Miracle-dz/UniFAR-FTUs huggingface dataset:
Genome-Scale Metabolic Modelling of Lifestyle Changes in Rhizobium leguminosarum

Rhizobia are soil bacteria that induce nodule formation on plant roots and differentiate into nitrogen-fixing bacteroids. A detailed understanding of this complex symbiosis is essential for advancing ongoing efforts to engineer novel symbioses with cereal crops for sustainable agriculture. ABSTRACT Biological nitrogen fixation in rhizobium-legume symbioses is of major importance for sustainable agricultural practices. To establish a mutualistic relationship with their plant host, rhizobia transition from free-living bacteria in soil to growth down infection threads inside plant roots and finally differentiate into nitrogen-fixing bacteroids. We reconstructed a genome-scale metabolic model for Rhizobium leguminosarum and integrated the model with transcriptome, proteome, metabolome, and gene essentiality data to investigate nutrient uptake and metabolic fluxes characteristic of these different lifestyles. Synthesis of leucine, polyphosphate, and AICAR is predicted to be important in the rhizosphere, while myo-inositol catabolism is active in undifferentiated nodule bacteria in agreement with experimental evidence. The model indicates that bacteroids utilize xylose and glycolate in addition to dicarboxylates, which could explain previously described gene expression patterns. Histidine is predicted to be actively synthesized in bacteroids, consistent with transcriptome and proteome data for several rhizobial species. These results provide the basis for targeted experimental investigation of metabolic processes specific to the different stages of the rhizobium-legume symbioses. IMPORTANCE Rhizobia are soil bacteria that induce nodule formation on plant roots and differentiate into nitrogen-fixing bacteroids. A detailed understanding of this complex symbiosis is essential for advancing ongoing efforts to engineer novel symbioses with cereal crops for sustainable agriculture. Here, we reconstruct and validate a genome-scale metabolic model for Rhizobium leguminosarum bv. viciae 3841. By integrating the model with various experimental data sets specific to different stages of symbiosis formation, we elucidate the metabolic characteristics of rhizosphere bacteria, undifferentiated bacteria inside root nodules, and nitrogen-fixing bacteroids. Our model predicts metabolic flux patterns for these three distinct lifestyles, thus providing a framework for the interpretation of genome-scale experimental data sets and identifying targets for future experimental studies.
Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids

Significance Although the circadian clock is essential for regulating the temporal order of physiological functions, circadian oscillation is strictly suppressed in the early-to-mid–stage embryos in mammalian developmental process. The biological significance controlling the suppression of the circadian clock and its delayed emergence in mammalian embryos has been unknown. Here, we show that the premature expression of the functional circadian components CLOCK/BMAL1 in mouse induced presomitic mesoderm and gastruloids can interfere with the segmentation clock Hes7 oscillation and somitogenesis through the Hes7 transcription and its regulatory pathways. This suggests that the CLOCK/BMAL1 function may need to be suppressed during somitogenesis. In mammals, circadian clocks are strictly suppressed during early embryonic stages, as well as in pluripotent stem cells, by the lack of CLOCK/BMAL1-mediated circadian feedback loops. During ontogenesis, the innate circadian clocks emerge gradually at a late developmental stage, and with these, the circadian temporal order is invested in each cell level throughout a body. Meanwhile, in the early developmental stage, a segmented body plan is essential for an intact developmental process, and somitogenesis is controlled by another cell-autonomous oscillator, the segmentation clock, in the posterior presomitic mesoderm (PSM). In the present study, focusing upon the interaction between circadian key components and the segmentation clock, we investigated the effect of the CLOCK/BMAL1 on the segmentation clock Hes7 oscillation, revealing that the expression of functional CLOCK/BMAL1 severely interferes with the ultradian rhythm of segmentation clock in induced PSM and gastruloids. RNA sequencing analysis implied that the premature expression of CLOCK/BMAL1 affects the Hes7 transcription and its regulatory pathways. These results suggest that the suppression of CLOCK/BMAL1-mediated transcriptional regulation during the somitogenesis may be inevitable for intact mammalian development.
Age- and Gender-Specific Prevalence of Frailty and Its Outcomes in the Longevous Population: The Chinese Longitudinal Healthy Longevity Study

