Genomic insights into the chromosomal elongation in a family of Collembola.

Collembola is a highly diverse and abundant group of soil arthropods with chromosome numbers ranging from 5 to 11. Previous karyotype studies indicated that the Tomoceridae family possesses an exceptionally long chromosome. To better understand chromosome size evolution in Collembola, we obtained a chromosome-level genome of Yoshiicerus persimilis with a size of 334.44 Mb and BUSCO completeness of 97.0% (n = 1013). Both genomes of Y. persimilis and Tomocerus qinae (recently published) have an exceptionally large chromosome (ElChr greater than 100 Mb), accounting for nearly one-third of the genome. Comparative genomic analyses suggest that chromosomal elongation occurred independently in the two species approximately 10 million years ago, rather than in the ancestor of the Tomoceridae family. The ElChr elongation was caused by large tandem and segmental duplications, as well as transposon proliferation, with genes in these regions experiencing weaker purifying selection (higher dN/dS) than conserved regions. Moreover, inter-genomic synteny analyses indicated that chromosomal fission/fusion events played a crucial role in the evolution of chromosome numbers (ranging from 5 to 7) within Entomobryomorpha. This study provides a valuable resource for investigating the chromosome evolution of Collembola.

Precision compensation method for visual measurement based on nonuniform refractive index field reconstruction.

Visual measurement is widely used in industrial manufacturing and assembly fields. Due to the fact that the refractive index field of the measurement environment is inhomogeneous, the transmitted light for visual measurements will produce errors. To compensate for these errors, we introduce a binocular camera for visual measurement based on the reconstruction of a nonuniform refractive index field using the schlieren method, followed by the reduction of the inverse ray path by the Runge-Kutta method to compensate for the measurement error introduced by the nonuniform refractive index field. Finally, the effectiveness of the method is experimentally verified, with a reduction in measurement error of about 60% in the built measurement environment.

A lab-on-disc centrifugal microfluidic system for ultraprecise plasma separation.

As the medical community puts forward higher requirements for the speed and convenience of disease diagnosis, point-of-care testing has become a hot research topic to overcome various kinds of healthcare problems. Blood test is considered to be highly sensitive and accurate in clinical diagnosis. However, conventional plasma separation system tends to be bulky and needs professional operations. Moreover, imprecise separation may cause residual biochemical substances such as blood cells to affect the detection results. In this work, to solve these problems, we designed a portable centrifugal microfluidic platform for automatic, rapid and ultraprecise blood separation. The disc consists of multichambers and multi-microchannels where a plasma reservoir and a cell reservoir are connected to each other and collinear with the center of the circle. This structure overcomes the weakness of low separation efficiency (when hematocrit increases) under the traditional blood separation structure (bifurcation structure). As a result, the proposed system achieved 99.9% plasma purity, 99.9% separation efficiency (with a blood hematocrit of 48%) and 32.5% plasma recovery rate in the 50s, which provides a strong guarantee for rapid blood diagnosis and analysis, especially in areas where medical resources are limited.

Ruptured brain aneurysm-induced subarachnoid hemorrhage with concurrent myocardial infarction in a rhesus monkey (Macaca mulatta).

Brain aneurysm ruptured subarachnoid hemorrhages (SAH) are extremely rare except in humans. This study described a SAH caused by a ruptured anterior communication artery aneurysm and concurrent myocardial infarction, along with pneumonia and intestinal obstruction in a rhesus monkey, which is rather rare in animal experiments.

Application of centrifugal microfluidics in immunoassay, biochemical analysis and molecular diagnosis.

