchronously growing cells. NanoForkSpeed retrieves previous Saccharomyces cerevisiae mean fork speed estimates (≈2 kb/min) in the BT1 strain exhibiting highly efficient bromodeoxyuridine incorporation and wild-type growth, and precisely quantifies speed changes in cells with altered replisome progression or exposed to hydroxyurea. The positioning of >125,000 fork velocities provides a genome-wide map of fork progression based on individual fork rates, showing a uniform fork speed across yeast chromosomes except for a marked slowdown at known pausing sites.
Defining TCRγδ lymphoproliferative disorders by combined immunophenotypic and molecular evaluation
Authors: Teramo Antonella , Binatti Andrea , Ciabatti Elena , Schiavoni Gianluca , Tarrini Giulia , Barilà Gregorio , Calabretto Giulia , Vicenzetto Cristina , Gasparini Vanessa Rebecca , Facco Monica , Petrini Iacopo , Grossi Roberto , Pisanti Nadia , Bortoluzzi Stefania , Falini Brunangelo , Tiacci Enrico , Galimberti Sara , Semenzato Gianpietro , Zambello Renato
Published: June 2022

Tγδ large granular lymphocyte leukemia (Tγδ LGLL) is a rare lymphoproliferative disease, scantily described in literature. A deep-analysis, in an initial cohort of 9 Tγδ LGLL compared to 23 healthy controls, shows that Tγδ LGLL dominant clonotypes are mainly public and exhibit different V-(D)-J γ/δ usage between patients with symptomatic and indolent Tγδ neoplasm. Moreover, some clonotypes share the same rearranged sequence. Data obtained in an enlarged cohort (n = 36) indicate the importance of a combined evaluation of immunophenotype and STAT mutational profile for the correct management of patients with Tγδ cell expansions. In fact, we observe an association between Vδ2/Vγ9 clonality and indolent course, while Vδ2/Vγ9 negativity correlates with symptomatic disease. Moreover, the 7 patients with STAT3 mutations have neutropenia and a CD56-/Vδ2- phenotype, and the 3 cases with STAT5B mutations display an asymptomatic clinical course and CD56/Vδ2 expression. All these data indicate that biological characterization is needed for Tγδ-cell neoplasm definition.
Transforming Ti3C2Tx MXene’s intrinsic hydrophilicity into superhydrophobicity for efficient photothermal membrane desalination
Authors: Zhang Baoping , Wong Pak Wai , Guo Jiaxin , Zhou Yongsen , Wang Yang , Sun Jiawei , Jiang Mengnan , Wang Zuankai , An Alicia Kyoungjin
Published: June 2022

Owing to its 100% theoretical salt rejection capability, membrane distillation (MD) has emerged as a promising seawater desalination approach to address freshwater scarcity. Ideal MD requires high vapor permeate flux established by cross-membrane temperature gradient (∆T) and excellent membrane durability. However, it’s difficult to maintain constant ∆T owing to inherent heat loss at feedwater side resulting from continuous water-to-vapor transition and prevent wetting transition-induced membrane fouling and scaling. Here, we develop a Ti3C2Tx MXene-engineered membrane that imparts efficient localized photothermal effect and strong water-repellency, achieving significant boost in freshwater production rate and stability. In addition to photothermal effect that circumvents heat loss, high electrically conductive Ti3C2Tx MXene also allows for self-assembly of uniform hierarchical polymeric nanospheres on its surface via electrostatic spraying, transforming intrinsic hydrophilicity into superhydrophobicity. This interfacial engineering renders energy-efficient and hypersaline-stable photothermal membrane distillation with a high water production rate under one sun irradiation.
Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts
Authors: Petropoulou-Vathi Lilian , Simitsi Athina , Valkimadi Politymi-Eleni , Kedariti Maria , Dimitrakopoulos Lampros , Koros Christos , Papadimitriou Dimitra , Papadimitriou Alexandros , Stefanis Leonidas , Alcalay Roy N. , Rideout Hardy J.
Published: June 2022