Background: Frailty is an epidemic age-related syndrome addressing heavy burden to the healthcare system. Subject to the rarity, age-, and gender-specific prevalence of frailty and its prognosis among the longevous population remains under-investigated. Methods: Based on the Chinese Longitudinal Healthy Longevity Study (CLHLS, 2008–2018), individuals aged ≥ 65 years having complete data of frailty were recruited. Modified Fried criteria (exhaustion, shrink, weakness, low mobility, and inactivity) were adopted to define pre-frailty (1–2 domains) and frailty (≥3 domains), respectively. The association between pre-frailty/frailty and adverse outcomes (frequent hospitalization, limited physical performance, cognitive decline, multimorbidity, and dependence) was analyzed using logistic regression models. The association between pre-frailty/frailty and mortality was analyzed using Cox proportional hazards models. Age- and gender-stratified analyses were performed. Results: Totally, 13,859 participants aged 85.8 ± 11.1 years, including 2,056 centenarians, were recruited. The overall prevalence of pre-frailty and frailty were 54.1 and 26.3%, respectively. Only 5.0% of centenarians were non-frailty whereas 59.9% of the young-old (65–79 years) showed pre-frailty. Both pre-frailty and frailty were associated with the increased risk of multiple adverse outcomes, such as incident limited physical performance, cognitive decline and dependence, respectively (P < 0.05). Frail males were more vulnerable to the risk of mortality (hazard ratio [HR] = 2.3, 95% confidence interval [CI], 2.1–2.6) compared with frail females (HR = 1.9, 95%CI, 1.7–2.1). The strongest association between frailty and mortality was observed among the young-old (HR = 3.6, 95%CI, 2.8–4.5). Exhaustion was the most common domain among patients with pre-frailty (74.8%) or frailty (83.2%), followed by shrink (32.3%) in pre-frailty and low mobility (83.0%) in frailty. Inactivity among females aged 65–79 years showed the strongest association with the risk of mortality (HR = 3.50, 95%CI, 2.52–4.87). Conclusion: A huge gap exists between longer life and healthy aging in China. According to the age- and gender-specific prevalence and prognosis of frailty, the strategy of frailty prevention and intervention should be further individualized.
Sleep Time Estimated by an Actigraphy Watch Correlates With CSF Tau in Cognitively Unimpaired Elders: The Modulatory Role of APOE

There is increasing evidence of the relationship between sleep and neurodegeneration, but this knowledge is not incorporated into clinical practice yet. We aimed to test whether a basic sleep parameter, as total sleep estimated by actigraphy for 1 week, was a valid predictor of CSF Alzheimer’s Disease core biomarkers (amyloid-β-42 and –40, phosphorylated-tau-181, and total-tau) in elderly individuals, considering possible confounders and effect modifiers, particularly the APOE ε4 allele. One hundred and twenty-seven cognitively unimpaired volunteers enrolled in the Valdecilla Study for Memory and Brain Aging participated in this study. Seventy percent of the participants were women with a mean age of 65.5 years. After adjustment for covariates, reduced sleep time significantly predicted higher t-tau and p-tau. This association was mainly due to the APOE ε4 carriers. Our findings suggest that total sleep time, estimated by an actigraphy watch, is an early biomarker of tau pathology and that APOE modulates this relationship. The main limitation of this study is the limited validation of the actigraphy technology used. Sleep monitoring with wearables may be a useful and inexpensive screening test to detect early neurodegenerative changes.
The Role of Epidermal Growth Factor Receptor Family of Receptor Tyrosine Kinases in Mediating Diabetes-Induced Cardiovascular Complications