Rapid diagnosis plays a vital role in daily life and is effective in reducing treatment costs and increasing curability, especially in remote areas with limited availability of resources. Among the various common methods of rapid diagnosis, centrifugal microfluidics has many unique advantages, such as less sample consumption, more precise valve control for sequential loading of samples, and accurately separated module design in a microfluidic network to minimize cross-contamination. Therefore, in recent years, centrifugal microfluidics has been extensively researched, and it has been found to play important roles in biology, chemistry, and medicine. Here, we review the latest developments in centrifugal microfluidic platforms in immunoassays, biochemical analyses, and molecular diagnosis, in recent years. In immunoassays, we focus on the application of enzyme-linked immunosorbent assay (ELISA); in biochemical analysis, we introduce the application of plasma and blood cell separation; and in molecular diagnosis, we highlight the application of nucleic acid amplification tests. Additionally, we discuss the characteristics of the methods under each platform as well as the enhancement of the corresponding performance parameters, such as the limit of detection, separation efficiency, etc. Finally, we discuss the limitations associated with the existing applications and potential breakthroughs that can be achieved in this field in the future.

Discovery of a highly efficient nitroaryl group for detection of nitroreductase and imaging of hypoxic tumor cells.

Hypoxia is a pathological hallmark of solid tumors. Detection of hypoxia is therefore of great interest for tumor diagnosis and treatment. As a well-established biomarker of hypoxia, nitroreductase (NTR) has been widely exploited in the development of hypoxia-responsive fluorescent probes on the basis of its enzymatic activity to reduce nitroaryl groups. However, studies on the relationship between the nitroaryl structure and the probe performance for optimal probe design are still rare. Here we report a comparative investigation of nitroaryl groups and identification of the optimal nitroaryl structure for developing new fluorescent probes with extremely high efficiency in the detection of NTR and the imaging of hypoxic tumor cells. Specifically, we synthesized a series of resorufin-based fluorescent probes containing different nitroaryl groups, compared their fluorescence responses to NTR, and identified 2-nitro-N-methyl-imidazolyl as the optimal nitroaryl group that is much more efficient than the most widely used 4-nitrophenyl for NTR detection. The structure-performance relationship was then studied by theoretical molecular docking, revealing the unique features of 2-nitro-N-methyl-imidazolyl in binding and reaction with NTR. We further incorporated the 2-nitro-N-methyl-imidazolyl group into a near-infrared (NIR) hemicyanine fluorophore and developed a NIR fluorescent probe NFP-7 for the detection of NTR and hypoxic tumor cells. NFP-7 exhibits a strong fluorescence increase toward NTR in vitro with an ultrafast (within 40 seconds to fluorescence maximum) and ultrasensitive (0.2 ng mL-1 detection limit) response. NFP-7 has also been demonstrated for imaging the degree of hypoxia in live tumor cells and, more importantly, in a murine tumor model. Our study provides important insights into hypoxia probe development and new tools for hypoxia imaging.

Making smart drugs smarter: The importance of linker chemistry in targeted drug delivery.

Smart drugs, such as antibody-drug conjugates, for targeted therapy rely on the ability to deliver a warhead to the desired location and to achieve activation at the same site. Thus, designing a smart drug often requires proper linker chemistry for tethering the warhead with a vehicle in such a way that either allows the active drug to retain its potency while being tethered or ensures release and thus activation at the desired location. Recent years have seen much progress in the design of new linker activation strategies. Herein, we review the recent development of chemical strategies used to link the warhead with a delivery vehicle for preferential cleavage at the desired sites.

Upregulation of p53 through induction of MDM2 degradation: Amino acid prodrugs of anthraquinone analogs.

Previously, we reported a class of MDM2-MDM4 dimerization inhibitors that upregulate p53 and showed potent anticancer activity in animal models. However, water solubility hinders their further development. Herein we describe our effort to develop a prodrug approach that overcomes the solubility problem. The prodrug of BW-AQ-238, a potent anthraquinone analog, was made by esterification of the hydroxyl group with various natural amino acids. Cytotoxicity of these compounds toward Hela and EU-1 cells, their aqueous solubility, and the release kinetics of these prodrugs in buffer and in the presence of hydrolytic enzymes were studied. The results demonstrate that the amino acid prodrug approach significantly improved the water solubility while maintaining the potency of the parent drug.

Click and release: bioorthogonal approaches to "on-demand" activation of prodrugs.