Despite several advances in the field, pharmacodynamic outcome measures reflective of LRRK2 kinase activity in clinical biofluids remain urgently needed. A variety of targets and approaches have been utilized including assessments of LRRK2 itself (levels, phosphorylation), or its substrates (e.g. Rab10 or other Rab GTPases). We have previously shown that intrinsic kinase activity of LRRK2 isolated from PBMCs of G2019S carriers is elevated, irrespective of disease status. In the present study we find that phosphorylation of Rab10 is also elevated in G2019S carriers, but only those with PD. Additionally, phosphorylation of this substrate is also elevated in two separate idiopathic PD cohorts, but not in carriers of the A53T mutation in α-synuclein. In contrast, Rab29 phosphorylation was specifically reduced in urinary exosomes from A53T and idiopathic PD patients. Taken together, our findings highlight the need for the assessment of multiple complimentary targets for a more comprehensive picture of the disease.
A repeating fast radio burst associated with a persistent radio source
Authors: Niu C.-H. , Aggarwal K. , Li D. , Zhang X. , Chatterjee S. , Tsai C.-W. , Yu W. , Law C. J. , Burke-Spolaor S. , Cordes J. M. , Zhang Y.-K. , Ocker S. K. , Yao J.-M. , Wang P. , Feng Y. , Niino Y. , Bochenek C. , Cruces M. , Connor L. , Jiang J.-A. , Dai S. , Luo R. , Li G.-D. , Miao C.-C. , Niu J.-R. , Anna-Thomas R. , Sydnor J. , Stern D. , Wang W.-Y. , Yuan M. , Yue Y.-L. , Zhou D.-J. , Yan Z. , Zhu W.-W. , Zhang B.
Published: June 2022

The dispersive sweep of fast radio bursts (FRBs) has been used to probe the ionized baryon content of the intergalactic medium1, which is assumed to dominate the total extragalactic dispersion. Although the host-galaxy contributions to the dispersion measure appear to be small for most FRBs2, in at least one case there is evidence for an extreme magneto-ionic local environment3,4 and a compact persistent radio source5. Here we report the detection and localization of the repeating FRB 20190520B, which is co-located with a compact, persistent radio source and associated with a dwarf host galaxy of high specific-star-formation rate at a redshift of 0.241 ± 0.001. The estimated host-galaxy dispersion measure of approximately $${903}_{-111}^{+72}$$

903

−
111

+
72

parsecs per cubic centimetre, which is nearly an order of magnitude higher than the average of FRB host galaxies2,6, far exceeds the dispersion-measure contribution of the intergalactic medium. Caution is thus warranted in inferring redshifts for FRBs without accurate host-galaxy identifications.
Direct measurement of the 3He+ magnetic moments
Authors: Schneider A. , Sikora B. , Dickopf S. , Müller M. , Oreshkina N. S. , Rischka A. , Valuev I. A. , Ulmer S. , Walz J. , Harman Z. , Keitel C. H. , Mooser A. , Blaum K.
Published: June 2022

Helium-3 has nowadays become one of the most important candidates for studies in fundamental physics1–3, nuclear and atomic structure4,5, magnetometry and metrology6, as well as chemistry and medicine7,8. In particular, 3He nuclear magnetic resonance (NMR) probes have been proposed as a new standard for absolute magnetometry6,9. This requires a high-accuracy value for the 3He nuclear magnetic moment, which, however, has so far been determined only indirectly and with a relative precision of 12 parts per billon10,11. Here we investigate the 3He+ ground-state hyperfine structure in a Penning trap to directly measure the nuclear g-factor of 3He+$${g}_{I}^{{\prime} }=-\,4.2550996069(30{)}_{{\rm{stat}}}(17{)}_{{\rm{sys}}}$$

g

I

′

=
−

4.2550996069
(
30

)

stat

(
17

)

sys

, the zero-field hyperfine splitting $${E}_{{\rm{HFS}}}^{\exp }=-\,8,\,665,\,649,\,865.77{(26)}_{{\rm{stat}}}{(1)}_{{\rm{sys}}}$$