Diabetes mellitus is a major debilitating disease whose global incidence is progressively increasing with currently over 463 million adult sufferers and this figure will likely reach over 700 million by the year 2045. It is the complications of diabetes such as cardiovascular, renal, neuronal and ocular dysfunction that lead to increased patient morbidity and mortality. Of these, cardiovascular complications that can result in stroke and cardiomyopathies are 2- to 5-fold more likely in diabetes but the underlying mechanisms involved in their development are not fully understood. Emerging research suggests that members of the Epidermal Growth Factor Receptor (EGFR/ErbB/HER) family of tyrosine kinases can have a dual role in that they are beneficially required for normal development and physiological functioning of the cardiovascular system (CVS) as well as in salvage pathways following acute cardiac ischemia/reperfusion injury but their chronic dysregulation may also be intricately involved in mediating diabetes-induced cardiovascular pathologies. Here we review the evidence for EGFR/ErbB/HER receptors in mediating these dual roles in the CVS and also discuss their potential interplay with the Renin-Angiotensin-Aldosterone System heptapeptide, Angiotensin-(1-7), as well the arachidonic acid metabolite, 20-HETE (20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid). A greater understanding of the multi-faceted roles of EGFR/ErbB/HER family of tyrosine kinases and their interplay with other key modulators of cardiovascular function could facilitate the development of novel therapeutic strategies for treating diabetes-induced cardiovascular complications.
Thriving Through Relationships in Sport: The Role of the Parent–Athlete and Coach–Athlete Attachment Relationship

The aim of this research was to examine whether attachment relationships to significant others, such as to parents and/or sports coaches, enable thriving and competition performance within sport. Two studies employing cross-sectional and prospective designs were carried out across different samples of athletes of varied skill levels and sports. In Study 1, we found athletes’ attachment to their sports coach was significantly associated with athlete thriving and mediated by psychological needs satisfaction. Results of Study 2 found that athletes’ secure attachment to their mother and/or father positively predicted the experience of thriving at the competition while athletes’ insecure attachment did not predict thriving. Furthermore, athletes’ attachment to both mother and father did not predict competition performance. Together, these two studies acknowledge the significant role that athletes’ secure attachment relationships with parents and coaches play in facilitating thriving in athletes. These findings have significant implications for research and practice.
Morpho-Phonetic Effects in Speech Production: Modeling the Acoustic Duration of English Derived Words With Linear Discriminative Learning

Recent evidence for the influence of morphological structure on the phonetic output goes unexplained by established models of speech production and by theories of the morphology-phonology interaction. Linear discriminative learning (LDL) is a recent computational approach in which such effects can be expected. We predict the acoustic duration of 4,530 English derivative tokens with the morphological functions DIS, NESS, LESS, ATION, and IZE in natural speech data by using predictors derived from a linear discriminative learning network. We find that the network is accurate in learning speech production and comprehension, and that the measures derived from it are successful in predicting duration. For example, words are lengthened when the semantic support of the word's predicted articulatory path is stronger. Importantly, differences between morphological categories emerge naturally from the network, even when no morphological information is provided. The results imply that morphological effects on duration can be explained without postulating theoretical units like the morpheme, and they provide further evidence that LDL is a promising alternative for modeling speech production.
Photodynamic Therapy for the Treatment and Diagnosis of Cancer–A Review of the Current Clinical Status

Photodynamic therapy (PDT) has been used as an anti-tumor treatment method for a long time and photosensitizers (PS) can be used in various types of tumors. Originally, light is an effective tool that has been used in the treatment of diseases for ages. The effects of combination of specific dyes with light illumination was demonstrated at the beginning of 20th century and novel PDT approaches have been developed ever since. Main strategies of current studies are to reduce off-target effects and improve pharmacokinetic properties. Given the high interest and vast literature about the topic, approval of PDT as the first drug/device combination by the FDA should come as no surprise. PDT consists of two stages of treatment, combining light energy with a PS in order to destruct tumor cells after activation by light. In general, PDT has fewer side effects and toxicity than chemotherapy and/or radiotherapy. In addition to the purpose of treatment, several types of PSs can be used for diagnostic purposes for tumors. Such approaches are called photodynamic diagnosis (PDD). In this Review, we provide a general overview of the clinical applications of PDT in cancer, including the diagnostic and therapeutic approaches. Assessment of PDT therapeutic efficacy in the clinic will be discussed, since identifying predictors to determine the response to treatment is crucial. In addition, examples of PDT in various types of tumors will be discussed. Furthermore, combination of PDT with other therapy modalities such as chemotherapy, radiotherapy, surgery and immunotherapy will be emphasized, since such approaches seem to be promising in terms of enhancing effectiveness against tumor. The combination of PDT with other treatments may yield better results than by single treatments. Moreover, the utilization of lower doses in a combination therapy setting may cause less side effects and better results than single therapy. A better understanding of the effectiveness of PDT in a combination setting in the clinic as well as the optimization of such complex multimodal treatments may expand the clinical applications of PDT.
Iron(II) Spin Crossover Coordination Polymers Derived From a Redox Active Equatorial Tetrathiafulvalene Schiff-Base Ligand

