Andrew H. Hunter, Nicholas Smith, Paulo R. P. Santiago
et al.
Background/Objectives: Passing is the most frequent and impactful action in soccer. It requires players to control the ball and pass accurately with either foot, make quick decisions, and scan the field while under pressure. Using a recently developed series of passing tests that vary in complexity and scanning demands, we examined how a player’s choice of technique when controlling and passing the ball, along with their ability to scan effectively, influenced passing performance. Methods: Forty-five elite U12 and U13 players from a Brazilian academy completed three passing tests involving directional turns across 120°, 180°, and 360°. Each pass was video-coded based on foot orientation (back or front foot), foot dominance (dominant or nondominant), and pass direction (toward the dominant or nondominant side). The study tested whether (i) the most common technique used varied with pass direction due to a preference for the dominant foot, (ii) performance varied across foot techniques, and (iii) scanning prior to ball reception enhanced outcomes. Results: Players preferred techniques that used their dominant foot, such as controlling and passing with their back foot (back–back) when turning to the dominant side (58% in 120° and 57% in 180° tests) and controlling with their back foot and passing with the front (back–front) for the nondominant side (66% and 55%; χ<sup>2</sup> = 292.96 and 312.87, <i>p</i> < 0.001). However, using the dominant foot sometimes led to slower, less efficient actions. In the 120° test, back–front was the fastest technique (+1.11 passes/min vs. back–back), while front–back was the slowest (−4.20 passes/min, <i>p</i> < 0.001). In the 360° test, scanning improved turn accuracy (from 51% to 73%) and performance, resulting in 4.20 more passes/min, fewer control errors (11% vs. 31%), and fewer target misses (3% vs. 10%; all <i>p</i> < 0.001). Conclusions: These findings highlight the value of effective scanning and foot technique under varied conditions, and offers coaches a practical tool for player analysis, feedback, and development.
Aki Fujii-Hanamoto, Hirokazu Tanaka, Ko Fujimoto
et al.
<b>Background</b>: FLT3 mutations, including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) point mutations, represent common genetic alterations in acute myeloid leukemia (AML), with FLT3-ITD associated with poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs), such as quizartinib (Quiz) and gilteritinib, have improved clinical outcomes, secondary TKD mutations, particularly the gatekeeper mutation F691L, confer significant resistance. We previously demonstrated that chlorpromazine (CPZ), an antipsychotic drug, inhibits clathrin-mediated endocytosis and selectively suppresses the growth of cancer cells harboring mutant receptor tyrosine kinases. <b>Methods</b>: In this study, we examined the efficacy of CPZ in overcoming TKI resistance using Ba/F3 cells expressing FLT3-ITD or FLT3-ITD/F692L, the murine analog of F691L. <b>Results</b>: Quiz inhibited proliferation of FLT3-ITD cells but was ineffective against FLT3-ITD/F692L cells. CPZ suppressed growth in both cell types. Co-treatment with CPZ and Quiz exhibited synergistic effects in FLT3-ITD cells, but not in FLT3-ITD/F692L cells. CPZ reduced STAT5 phosphorylation and modulated downstream signaling in FLT3-ITD cells, while only partially affecting STAT5 in FLT3-ITD/F692L cells. Expression of constitutively active STAT5 partially rescued CPZ-induced growth inhibition. <b>Conclusions</b>: These findings suggest that STAT5 suppression is a key mechanism of CPZ’s antileukemic activity and support its potential as a therapeutic strategy for FLT3-ITD-positive AML.
Berent Aldikacti, Hidayet Putun, Vishal Sarsani
et al.