E

HFS

exp

=
−

8
,

665
,

649
,

865.77

(

26

)

stat

(
1
)

sys

Hz and the bound electron g-factor $${g}_{e}^{{\rm{\exp }}}=-\,2.00217741579(34{)}_{{\rm{stat}}}(30{)}_{{\rm{sys}}}$$

g

e

exp

=
−

2.00217741579
(
34

)

stat

(
30

)

sys

. The latter is consistent with our theoretical value $${g}_{e}^{{\rm{theo}}}=-\,2.00217741625223(39)$$

g

e

theo

=
−

2.00217741625223
(
39
)

based on parameters and fundamental constants from ref. 12. Our measured value for the 3He+ nuclear g-factor enables determination of the g-factor of the bare nucleus $${g}_{I}=-\,4.2552506997(30{)}_{{\rm{stat}}}(17{)}_{{\rm{sys}}}(1{)}_{{\rm{theo}}}$$

g

I

=
−

4.2552506997
(
30

)

stat

(
17

)

sys

(
1

)

theo

via our accurate calculation of the diamagnetic shielding constant13$${\sigma }_{{}^{3}{\mathrm{He}}^{+}}=0.00003550738(3)$$

σ

3

He

+

=
0.00003550738

(
3
)

. This constitutes a direct calibration for 3He NMR probes and an improvement of the precision by one order of magnitude compared to previous indirect results. The measured zero-field hyperfine splitting improves the precision by two orders of magnitude compared to the previous most precise value14 and enables us to determine the Zemach radius15 to $${r}_{Z}=2.608(24)$$

r

Z

=
2.608
(
24
)

 fm.
Potentiating adoptive cell therapy using synthetic IL-9 receptors
Authors: Kalbasi Anusha , Siurala Mikko , Su Leon L. , Tariveranmoshabad Mito , Picton Lora K. , Ravikumar Pranali , Li Peng , Lin Jian-Xin , Escuin-Ordinas Helena , Da Tong , Kremer Sarah V. , Sun Amy L. , Castelli Sofia , Agarwal Sangya , Scholler John , Song Decheng , Rommel Philipp C. , Radaelli Enrico , Young Regina M. , Leonard Warren J. , Ribas Antoni , June Carl H. , Garcia K. Christopher
Published: June 2022

Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γccytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD–IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.
Cohesin-mediated loop anchors confine the locations of human replication origins
Authors: Emerson Daniel J. , Zhao Peiyao A. , Cook Ashley L. , Barnett R. Jordan , Klein Kyle N. , Saulebekova Dalila , Ge Chunmin , Zhou Linda , Simandi Zoltan , Minsk Miriam K. , Titus Katelyn R. , Wang Weitao , Gong Wanfeng , Zhang Di , Yang Liyan , Venev Sergey V. , Gibcus Johan H. , Yang Hongbo , Sasaki Takayo , Kanemaki Masato T. , Yue Feng , Dekker Job , Chen Chun-Long , Gilbert David M. , Phillips-Cremins Jennifer E.
Published: June 2022

DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability1,2. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)3–6, subTADs7 and loops8 in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.
Important marine areas for endangered African penguins before and after the crucial stage of moulting
Authors: Carpenter-Kling Tegan , de Blocq Andrew , Hagen Christina , Harding Craig , Morris Taryn , Pichegru Lorien , Roberts Jennifer , Ryan Peter G. , Wanless Ross M. , McInnes Alistair
Published: June 2022

The population of the Endangered African penguinSpheniscus demersushas decreased by > 65% in the last 20 years. A major driver of this decrease has been the reduced availability of their principal prey, sardineSardinops sagaxand anchovyEngraulis encrasicolus.To date, conservation efforts to improve prey availability have focused on spatial management strategies to reduce resource competition with purse-seine fisheries during the breeding season. However, penguins also undergo an annual catastrophic moult when they are unable to feed for several weeks. Before moulting they must accumulate sufficient energy stores to survive this critical life-history stage. Using GPS tracking data collected between 2012 and 2019, we identify important foraging areas for pre- and post-moult African penguins at three of their major colonies in South Africa: Dassen Island and Stony Point (Western Cape) and Bird Island (Eastern Cape). The foraging ranges of pre- and post-moult adult African penguins (c. 600 km from colony) was far greater than that previously observed for breeding penguins (c. 50 km from colony) and varied considerably between sites, years and pre- and post-moult stages. Despite their more extensive range during the non-breeding season, waters within 20 and 50 km of their breeding colonies were used intensively and represent important foraging areas to pre- and post-moult penguins. Furthermore, penguins in the Western Cape travelled significantly further than those in the Eastern Cape which is likely a reflection of the poor prey availability along the west coast of South Africa. Our findings identify important marine areas for pre- and post-moult African penguins and support for the expansion of fisheries-related spatio-temporal management strategies to help conserve African penguins outside the breeding season.
ADHD symptoms and use of anabolic androgenic steroids among male weightlifters
Authors: Kildal Emilie , Hassel Bjørnar , Bjørnebekk Astrid
Published: June 2022

