Application of advanced causal analyses to identify processes governing secondary organic aerosols.

Understanding how different physical and chemical atmospheric processes affect the formation of fine particles has been a persistent challenge. Inferring causal relations between the various measured features affecting the formation of secondary organic aerosol (SOA) particles is complicated since correlations between variables do not necessarily imply causality. Here, we apply a state-of-the-art information transfer measure coupled with the Koopman operator framework to infer causal relations between isoprene epoxydiol SOA (IEPOX-SOA) and different chemistry and meteorological variables derived from detailed regional model predictions over the Amazon rainforest. IEPOX-SOA represents one of the most complex SOA formation pathways and is formed by the interactions between natural biogenic isoprene emissions and anthropogenic emissions affecting sulfate, acidity and particle water. Since the regional model captures the known relations of IEPOX-SOA with different chemistry and meteorological features, their simulated time series implicitly include their causal relations. We show that our causal model successfully infers the known major causal relations between total particle phase 2-methyl tetrols (the dominant component of IEPOX-SOA over the Amazon) and input features. We provide the first proof of concept that the application of our causal model better identifies causal relations compared to correlation and random forest analyses performed over the same dataset. Our work has tremendous implications, as our methodology of causal discovery could be used to identify unknown processes and features affecting fine particles and atmospheric chemistry in the Earth's atmosphere.

Reducing Salivary Toxicity with Adaptive Radiotherapy (ReSTART): A Randomized Controlled Trial Comparing Conventional IMRT to Adaptive IMRT in Head and Neck Squamous Cell Carcinomas.

BACKGROUND: The utility of Adaptive Radiotherapy (ART) in Head and Neck Squamous Cell Carcinoma (HNSCC) remains to be ascertained. While multiple retrospective and single-arm prospective studies have demonstrated its efficacy in decreasing parotid doses and reducing xerostomia, adequate randomized evidence is lacking. METHODS AND ANALYSIS: ReSTART (Reducing Salivary Toxicity with Adaptive Radiotherapy) is an ongoing phase III randomized trial of patients with previously untreated, locally advanced HNSCC of the oropharynx, larynx, and hypopharynx. Patients are randomized in a 1:1 ratio to the standard Intensity Modulated Radiotherapy (IMRT) arm {Planning Target Volume (PTV) margin 5 mm} vs. Adaptive Radiotherapy arm (standard IMRT with a PTV margin 3 mm, two planned adaptive planning at 10th and 20th fractions). The stratification factors include the primary site and nodal stage. The RT dose prescribed is 66Gy in 30 fractions for high-risk PTV and 54Gy in 30 fractions for low-risk PTV over six weeks, along with concurrent chemotherapy. The primary endpoint is to compare salivary toxicity between arms using salivary scintigraphy 12 months' post-radiation. To detect a 25% improvement in the primary endpoint at 12 months in the ART arm with a two-sided 5% alpha value and a power of 80% (and 10% attrition ratio), a sample size of 130 patients is required (65 patients in each arm). The secondary endpoints include acute and late toxicities, locoregional control, disease-free survival, overall survival, quality of life, and xerostomia scores between the two arms. DISCUSSION: The ReSTART trial aims to answer an important question in Radiation Therapy for HNSCC, particularly in a resource-limited setting. The uniqueness of this trial, compared to other ongoing randomized trials, includes the PTV margins and the xerostomia assessment by scintigraphy at 12 months as the primary endpoint.

Re-exploring the relationship between skull thickness and alpha asymmetry: A CT/MR imaging correlation study.