Protein quality control (PQC) systems are essential for cellular resilience to proteotoxic stress. Despite intensive study for decades, functional redundancies in the system obscure the contributions of the collectively important individual genes. Here, we leverage transposon sequencing across bacteria strains lacking key chaperones and proteases to reveal hidden determinants of stress response in protein homeostasis. By profiling fitness under multiple proteotoxic stresses, we uncover stress-specific vulnerabilities and reveal how major players of PQC mask correlations between transcriptomic responses and gene fitness. As an illustration of unexpected connections, we identify a heat-specific synthetic lethality between the disaggregase ClpB and DNA Polymerase I (PolA) mediated by persistent aggregation of the RecA recombinase and toxic persistence of the heat shock regulon. Our findings reveal that stress-induced aggregation is not broadly toxic. Rather, it becomes lethal in specific genetic or environmental contexts due to the depletion of components only needed in those specific circumstances. This work presents a framework to reveal normally hidden fragility in stress responses using gene fitness scores adaptable to a variety of systems.
Adam J. Carlton, Jing-Yi Jeng, Fiorella C. Grandi
et al.
Summary: Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming synapses with inner hair cells (IHCs) in the mammalian cochlea. The molecular mechanisms regulating the formation of the post-synaptic density (PSD) in the SGN afferent terminals are still unclear. Here, we demonstrate that brain-specific angiogenesis inhibitor 1 (BAI1) is required for the clustering of AMPA receptors GluR2–4 (glutamate receptors 2–4) at the PSD. Adult Bai1-deficient mice have functional IHCs but fail to transmit information to the SGNs, leading to highly raised hearing thresholds. Despite the almost complete absence of AMPA receptor subunits, the SGN fibers innervating the IHCs do not degenerate. Furthermore, we show that AMPA receptors are still expressed in the cochlea of Bai1-deficient mice, highlighting a role for BAI1 in trafficking or anchoring GluR2–4 to the PSDs. These findings identify molecular and functional mechanisms required for sound encoding at cochlear ribbon synapses.
Petros Skiadas, Sofía Riera Vidal, Joris Dommisse
et al.
Plant pathogens adapt at speeds that challenge contemporary disease management strategies like the deployment of disease resistance genes. The strong evolutionary pressure to adapt, shapes pathogens' genomes, and comparative genomics has been instrumental in characterizing this process. With the aim to capture genomic variation at high resolution and study the processes contributing to adaptation, we here leverage an innovative, multi-genome method to construct and annotate the first pangenome graph of an oomycete plant pathogen. We expand on this approach by analysing the graph and creating synteny based single-copy orthogroups for all genes. We generated telomere-to-telomere genome assemblies of six genetically diverse isolates of the oomycete pathogen Peronospora effusa, the economically most important disease in cultivated spinach worldwide. The pangenome graph demonstrates that P. effusa genomes are highly conserved, both in chromosomal structure and gene content, and revealed the continued activity of transposable elements which are directly responsible for 80% of the observed variation between the isolates. While most genes are generally conserved, virulence related genes are highly variable between the isolates. Most of the variation is found in large gene clusters resulting from extensive copy-number expansion. Pangenome graph-based discovery can thus be effectively used to capture genomic variation at exceptional resolution, thereby providing a framework to study the biology and evolution of plant pathogens.
María J. Esteban-Amo, Patricia Jiménez-Cuadrado, Pablo Serrano-Lorenzo
et al.
Succinate dehydrogenase (also known as complex II) plays a dual role in respiration by catalyzing the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle and transferring electrons from succinate to ubiquinone in the mitochondrial electron transport chain (ETC). Owing to the privileged position of SDH/CII, its dysfunction leads to TCA cycle arrest and altered respiration. This review aims to elucidate the widely documented profound metabolic effects of SDH/CII deficiency, along with the newly unveiled survival mechanisms in SDH/CII-deficient cells. Such an understanding reveals exploitable vulnerabilities for strategic targeting, which is crucial for the development of novel and more precise therapies for primary mitochondrial diseases, as well as for familial and sporadic cancers associated with SDH/CII mutations.