Use of anabolic androgenic steroids (AAS) is associated with adverse health effects. The factors that predispose to AAS use among athletes are poorly understood, but attention deficit/hyperactivity disorder (ADHD), which is known to occur among athletes more often than in the general population, is associated with risk behaviors, including substance abuse. We aimed to see if AAS use in male weightlifters was associated with ADHD symptoms, and test the link between ADHD symptoms and cognitive performance. Hundred and forty male weightlifters, 72 AAS users and 68 weightlifting controls (WLC), completed the Achenbach system of empirically based assessment (ASEBA) for ADHD symptoms and underwent cognitive examination. Self-reported ADHD symptom scores were significantly higher among AAS users compared to WLC, and scores in the range indicating clinically important ADHD was significantly more common in the AAS-using group. Age of onset of AAS use correlated inversely with ADHD scale score (r = − 0.35; p = 0.003). ADHD score correlated inversely with cognitive scores for working memory (r = − 0.25, p < 0.001), processing speed (r = − 0.24, p < 0.001), verbal learning and memory (r = − 0.19, p = 0.03), and problem solving (r = − 0.20, p = 0.02). AAS use among weightlifters is associated with ADHD symptoms and corresponding lower cognitive performance. Recognising a relationship between ADHD symptoms and AAS use may guide drug prevention strategies in sports.
Transient dynamics of a single molecular transistor in the presence of local electron–phonon and electron–electron interactions and quantum dissipation
Authors: Kalla Manasa , Chebrolu Narasimha Raju , Chatterjee Ashok
Published: June 2022

We consider a single molecular transistor in which a quantum dot with local electron–electron and electron–phonon interactions is coupled to two metallic leads, one of which acts like a source and the other like a drain. The system is modeled by the Anderson-Holstein (AH) model. The quantum dot is mounted on a substrate that acts as a heat bath. Its phonons interact with the quantum dot phonons by the Caldeira–Leggett interaction giving rise to dissipation in the dynamics of the quantum dot system. A simple canonical transformation exactly treats the interaction of the quantum dot phonons with the substrate phonons. The electron–phonon interaction of the quantum dot is eliminated by the celebrated Lang-Firsov transformation. The time-dependent current is finally calculated by the Keldysh Green function technique with various types of bias. The transient-time phase diagram is analysed as a function of the system parameters to explore regions that can be used for fast switching in devices like nanomolecular switches.
Optimal self-assembly of lipid nanoparticles (LNP) in a ring micromixer
Authors: Ripoll Manon , Martin Elian , Enot Mathilde , Robbe Oscar , Rapisarda Chiara , Nicolai Marie-Claire , Deliot Aurélie , Tabeling Patrick , Authelin Jean-René , Nakach Mostafa , Wils Pierre
Published: June 2022

Lipid nanoparticles (LNPs) for RNA and DNA delivery have attracted considerable attention for their ability to treat a broad range of diseases and to vectorize mRNA for COVID vaccines. LNPs are produced by mixing biomolecules and lipids, which self-assemble to form the desired structure. In this domain, microfluidics shows clear advantages: high mixing quality, low-stress conditions, and fast preparation. Studies of LNPs produced in micromixers have revealed, in certain ranges of flow rates, a degradation in performance in terms of size, monodispersity and encapsulation efficiency. In this study, we focus on the ring micromixer, which is well adapted to high throughput. We reveal three regimes, side-by-side, transitional and highly mixed, that control the mixing performance of the device. Furthermore, using cryo-TEM and biochemical analysis, we show that the mixing performances are strongly correlated to the characteristics of the LNPs we produce. We emphasize the importance of the flow-rate ratio and propose a physical criterion based on the onset of temporal instabilities for producing LNPs with optimal characteristics in terms of geometry, monodispersity and encapsulation yield. These criteria are generally applicable.
Three-dimensional analysis of interstitial cells in the lamina propria of the murine vas deferens by confocal laser scanning microscopy and FIB/SEM
Authors: Hiroshige Tasuku , Uemura Kei-Ichiro , Hirashima Shingo , Togo Akinobu , Ohta Keisuke , Nakamura Kei-Ichiro , Igawa Tsukasa
Published: June 2022