Two polymorphic FeII coordination polymers [FeIIL (TPPE)0.5] 1) and [(FeII 3L3 (TPPE)1.5)] 2), were obtained from a redox-active tetrathiafulvalene (TTF) functionalized ligand [H2L = 2,2’-(((2-(4,5-bis-(methylthio)-1,3-dithiol-2-ylidene)benzo(d) (1,3) dithiole-5,6-diyl)bis-(azanediyl))bis-(meth anylylidene)) (2E,2E')-bis(3-oxobutanoate)] and a highly luminescent connector {TPPE = 1,1,2,2-tetrakis[4-(pyridine-4-yl)phenyl]-ethene}. Complex 1 has a layered structure where the TPPE uses its four diverging pyridines from the TPPE ligand are coordinated by the trans positions to the flat TTF Schiff-base ligand, and complex 2 has an unprecedented catenation of layers within two interpenetrated frameworks. These coordination polymers reserved the redox activity of the TTF unit. Complex 1 shows gradual spin transition behavior without hysteresis. And the fluorescence intensity of TPPE in 1 changes in tandem with the spin crossover (SCO) transition indicating a possible interplay between fluorescence and SCO behavior.
Altered Serum Immunological and Biochemical Parameters and Microbiota Composition in Patients With AN During Realimentation

Anorexia nervosa (AN) is a life-threatening psychiatric disorder with not well-described pathogenesis. Besides the genetic and sociological factors, autoimmunity is also considered to take part in AN pathogenesis. We evaluated general serological factors showing the physiological state of 59 patients with AN at hospital admission and their discharge. We detected the altered levels of some general biochemical and immunological parameters. We also detected decreased levels of appetite-regulating alpha-melanocyte stimulating hormone (α-MSH) in patients at hospital admission. Moreover, elevated anti-α-MSH IgM levels and decreased anti-α-MSH IgA levels were observed in patients with AN. Therefore, we analyzed the gut microbiota composition with special focus on α-MSH antigen-mimetic containing microbes from the Enterobacteriaceae family. We correlated gut bacterial composition with anti-α-MSH Ig levels and detected decreasing IgG levels with increasing alpha diversity. The upregulation of pro-inflammatory cytokines IL-6, IL-17, and TNF-α were detected in patients with AN both prior and after hospitalization. We also evaluated the treatment outcome and improvement was observed in the majority of patients with AN. We provide new data about various serum biochemical parameters and their changes during the patients' hospitalization, with emphasis on the immune system, and its possible participation in AN pathogenesis.
Cytospora and Diaporthe Species Associated With Hazelnut Canker and Dieback in Beijing, China

Hazelnut (Corylus heterophylla Fisch.) is an important nut crop in China but has been declining owing to the destructive effects of fungal branch canker and dieback. The identification and management of these pathogens are difficult because of the lack of attention to branch canker, insufficient understanding of phylogenetic, and overlapping morphological characteristics of the pathogens. In total, 51 strains were isolated from Chinese wild hazelnut in this study, and three species of Cytospora and two of Diaporthe were identified through morphological observation and multi-locus phylogenetic analyses (ITS, act, rpb2, tef1-α, and tub2 for Cytospora; ITS, cal, his3, tef1-α, and tub2 for Diaporthe). Three new species, Cytospora corylina, C. curvispora, and Diaporthe corylicola, and two known species, Cytospora leucostoma and Diaporthe eres, grew at 5–30°C and a pH of 3.0–11.0, with optimum growth at approximately 25°C and pH 4.0–7.0. Additionally, the effects of six carbon sources on mycelial growth were investigated. This study explored the main pathogenic fungi species of Corylus heterophylla, completed the corresponding database of pathogenic fungi information, and clarified their biological characteristics. Moreover, the results of this study provided a theoretical basis for Corylus heterophylla disease management and prevention in China.
“The First Thousand Days” Define a Fetal/Neonatal Neurology Program