Urban remnant mountains (URMs) are precious natural green habitat patches that can provide a series of ecosystem services for multi-mountainous cities. The increase in ecological sensitivity and degradation of ecosystem services affected by urban expansion and climate change have led to an increasing vulnerability of urban remnant mountain ecosystems (URMEs). To explore the vulnerability of URMEs, taking the central urban built-up area of the Guiyang city as the study area and URMs as the research object, the vulnerability of URMEs under natural factors and human disturbance was analyzed based on the Pressure-State-Response (PSR) model. The results showed that: (1) Karst rocky desertification, human disturbance, and road density within the buffer zones around URMs were the most important factors affecting the vulnerability of URMEs. Karst rocky desertification was the most likely eco-environmental problem of URMs, and carbon storage was the most important ecosystem service of URMEs. (2) Characteristics of fragile karst habitats in URMs and unreasonable human activities led to high ecological vulnerability, mainly with moderate and severe vulnerability predominating, and the low vulnerability of URMEs when they had moderate park utilization. (3) The ecological vulnerability of small URMs and those distributed in the urban center is higher, and the invulnerable URMEs and the slightly vulnerable URMEs are mainly distributed in the urban edge. The results of this study could provide references for ecological restoration and protection of URMs, and offer a basis for improving the resilience of multi-mountainous cities.
Abstract Background Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of beta cells in pancreatic islets. Identification of the key genes involved in T1D progression and their mechanisms of action may contribute to a better understanding of T1D. Methods The microarray profile of T1D-related gene expression was searched using the Gene Expression Omnibus (GEO) database. Then, the expression data of two messenger RNAs (mRNAs) were integrated for Weighted Gene Co-Expression Network Analysis (WGCNA) to generate candidate genes related to T1D. In parallel, T1D microRNA (miRNA) data were analyzed to screen for possible regulatory miRNAs and their target genes. An miRNA–mRNA regulatory network was then established to predict the key regulatory genes and their mechanisms. Results A total of 24 modules (i.e., clusters/communities) were selected using WGCNA analysis, in which three modules were significantly associated with T1D. Further correlation analysis of the gene module revealed 926 differentially expressed genes (DEGs), of which 327 genes were correlated with T1D. Analysis of the miRNA microarray showed that 13 miRNAs had significant expression differences in T1D. An miRNA–mRNA network was established based on the prediction of miRNA target genes and the combined analysis of mRNA, in which the target genes of two miRNAs were found in T1D correlated genes. Conclusion An miRNA–mRNA network for T1D was established, based on which 2 miRNAs and 12 mRNAs were screened, suggesting that they may play key regulatory roles in the initiation and development of T1D.
Immumomodulatory actions of natural ingredients have been recognized from the time of early civilization. Though herbal medicines are equally used to treat deadly diseases, but till date there are lacks of evidences. In the present work, an herbal preparation IMT-03 was used to find out its immunostimulatory efficacy against chemotherapeutics. Although, most of the individual ingredients present in IMT-03 have been reported for their protective roles against chemotherapeutics, but there is no report in combination. Cyclophosphamide (300 mg/kg, intraperitoneally) induces immunosuppression through myelosuppression. Pretreatment with of IMT-03 at dose of 100 mg/kg and 200 mg/kg in Cyclophosphamide induced immunosuppressive mice showed dose dependently and significantly (p<0.001) improvement in total WBC and absolute neutrophil counts. It also protects the general health of animals from chemotherapeutic induced serious adverse events like signs of sickness, lethargy, immobility, reducing food habit, infections in nostrils and pinna etc. Moreover, IMT-03 has the abilities to counter the macrophages surge during the LPS challenge. The test drug also showed safe up to the oral dose of 2 g/kg. In vitro studies revealed IMT-03 has polyphenols and also radical scavenging actions. There are several evidences that polyphenols can able to modulate cytokines and chemokines signaling pathways in immune cells. Therefore, it is assumed that polyphenols present in IMT-03 either modulate the inflammatory signaling pathways or protect from oxidative stress related DNA damage in myeloid tissues.
Pauline van Schouwenburg, Pauline van Schouwenburg, Susanne Unger
et al.
Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes, and poor antigen-specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is regularly associated with a severe decrease of germinal center (GC)-derived B-cell populations in peripheral blood. However, data from B-cell differentiation within GC is limited. We present a multiplex approach combining histology, flow cytometry, and B-cell receptor repertoire analysis of sorted GC B-cell populations allowing the modeling of distinct disturbances in GCs of three CVID patients. Our results reflect pathophysiological heterogeneity underlying the reduced circulating pool of post-GC memory B cells and plasmablasts in the three patients. In patient 1, quantitative and qualitative B-cell development in GCs is relatively normal. In patient 2, irregularly shaped GCs are associated with reduced somatic hypermutation (SHM), antigen selection, and class-switching, while in patient 3, high SHM, impaired antigen selection, and class-switching with large single clones imply increased re-cycling of cells within the irregularly shaped GCs. In the lymph nodes of patients 2 and 3, only limited numbers of memory B cells and plasma cells are formed. While reduced numbers of circulating post GC B cells are a general phenomenon in CVID, the integrated approach exemplified distinct defects during GC maturation ranging from near normal morphology and function to severe disturbances with different facets of impaired maturation of memory B cells and/or plasma cells. Integrated dissection of disturbed GC B-cell maturation by histology, flow cytometry, and BCR repertoire analysis contributes to unraveling defects in the essential steps during memory formation.
Every year more interest is focused on high frequencies (HF) communications for remote sensing platforms due to their capacity to establish links of more than 250 km without a line of sight and due to them being a low-cost alternative to satellite communications. In this article, we study the ionospheric ordinary and extraordinary waves to improve the applications of near vertical incidence skywave (NVIS) on a single input multiple output (SIMO) configuration. To obtain the results, we established a link of 95 km to test the diversity combining of ordinary and extraordinary waves by using selection combining (SC) and equal-gain combining (EGC) on a remote sensing platform. The testbench is based on digital modulation transmissions with power transmission between 3 and 100 W. The results show us the main energy per bit to noise spectral density ratio (E<sub>b</sub>/N<sub>0</sub>) and the bit error rate (BER) differences between ordinary and extraordinary waves, SC, and EGC. To conclude, diversity techniques show us a decrease of the power transmission need, allowing for the use of compact antennas and increasing battery autonomy. Furthermore, we present three different improvement options for NVIS SIMO remote sensing platforms depending on the requirements of bitrate, power consumption, and efficiency of communication.
Chien Thang Doan, Thi Ngoc Tran, Van Bon Nguyen
et al.
Chitosanase has attracted great attention due to its potential applications in medicine, agriculture, and nutraceuticals. In this study, <i>P. mucilaginosus</i> TKU032, a bacterial strain isolated from Taiwanese soil, exhibited the highest chitosanase activity (0.53 U/mL) on medium containing shrimp heads as the sole carbon and nitrogen (C/N) source. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, a chitosanase isolated from <i>P. mucilaginosus</i> TKU032 cultured on shrimp head medium was determined at approximately 59 kDa. The characterized chitosanase showed interesting properties with optimal temperature and thermal stability up to 70 °C. Three chitosan oligosaccharide (COS) fractions were isolated from hydrolyzed colloidal chitosan that was catalyzed by TKU032 chitosanase. Of these, fraction I showed the highest α-glucosidase inhibitor (aGI) activity (65.86% at 20 mg/mL); its inhibitory mechanism followed the mixed noncompetitive inhibition model. Fractions II and III exhibited strong 2,2-diphenyl1-picrylhydrazyl (DPPH) radical scavenging activity (79.00% at 12 mg/mL and 73.29% at 16 mg/mL, respectively). In summary, the COS fractions obtained by hydrolyzing colloidal chitosan with TKU032 chitosanase may have potential use in medical or nutraceutical fields due to their aGI and antioxidant activities.
Hussein Sabit, Shaimaa Nazir, Shimaa Abdel-Ghany
et al.