Prodrug approaches represent an excellent solution to certain pharmaceutical issues commonly encountered in the drug discovery and development process. Along this line, the chemistry needed for the bio-reversible derivatization of drug functional groups for on-demand release is critical. In recent years, "click and release" approaches have shown great promise in the design of prodrugs because of their bioorthogonality and controlled bond-cleavage, which help ensure prodrug stability during circulation and ready cleavage at the desired site of action. This review highlights recent developments of this research field and discusses issues yet to be addressed.

Organic CO Prodrugs: Structure-CO-Release Rate Relationship Studies.

Carbon monoxide (CO) is an endogenously produced gasotransmitter in mammals, and may have signaling roles in bacteria as well. It has many recognized therapeutic effects. A significant challenge in this field is the development of pharmaceutically acceptable forms of CO delivery with controllable and tunable release rates. Herein, the structure-release rate studies of the first class of organic CO prodrugs that release CO in aqueous solution at neutral pH is described.

Esterase-Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide.

Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2 S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2 S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2 S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H2 S prodrugs shows great potential as both research tools and therapeutic agents.

Click and Release: A Chemical Strategy toward Developing Gasotransmitter Prodrugs by Using an Intramolecular Diels-Alder Reaction.

Prodrug strategies have been proven to be a very effective way of addressing delivery problems. Much of the chemistry in prodrug development relies on the ability to mask an appropriate functional group, which can be removed under appropriate conditions. However, developing organic prodrugs of gasotransmitters represent unique challenges. This is especially true with carbon monoxide, which does not have an easy "handle" for bioreversible derivatization. By taking advantage of an intramolecular Diels-Alder reaction, we have developed a prodrug strategy for preparations of organic CO prodrugs that are stable during synthesis and storage, and yet readily release CO with tunable release rates under near physiological conditions. The effectiveness of the CO prodrug system in delivering a sufficient quantity of CO for possible therapeutic applications has been studied using a cell culture anti-inflammatory assay and a colitis animal model. These studies fully demonstrate the proof of concept, and lay a strong foundation for further medicinal chemistry work in developing organic CO prodrugs.

New coumarin derivatives: design, synthesis and use as inhibitors of hMAO.

A series new 2H-chromene-3-carboxamides (4a-4i) and S-2H-chromene-3-carbothioates (5j-5t) were synthesized and evaluated as monoamine oxidase A and B inhibitors. Among them, compound 5k (IC50=0.21µM, IC50 iproniazid=7.65µM) showed the most activity and higher MAO-B selectivity (189.2-fold vs 1-fold) with respect to the MAO-A isoform. The need to clarify at a 3D level some important molecular aspects of discussed SAR, we undertaked a number of docking simulations to better assess. The steric effect was analyzed interms of both posing and scoring by investigating the nature of the binding interactions. The docking results of active compound 5k with hMAO-B complex indicated that conserved residue ILE 199 was important for ligand binding via Sigma-Pi interaction.

Cardiac lipidomic profiles in mice undergo changes from fetus to adult.

AIMS: Lipids are essential cellular components with many important biological functions. Disturbed lipid biosynthesis and metabolism has been shown to cause cardiac developmental abnormality and cardiovascular diseases. In this study, we aimed to investigate the composition and the molecular profiles of lipids in mammalian hearts between embryonic and adult stages and uncover the underlying links between lipid and cardiac development and maturation. MATERIALS AND METHODS: We collected mouse hearts at the embryonic day 11.5 (E11.5), E15.5, and the age of 2 months, 4 months and 10 months, and performed lipidomic analysis to determine the changes of the composition, molecular species, and relative abundance of cardiac lipids between embryonic and adult stages. Additionally, we also performed the electronic microscopy and RNA sequencing in both embryonic and adult mouse hearts. KEY FINDINGS: The relative abundances of certain phospholipids and sphingolipids including cardiolipin, phosphatidylglycerol, phosphatidylethanolamine, and ceramide, are different between embryonic and adult hearts. Such lipidomic changes are accompanied with increased densities of mitochondrial membranes and elevated expression of genes related to mitochondrial formation in adult mouse hearts. We also analyzed individual molecular species of phospholipids and sphingolipids, and revealed that the composition and distribution of lipid molecular species in hearts also change with development. SIGNIFICANCE: Our study provides not only a lipidomic view of mammalian hearts when developing from the embryonic to the adult stage, but also a potential pool of lipid indicators for cardiac cell development and maturation.