The present study aimed to explore the three-dimensional (3D) ultrastructure of interstitial cells (ICs) within the lamina propria of the murine vas deferens and the spatial relationships between epithelial cells and surrounding cells. Focused ion beam scanning electron microscopy and confocal laser scanning microscopy were performed. ICs within the lamina propria had a flat, sheet-like structure of cytoplasm with multiple cellular processes. In addition, two types of 3D structures that comprised cell processes of flat, sheet-like ICs were observed: one was an accordion fold-like structure and the other was a rod-shaped structure. ICs were located parallel to the epithelium and were connected to each other via gap junctions or adherens junctions. Moreover, multiple sphere-shaped extracellular vesicle-like structures were frequently observed around the ICs. The ICs formed a complex 3D network comprising sheet-like cytoplasm and multiple cell processes with different 3D structures. From this morphological study, we noted that ICs within the lamina propria of murine vas deferens may be involved in signal transmission between the epithelium and smooth muscle cells by physical interaction and by exchanging extracellular vesicles.
Single machine scheduling problems with sequence-dependent setup times and precedence delays
Authors: Lin Shih-Wei , Ying Kuo-Ching
Published: June 2022

Sequence-dependent setup times and precedence delays occur frequently in various production environments. This study investigates the single machine scheduling problem with setup times and precedence delays that occur in an amplifier assembly company. This study proposes a novel mixed-integer linear programming model and a lean iterated greedy algorithm to minimize the makespan for this problem. Based on the property of delayed precedence constraints, the lean iterated greedy (LIG) algorithm uses a simple but effective lean construction mechanism that can discard infeasible solutions to reduce the waste of unnecessary searches and quickly converge to the (near) global optimum. The computational results show that LIG significantly outperforms the state-of-the-art algorithm in terms of solution quality and computational efficiency. This study mainly contributes to providing a simple, effective, and efficient algorithm that can facilitate industrial applications and serve as a new benchmark approach for future research.
Modular microfluidic system for on-chip extraction, preconcentration and detection of the cytokine biomarker IL-6 in biofluid
Authors: Alexandre Lucile , Bendali Amel , Pereiro Iago , Azimani Madad , Dumas Simon , Malaquin Laurent , Mai Thanh Duc , Descroix Stéphanie
Published: June 2022

The cytokine interleukin 6 (IL-6) is involved in the pathogenesis of different inflammatory diseases, including cancer, and its monitoring could help diagnosis, prognosis of relapse-free survival and recurrence. Here, we report an innovative microfluidic approach that uses the fluidization of magnetic beads to specifically extract, preconcentrate and fluorescently detect IL-6 directly on-chip. We assess how the physical properties of the beads can be tuned to improve assay performance by enhancing mass transport, reduce non-specific binding and multiply the detection signal threefold by transitioning between packed and fluidization states. With the integration of a full ELISA protocol in a single microfluidic chamber, we show a twofold reduction in LOD compared to conventional methods along with a large dynamic range (10 pg/mL to 2 ng/mL). We additionally demonstrate its application to IL-6 detection in undiluted serum samples.
Effect of sarcopenia and poor balance on vertebral spinal osteoporotic fracture in female rheumatoid arthritis
Authors: Zhang Mei , Xu Shengqian , Zong Hexiang , Wang Jianxiong , Chu Yiran , Cai Jingyu , Chang Ling
Published: June 2022