Gene–environment interactions begin at conception to influence maternal/placental/fetal triads, neonates, and children with short- and long-term effects on brain development. Life-long developmental neuroplasticity more likely results during critical/sensitive periods of brain maturation over these first 1,000 days. A fetal/neonatal program (FNNP) applying this perspective better identifies trimester-specific mechanisms affecting the maternal/placental/fetal (MPF) triad, expressed as brain malformations and destructive lesions. Maladaptive MPF triad interactions impair progenitor neuronal/glial populations within transient embryonic/fetal brain structures by processes such as maternal immune activation. Destructive fetal brain lesions later in pregnancy result from ischemic placental syndromes associated with the great obstetrical syndromes. Trimester-specific MPF triad diseases may negatively impact labor and delivery outcomes. Neonatal neurocritical care addresses the symptomatic minority who express the great neonatal neurological syndromes: encephalopathy, seizures, stroke, and encephalopathy of prematurity. The asymptomatic majority present with neurologic disorders before 2 years of age without prior detection. The developmental principle of ontogenetic adaptation helps guide the diagnostic process during the first 1,000 days to identify more phenotypes using systems-biology analyses. This strategy will foster innovative interdisciplinary diagnostic/therapeutic pathways, educational curricula, and research agenda among multiple FNNP. Effective early-life diagnostic/therapeutic programs will help reduce neurologic disease burden across the lifespan and successive generations.
The Effect of Seat Back Inclination on Spinal Alignment in Automotive Seating Postures

Experimental studies have demonstrated a relationship between spinal injury severity and vertebral kinematics, influenced by the initial spinal alignment of automotive occupants. Spinal alignment has been considered one of the possible causes of gender differences in the risk of sustaining spinal injuries. To predict vertebral kinematics and investigate spinal injury mechanisms, including gender-related mechanisms, under different seat back inclinations, it is needed to investigate the effect of the seat back inclination on initial spinal alignment in automotive seating postures for both men and women. The purpose of this study was to investigate the effect of the seat back inclination on spinal alignments, comparing spinal alignments of automotive seating postures in the 20° and 25° seat back angle and standing and supine postures. The spinal columns of 11 female and 12 male volunteers in automotive seating, standing, and supine postures were scanned in an upright open magnetic resonance imaging system. Patterns of their spinal alignments were analyzed using Multidimensional Scaling presented in a distribution map. Spinal segmental angles (cervical curvature, T1 slope, total thoracic kyphosis, upper thoracic kyphosis, lower thoracic kyphosis, lumbar lordosis, and sacral slope) were also measured using the imaging data. In the maximum individual variances in spinal alignment, a relationship between the cervical and thoracic spinal alignment was found in multidimensional scaling analyses. Subjects with a more lordotic cervical spine had a pronounced kyphotic thoracic spine, whereas subjects with a straighter to kyphotic cervical spine had a less kyphotic thoracic spine. When categorizing spinal alignments into two groups based on the spinal segmental angle of cervical curvature, spinal alignments with a lordotic cervical spine showed significantly greater absolute average values of T1 slope, total thoracic kyphosis, and lower thoracic kyphosis for both the 20° and 25° seat back angles. For automotive seating postures, the gender difference in spinal alignment was almost straight cervical and less-kyphotic thoracic spine for the female subjects and lordotic cervical and more pronounced kyphotic thoracic spine for the male subjects. The most prominent influence of seatback inclination appeared in Total thoracic kyphosis, with increased angles for 25° seat back, 8.0° greater in spinal alignments with a lordotic cervical spine, 3.2° greater in spinal alignments with a kyphotic cervical spine. The difference in total thoracic kyphosis between the two seatback angles and between the seating posture with the 20° seat back angle and the standing posture was greater for spinal alignments with a lordotic cervical spine than for spinal alignments with a kyphotic cervical spine. The female subjects in this study had a tendency toward the kyphotic cervical spine. Some of the differences between average gender-specific spinal alignments may be explained by the findings observed in the differences between spinal alignments with a lordotic and kyphotic cervical spine.