The first chromosome-level genome assembly of Entomobrya proxima Folsom, 1924 (Collembola: Entomobryidae).

The Entomobryoidea, the largest superfamily of Collembola, encompasses over 2,000 species in the world. However, the lack of high-quality genomes hinders our understanding of the evolution and ecology of this group. This study presents a chromosome-level genome of Entomobrya proxima by combining PacBio long reads, Illumina short reads, and Hi-C data. The genome has a size of 362.37 Mb, with a scaffold N50 size of 57.67 Mb, and 97.12% (351.95 Mb) of the assembly is located on six chromosomes. The BUSCO analysis of our assembly indicates a completeness of 96.1% (n = 1,013), including 946 (93.4%) single-copy BUSCOs and 27 (2.7%) duplicated BUSCOs. We identified that the genome contains 22.16% (80.06 Mb) repeat elements and 20,988 predicted protein-coding genes. Gene family evolution analysis of E. proxima identified 177 gene families that underwent significant expansions, which were primarily associated with detoxification and metabolism. Moreover, our inter-genomic synteny analysis showed strong chromosomal synteny between E. proxima and Sinella curviseta. Our study provides valuable genomic information for comprehending the evolution and ecology of Collembola.

Chromosome-Level Genome Assembly of Papilio elwesi Leech, 1889 (Lepidoptera: Papilionidae).

A rarely seen butterfly species, the large swallowtail butterfly Papilio elwesi Leech, 1889 (Lepidoptera: Papilionidae), endemic to the Chinese mainland, has been declared a state-protected animal in China since 2000, but its genome is not yet available. To obtain high-quality genome assembly and annotation, we sequenced the genome and transcriptome of P. elwesi using the PacBio and PromethION platforms, respectively. The final assembled genome was 358.51 Mb, of which 97.59% was anchored to chromosomes (30 autosomes and 1 Z sex chromosome), with a contig/scaffold N50 length of 6.79/12.32 Mb and 99.0% (n = 1367) BUSCO completeness. The genome annotation pointed to 36.82% (131.99 Mb) repetitive elements and 1296 non-coding RNAs in the genome, along with 13,681 protein-coding genes that cover 98.6% (1348) of the BUSCO genes. Among the 11,499 identified gene families, 104 underwent significantly rapid expansions or contractions, and these rapidly expanding families play roles in detoxification and metabolism. Additionally, strong synteny exists between the chromosomes of P. elwesi and P. machaon. The chromosome-level genome of P. elwesi could serve as an important genomic resource for furthering our understanding of butterfly evolution and for more in-depth genomic analyses.

Milk fat globule membrane promotes brain development in piglets by enhancing the connection of white matter fiber trace.

Introduction: Brain development during infancy is crucial for later health and development. Although Milk Fat Globule Membrane (MFGM) has been demonstrated to enhance brain development, further investigation is needed to determine the optimal dose. Methods: In this study, 80 piglets aged 2 days were randomly assigned to four groups: Control group, MFGM-L (1.74 g MFGM per 100 g diet), MFGM-M (4.64 g MFGM per 100 g diet), and MFGM-H (6.09 g MFGM per 100 g diet). Daily body weight and milk intake of the piglets were recorded until 31 days postnatal. Learning and memory abilities were evaluated using the spatial T-maze test on day 15. MRI analysis was conducted to assess functional and structural changes in brain tissues. Additionally, mRNA and protein expression of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NTF-3) in the hippocampus and prefrontal cortex were evaluated. Results: The results indicated that the MFGM supplemented diet significantly improved the accuracy of the piglets in the T-maze test, with the MFGM-L group exhibiting the best performance. MRI showed no volumetric differences in the gray and white matter between the groups. However, the fractional anisotropy in the left and right hippocampus of piglets in the MFGM-L group was significantly higher than in the other three groups. Furthermore, there was a strong correlation between the accuracy of the T-maze test and hippocampal fractional anisotropy. Discussion: The MFGM supplemented diet also increased the expression of BDNF in the cerebral cortex. However, the changes in BDNF were not consistent with the results of the T-maze test. In conclusion, adding 1.74 g MFGM per 100 g diet can significantly improve neonatal piglets' learning and memory abilities, potentially by enhancing the connection of white matter fiber bundles in the brain.