OBJECTIVE: The alpha rhythm has been a subject of research for the past few decades. Right-left alpha amplitude asymmetry is a common phenomenon. Several explanations have been proposed to explain this asymmetry, including differences in skull thickness. Our research aims to improve our understanding of the relationship between alpha asymmetry and skull thickness as measured by CT/MRI images. METHODS: We analyzed EEGs to study alpha rhythm characteristics. Alpha rhythm amplitude was measured using peak-to-peak values in O1 and O2 reference channels. Significant alpha asymmetry was defined as exceeding 20%. Skull thickness differences at corresponding locations were determined through CT/MRI scans. We examined the correlation between alpha and skull thickness asymmetry using Kruskal-Wallis, Spearman correlation, and median regression. RESULTS: We examined 401 EEGs and images, categorizing patients into three groups based on alpha asymmetry. Group 1(n= 211) had less than 20 percent alpha asymmetry, Group 2(n=107) showed higher right-side alpha amplitudes, and Group 3(n= 83) displayed higher left-side alpha amplitudes. Our analysis revealed a significant association between groups with asymmetry and skull thickness differences (p<0.001), with a Spearman correlation (Rs) of -0.25 (p<0.001), indicating a significant negative correlation. After adjusting for age, sex, and handedness, Median Regression confirmed a statistically significant variation in skull thickness difference among the groups. SIGNIFICANCE: The present study involving a large cohort, the first of its kind, demonstrated a significant relationship between alpha amplitude asymmetry and skull thickness.

Contralateral Nodal Relapse in Well-lateralised Oral Cavity Cancers Treated Uniformly with Ipsilateral Surgery and Adjuvant Radiotherapy With or Without Concurrent Chemotherapy: a Retrospective Study.

AIMS: To evaluate the incidence and pattern of contralateral nodal relapse (CLNR), contralateral nodal relapse-free survival (CLNRFS) and risk factors predicting CLNR in well-lateralised oral cavity cancers (OCC) treated with unilateral surgery and adjuvant ipsilateral radiotherapy with or without concurrent chemotherapy. MATERIALS AND METHODS: Consecutive patients of well-lateralised OCC treated between 2012 and 2017 were included. The primary endpoint was incidence of CLNR and CLNRFS. Univariable and multivariable analyses were carried out to identify potential factors predicting CLNR. RESULTS: Of the 208 eligible patients, 21 (10%) developed isolated CLNR at a median follow-up of 45 months. The incidence of CLNR was 21.3% in node-positive patients. CLNR was most common at level IB (61.9%) followed by level II. The 5-year CLNRFS and overall survival were 82.5% and 57.7%, respectively. Any positive ipsilateral lymph node (P = 0.001), two or more positive lymph nodes (P < 0.001), involvement of ipsilateral level IB (P = 0.002) or level II lymph node (P < 0.001), presence of extranodal extension (P < 0.001), lymphatic invasion (P = 0.015) and perineural invasion (P = 0.021) were significant factors for CLNR on univariable analysis. The presence of two or more positive lymph nodes (P < 0.001) was an independent prognostic factor for CLNR on multivariable analysis. CLNR increased significantly with each increasing lymph node number beyond two compared with node-negative patients. CONCLUSION: The overall incidence of isolated CLNR is low in well-lateralised OCC. Patients with two or more positive lymph nodes have a higher risk of CLNR and may be considered for elective treatment of contralateral neck.

Online real-time learning of dynamical systems from noisy streaming data.

Recent advancements in sensing and communication facilitate obtaining high-frequency real-time data from various physical systems like power networks, climate systems, biological networks, etc. However, since the data are recorded by physical sensors, it is natural that the obtained data is corrupted by measurement noise. In this paper, we present a novel algorithm for online real-time learning of dynamical systems from noisy time-series data, which employs the Robust Koopman operator framework to mitigate the effect of measurement noise. The proposed algorithm has three main advantages: (a) it allows for online real-time monitoring of a dynamical system; (b) it obtains a linear representation of the underlying dynamical system, thus enabling the user to use linear systems theory for analysis and control of the system; (c) it is computationally fast and less intensive than the popular extended dynamic mode decomposition (EDMD) algorithm. We illustrate the efficiency of the proposed algorithm by applying it to identify the Van der Pol oscillator, the chaotic attractor of the Henon map, the IEEE 68 bus system, and a ring network of Van der Pol oscillators.

Nonequilibrium dynamics of the Jaynes-Cummings dimer.