This study investigated the effect of poor balance and sarcopenia on vertebral spinal osteoporotic fracture (VOPF) in female rheumatoid arthritic (RA) patients. A total of 195 female RA and 126 normal subjects were enrolled, and the correlations between sarcopenia, poor balance and VOPF were analyzed. Furthermore, we explored the relationships between sarcopenia or poor balance with disease related indexes of female RA. Binary logistic regression analyses were performed to identify potential risk factors for VOPF in female RA. We found that female RA had an increased risk of sarcopenia, poor balance (Berg balance scale, BBS ≤ 40) and VOPF than controls (P < 0.0001). Female RA with VOPF were more likely to have poor balance and sarcopenia than those without VOPF (P < 0.0001–0.05). Meanwhile, female RA with sarcopenia and poor balance often had higher disease activity, more serious joint damage and worse joint function (P < 0.05) compared with those without sarcopenia and poor balance. Binary logistic regression analysis (LR backwald) revealed that age (OR = 1.112, 95% CI 1.065–1.160, P < 0.0001), OP (OR = 10.137, 95% CI 4.224–24.330, P < 0.0001) and GCs usage (OR = 3.532, 95% CI 1.427–8.741, P = 0.006) were risk factors, while SMI (OR = 0.386, 95% CI 0.243–0.614, P < 0.0001) and BBS (OR = 0.952, 95% CI 0.929–0.976, P < 0.0001) were protective factors for VOPF in female RA. Hence, sarcopenia and poor balance are associated with a higher risk for VOPF and are closely related to disease activity and joint structure damage of female RA.
Caveolin-initiated macropinocytosis is required for efficient silica nanoparticles’ transcytosis across the alveolar epithelial barrier
Authors: Detampel Pascal , Tehranian Sara , Mukherjee Priyanka , Foret Morgan , Fuerstenhaupt Tobias , Darbandi Ali , Bogari Nawaf , Hlasny Magda , Jeje Ayodeji , Olszewski Michal A. , Ganguly Anutosh , Amrein Matthias
Published: June 2022

Removal of particulate materials that would otherwise cumulate within the airspace and hinder the gas exchange is one of the central processes of maintaining lung homeostasis. While the importance of the particle uptake by alveolar macrophages and their expulsion via the airways mucociliary escalator is well established, very little is known about the alternative route for removing the particles via direct crossing the lung epithelium for transfer into the pulmonary lymph and bloodstream. This study dissected sequential mechanisms involved in nanoparticle transcytosis through the alveolar epithelial cell layer. By a combination of live cell, super resolution, and electron microscopy and RNA interference study, we have dissected temporal steps of nanoparticle transcytosis through alveolar epithelium. Our study revealed that caveolin is essential for the firm adhesion of the silica nanoparticle agglomerates to the apical membrane and their subsequent rapid internalization with the help of macropinocytic elements C-terminal-binding protein1 and Rabankyrin-5 but not dynamin. Actin, but not microtubules, played a major role in nanoparticle uptake and subsequent transportation. The compartments with nanoparticles were tethered to trans-Golgi network to be jointly transported along actin stress fibers across the cytoplasm, employing a myosin-dependent mechanism. The trans-Golgi nanoparticle transport machinery was positive to Rab6A, a marker linked to vesicle exocytosis. Exocytosis was primarily occurring at the basolateral plane of the alveolar epithelial cells. The high-proficiency novel caveolin and Rabankyrin-5 associated uptake and transcellular transport of nanoparticles across the AEC barrier supports its importance in clearance of amorphous silica and other types of non-inflammatory nanoparticles that are rapidly removed from the lungs following their inhalation.
Multifunctional green synthesized Cu–Al layered double hydroxide (LDH) nanoparticles: anti-cancer and antibacterial activities
Authors: Kiani Mahsa , Bagherzadeh Mojtaba , Ghadiri Amir Mohammad , Makvandi Pooyan , Rabiee Navid
Published: June 2022

Doxorubicin (DOX) is a potent anti-cancer agent and there have been attempts in developing nanostructures for its delivery to tumor cells. The nanoparticles promote cytotoxicity of DOX against tumor cells and in turn, they reduce adverse impacts on normal cells. The safety profile of nanostructures is an important topic and recently, the green synthesis of nanoparticles has obtained much attention for the preparation of biocompatible carriers. In the present study, we prepared layered double hydroxide (LDH) nanostructures for doxorubicin (DOX) delivery. The Cu–Al LDH nanoparticles were synthesized by combining Cu(NO3)2·3H2O and Al(NO3)3·9H2O, and then, autoclave at 110. The green modification of LDH nanoparticles with Plantago ovata (PO) was performed and finally, DOX was loaded onto nanostructures. The FTIR, XRD, and FESEM were employed for the characterization of LDH nanoparticles, confirming their proper synthesis. The drug release study revealed the pH-sensitive release of DOX (highest release at pH 5.5) and prolonged DOX release due to PO modification. Furthermore, MTT assay revealed improved biocompatibility of Cu–Al LDH nanostructures upon PO modification and showed controlled and low cytotoxicity towards a wide range of cell lines. The CLSM demonstrated cellular uptake of nanoparticles, both in the HEK-293 and MCF-7 cell lines; however, the results were showed promising cellular internalizations to the HEK-293 rather than MCF-7 cells. The in vivo experiment highlighted the normal histopathological structure of kidneys and no side effects of nanoparticles, further confirming their safety profile and potential as promising nano-scale delivery systems. Finally, antibacterial test revealed toxicity of PO-modified Cu–Al LDH nanoparticles against Gram-positive and -negative bacteria.
Effect of thermal and chemical treatments used for SARS-COV-2 inactivation in the measurement of saliva analytes
Authors: Lamy Elsa , Rubio Camila P. , Carreira Laura , Capela e Silva Fernando , Martinez-Subiela Silvia , Tecles Fernando , Lopez-Jornet Pia , Ceron Jose J. , Tvarijonaviciute Asta
Published: June 2022