Chromosomal-Level Genome Assembly of the Springtail Tomocerus qinae (Collembola: Tomoceridae).

The family Tomoceridae is among the earliest derived collembolan lineages, thus is of key importance in understanding the evolution of Collembola. Here, we assembled a chromosome-level genome of one tomocerid species Tomocerus qinae by combining Nanopore long reads and Hi-C data. The final genome size was 334.44 Mb with the scaffold/contig N50 length of 71.85/13.94 Mb. BUSCO assessment indicated that 96.80% of complete arthropod universal single-copy orthologs (n = 1,013) were present in the assembly. The repeat elements accounted for 26.11% (87.26 Mb) and 494 noncoding RNAs were identified in the genome. A total of 20,451 protein-coding genes were predicted, which captured 96.0% (973) BUSCO genes. Gene family evolution analyses identified 4,825 expanded gene families of T. qinae, among them, 47 experienced significant expansions, and these significantly expanded gene families mainly involved in proliferation and growth. This study provides an important genomic resource for future evolution and comparative genomics analyses of Collembola.

First and second instar larvae and adults of a new Homidia species (Collembola, Entomobryidae) recorded from Xizang Autonomous Region with three new records.

Three new recorded species of genus Homidia were collected from Xizang Autonomous Region, China, in the present paper. Among them, a new species, Homidiabreviseta Pan, sp. nov., is included in the present paper. This new species can be identified by having a single uninterrupted dark band on central thoracic segment III; 14 macrochaetae on abdominal segment I and seven on the posterior central abdominal segment IV (half segment); and very short bothriotricha on abdominal segments II-IV. It can be easily discriminated from similar species of Homidia by its colour pattern, chaetotaxy of the labium, and abdominal segments I and IV. The chaetotaxy of the first and second instar larvae of this new species and a key to four species of genus Homidia from Xizang are also provided.

Chronic cerebral hypoperfusion and blood-brain barrier disruption in uninjured brain areas of rhesus monkeys subjected to transient ischemic stroke.

Blood-brain barrier (BBB) disruption is a pivotal pathophysiological process in ischemic stroke. Although temporal changes in BBB permeability during the acute phase have been widely studied, little is known about the chronic phase of cerebrovascular changes that may have a large impact on the long-term outcome. Therefore, this study was aimed to measure cerebral vascular abnormalities using CT perfusion in nine rhesus monkeys subjected to transient middle cerebral artery occlusion (tMCAO) for ≥1 year (MCAO-1Y+). The level of cerebral perfusion demonstrated by mean transit time was significantly higher in the ipsilateral caudate nucleus, white matter, thalamus, hippocampus, and contralateral thalamus in MCAO-1Y+ compared with the other nine age-matched control monkeys. The increase in BBB permeability measured through the permeability surface was found in the same ten regions of interest ipsilaterally and contralaterally. We also found decreased levels of Aß 42/40 ratio in the cerebrospinal fluid (CSF), suggesting a potential link between post-MCAO cognitive decline and Aß metabolism. Overall, we demonstrated significant cerebral hypoperfusion, BBB disruption, and CSF Aß decrease during the rehabilitation stage of ischemic stroke in a non-human primate model. Future studies are needed to elucidate the cause-effect relationship between cerebrovascular disruptions and long-term neurological deficits.