We investigate the nonequilibrium dynamics of a Josephson-coupled Jaynes-Cummings dimer in the presence of Kerr nonlinearity, which can be realized in the cavity and circuit quantum electrodynamics systems. The semiclassical dynamics is analyzed systematically to chart out a variety of photonic Josephson oscillations and their regime of stability. Different types of transitions between the dynamical states lead to the self-trapping phenomenon, which results in photon population imbalance between the two cavities. We also study the dynamics quantum mechanically to identify characteristic features of different steady states and to explore fascinating quantum effects, such as spin dephasing, phase fluctuation, and revival phenomena of the photon field, as well as the entanglement of spin qubits. For a particular "self-trapped" state, the mutual information between the atomic qubits exhibits a direct correlation with the photon population imbalance, which is promising for generating photon mediated entanglement between two non interacting qubits in a controlled manner. Under a sudden quench from stable to unstable regime, the photon distribution exhibits phase space mixing with a rapid loss of coherence, resembling a thermal state. Finally, we discuss the relevance of the new results in experiments, which can have applications in quantum information processing and quantum technologies.

Effect of membrane stabilizers on semen quality and sperm membrane protein expression during cryopreservation of goat semen.

BACKGROUND: Semen cryopreservation is a complex process during which there is alteration in the expression of sperm and seminal plasma proteins, molecular weight of protein or loss of membrane proteins during the process. In order to compensate for these changes, different membrane stabilizers are used in freezing semen extenders. However, there is scarcity of such studies during cryopreservation of goat semen. OBJECTIVE: To investigate the effect of membrane stabilizers on sperm membrane protein expression during cryopreservation of goat semen. MATERIALS AND METHODS: A total of 36 semen ejaculates from nine Assam Hill Goat bucks aged 2 to 2.5 years was collected by artificial vagina method. Three membrane stabilizers, each at two different concentrations viz. 50 and 80 mM sucrose, 50 and 100 mM trehalose, and 100 and 150 ng per mL IGF-1 (insulin-like growth factor 1 protein) were added to Tris-citric acid fructose egg yolk glycerol (TCFEYG) extender and semen samples were cryopreserved. The sperm membrane protein profile was studied in fresh and cryopreserved semen by SDS-PAGE. RESULTS: SDS- PAGE of sperm membrane extract of fresh semen revealed the presence of 24 protein bands with molecular weights ranging from 10 kDa to 240 kDa. Samples supplemented with 50 mM sucrose and 80 mM sucrose revealed 21 protein bands with molecular weights ranging from 10 kDa to 240 kDa. All the 21 protein bands were same as those observed in the sperm membrane of fresh spermatozoa, except that the 23 kDa, 29 kDa and 42 kDa bands were absent in frozen semen. Similarly, frozen semen extended with 50 mM trehalose and 100 mM trehalose revealed 22 protein bands with molecular weights ranging from 10 kDa to 240 kDa, but lacking the 29 kDa and 42 kDa bands. Proteins with molecular weights of 29 kDa, 130 kDa and 240 kDa were absent in frozen semen supplemented with 100 ng per mL IGF-1 and 150 ng per mL IGF-1. CONCLUSION: The present study revealed that supplementation of tris basic extender with trehalose at 100 mM and or IGF-1 at 100 ng/mL or 150 ng per mL improves the post-thaw semen characteristics and protects certain fertility related sperm membrane proteins. Doi.org/10.54680/fr23510110612.

Insights into the Growth of Ternary WSSe Nanotubes in an Atmospheric CVD Reactor.