The present study aims to assess the effects of thermal and chemical inactivating procedures, that can be used for SARS-CoV-2 inactivation, on different salivary analytes. SDS–Polyacrylamide Gel Electrophoresis (SDS-PAGE) protein profile and a panel of 25 specific biomarkers of oxidative status, stress, metabolism and tissue damage were evaluated in samples subjected to different treatments: thermal (65 °C or 92 °C) and chemical with detergents [sodium dodecyl sulphate (SDS), Triton X-100 or NP-40]. Salivary SDS-PAGE profile was most affected by heating at 92 °C, with three and two protein bands decreasing and increasing their expression levels, respectively. This treatment also affected the results of several enzymes, with some of them being also affected by heating at 65 °C and incubation with SDS. The use of Triton X-100 or NP-40 resulted in increased values of cortisol, triglycerides and glucose, not affecting the other tested biomarkers. The present results will help researchers and clinicians to select the best protocols to work in safe conditions with saliva, taking into account the target analyte planned to be measured.
Gain and isolation enhancement of a wideband MIMO antenna using metasurface for 5G sub-6 GHz communication systems
Authors: Hasan Md. Mhedi , Islam Mohammad Tariqul , Samsuzzaman Md , Baharuddin Mohd Hafiz , Soliman Mohamed S. , Alzamil Ahmed , Abu Sulayman Iman I. M. , Islam Md. Shabiul
Published: June 2022

This work proposes a compact metasurface (MS)-integrated wideband multiple-input multiple-output (MIMO) antenna for fifth generation (5G) sub-6 GHz wireless communication systems. The perceptible novelty of the proposed MIMO system is its wide operating bandwidth, high gain, lower interelement gap, and excellent isolation within the MIMO components. The radiating patch of the antenna is truncated diagonally with a partially ground plane, and a metasurface has been employed for enhancing the antenna performance. The suggested MS integrated single antenna prototype has a miniature dimension of 0.58λ × 0.58λ × 0.02λ. The simulated and measured findings demonstrate a wideband characteristic starting from 3.11 to 7.67 GHz including a high realized gain of 8 dBi. The four-element MIMO system has been designed by rendering each single antenna orthogonally to one another while retaining compact size and wideband properties between 3.2 and 7.6 GHz. The suggested MIMO prototype has been designed and fabricated on a low loss Rogers RT5880 substrate with a miniature dimension of 1.05λ × 1.05λ × 0.02λ and its performance is evaluated using a suggested 10 × 10 array of a square enclosed circular split ring resonators within the same substrate material. The inclusion of the proposed metasurface with a backplane significantly reduces antenna backward radiation and manipulates the electromagnetic field, thus improving the bandwidth, gain and isolation of MIMO components. The suggested 4-port MIMO antenna offers a high realized gain of 8.3 dBi compared to existing MIMO antennas with an excellent average total efficiency of 82% in the 5G sub-6 GHz spectrum and is in good accordance with measured results. Furthermore, the developed MIMO antenna exhibits outstanding diversity characteristics in respect of envelope correlation coefficient (ECC) less than 0.004, diversity gain (DG) close to 10 dB (> 9.98 dB) and high isolation between MIMO components (> 15.5 dB). Therefore, the proposed MS-inspired MIMO antenna substantiates its applicability for 5G sub-6 GHz communication networks.