Being the most common cause of female deaths worldwide, breast cancer (BC) is intensively studied over the last two decades. In the present investigation, we evaluated the promoter methylation of three cancer-related genes; PARP-1, p21, and Rb in 10 bi-matched BC samples (ductal carcinoma and lobular carcinoma) included the core tumor and the adjacent normal tissue. H&E-stained histopathological sectioning revealed grade 2 and grade 3 tumor cells. Methylation-specific PCR (MSP) was performed using methylated (M) and unmethylated (U) primers for the three genes understudy. Histone acetyltransferase was measured in tumor and healthy tissues. A variation in the methylation state of the promoter region of the three genes were observed in core tumor and healthy tissue. PARP and Rb were hypermethylated in tumor tissues while p21 was partially methylated. HAT activities were positively correlated with the methylation pattern observed in healthy tissues, as HAT was highly expressed in healthy vs. tumor tissues. The obtained data might indicate that patients might be at risk of BC recurrence after being subjected to mastectomy. These data could be employed as a core in epigenetic-based data mining to establish a model for predicting the breast cancer-predisposed patients. However, further investigations are needed to fulfill this goal.
Nicole Nasby-Lucas, Heidi Dewar, Oscar Sosa-Nishizaki
et al.
Abstract Background Most information on shortfin makos (Isurus oxyrinchus) in the eastern North Pacific (ENP) currently comes from fisheries data and short-term tracking studies. Although range has been inferred from catch and conventional tag data, little is known about the migration patterns and behavior in the ENP. This long-term electronic tagging study was designed to examine in detail the movement patterns and behavior of mako sharks in the ENP. Results In this study, a total of 105 mako sharks (104–280 cm fork length) were successfully tagged in the California Current between 2002 and 2014 with Argos satellite tags, including 93 satellite-linked radio-transmitting (SLRT) tags and 71 pop-up satellite archival tags (PSATs). This included 29 males that are in the size range of maturity, but only one mature female. Mean track durations from SLRT data were 337 days (max 1025), and PSAT tags were 136 days (max 272). Estimated minimum distance traveled in 1 year ranged from 6945 to 18,800 km/year. Habitats utilized included the entire California Current, the Sea of Cortez and offshore in the areas of the North Pacific Subtropical Gyre, North Pacific Transition Zone and North Equatorial Current. Seasonal movements within the California Current coincided with periods of higher primary productivity and chlorophyll a, and sea surface temperatures (SSTs) between 15 and 25 °C. SST ranged from 11 to 31 °C throughout the range, indicating a broad thermal tolerance. Conclusions Some of the key findings include the discovery of a high degree of variability between individuals in their vertical and horizontal movements, a strong influence of body size and season on mako shark movements, and the repetitive use of certain areas by individuals. These results expand our understanding of the distribution of mako sharks in the ENP. Although mako sharks are thought to comprise a single stock throughout the North Pacific, horizontal distribution of tagged mako sharks in this study was limited to the ENP demonstrating some spatial substructure. This study provides important data that can be used to identify fishery and gear vulnerabilities and inform management.
Behnaz Moradi, Ahmad-Reza Tahmasebpour, Mohamad Ali Kazemi
et al.
Arteriovenous malformations (AVMs) are rarely reported antenatally. Most in utero diagnosis of vascular malformation is related to vein of Galen malformation (VGM). We describe a case of simultaneously diagnosed pial arteriovenous fistula (AVF) and facial vascular malformation in a 20 weeks old fetus. The dilated intracranial venous pouch appeared as a midline anechoic structure which was misdiagnosed as a VGM in her previous ultrasound exam. Another AVM was diagnosed in the same side of fetal face which fed by a branch of external carotid artery and communicated with the mentioned pial AVF. High output cardiac failure and hydrops were evident. To our knowledge this is the first report of prenatally detected combination of facial and cerebral vascular malformations at such as early pregnancy week.