The synthesis of complex new nanostructures is challenging but also bears the potential for observing new physiochemical properties and offers unique applications in the long run. High-temperature synthesis of ternary WSe2xS2(1-x) (denoted as WSSe) nanotubes in a pure phase and in substantial quantities is particularly challenging, requiring a unique reactor design and control over several parameters, simultaneously. Here, the growth of WSSe nanotubes with the composition 0 ≤ x < 1 from W18O49 nanowhiskers in an atmospheric chemical vapor deposition (CVD) flow reactor is investigated. The oxide precursor powder is found to be heavily agglomerated, with long nanowhiskers decorating the outer surface of the agglomerates and their core being enriched with oxide microcrystallites. The reaction kinetics with respect to the chalcogen vapors varies substantially between the two kinds of oxide morphologies. Insights into the chemical reactivity and diffusion kinetics of S and Se within W18O49 nanowhishkers and the micro-oxide crystallites were gained through detailed microscopic, spectroscopic analysis of the reaction products and also through density functional theory (DFT) calculations. For safety reasons, the reaction duration was limited to half an hour each. Under these circumstances, the reaction was completed for some 50% of the nanotubes and the other half remained with thick oxide core producing new WOx@WSSe core-shell nanotubes. Furthermore, the selenium reacted rather slowly with the WOx nanowhiskers, whereas the more ionic and smaller sulfur atoms were shown to diffuse and react faster. The yield of the combined hollow and core-shell nanotubes on the periphery of the agglomerated oxide was very high, approaching 100% in parts of the reactor boat. The nanotubes were found to be very thin (∼80% with a diameter <40 nm). The optical properties of the nanotubes were studied, and almost linear bandgap modulation was observed with respect to the selenium content in the nanotubes. This investigation paves the way for further scaling up the synthesis and for a detailed study of the different properties of WSSe nanotubes.

A Meta-Analysis on Comparison of Open vs Closed Reduction of Gartland Type 3 Supracondylar Humerus Fractures in Children.

PURPOSE OF THE STUDY Although there are numerous studies on outcomes and comparison of open and closed reduction but there is no clarity on relationship between outcomes and complications with type of surgical intervention done for Type 3 Gartland supracondylar humerus fracture. The aim of this study is to compare the outcomes and complications of closed vs open reduction in Type 3 Gartland supracondylar humerus fractures. MATERIAL AND METHODS Electronic literature searches of Embase, MEDLINE and the Cochrane Library was conducted in February 2022 using the terms "supracondylar", "humerus", "fracture", "Gartland type 3" and synonymous. The data extracted included the study details, demographic data, procedure performed, final functional and cosmetic outcome according to Flynn criteria and complications of included studies. RESULTS Pooled data analysis revealed no significant difference in mean satisfactory outcome rate according to Flynn cosmetic criteria in open group (97%, 95% CI 95.5%-98.5%), as compared to closed group (97.5%, 95% CI 96.3%-98.7%), although a statistically significant difference in mean satisfactory rate according to Flynn functional criteria in open group (93.4%, 95% CI 90.8%- 96.1%) as compared to closed group (98.5%, 95% CI 97.5%-99.4%) was noted. On separate comparison of the two-arm studies, closed reduction favoured better functional outcomes (RR 0.92, 95% CI 0.86-0.99). CONCLUSIONS Closed reduction and percutaneous fixation have better functional outcome than open reduction with K-wire fixation. But there was no significant difference in cosmetic outcomes, overall complication rate and nerve injury with either open or closed reduction. The threshold of converting a closed reduction to an open reduction in supracondylar humerus fractures of children should be high. Key words: supracondylar humerus, open reduction, percutaneous pinning, Flynn criteria.

Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

Self-reported beta-lactam allergy in government and private hospitals in Cape Town, South Africa.

BACKGROUND: Up to a quarter of inpatients in high-income countries (HICs) self-report beta-lactam allergy (BLA), which if incorrect,increases the use of alternative antibiotics, worsening individual health outcomes and driving bacterial resistance. In HICs, up to 95% ofself-reported BLAs are incorrect. The epidemiology of BLA in low- and middle-income African countries is unknown. OBJECTIVES: To describe the epidemiology and de-labelling outcomes of self-reported BLA in hospitalised South African (SA) patients. METHODS: Point-prevalence surveys were conducted at seven hospitals (adult, paediatric, government and privately funded, district andtertiary level) in Cape Town, SA, between April 2019 and June 2021. Ward prescription records and in-person interviews were conductedto identify and risk-stratify BLA patients using the validated PEN-FAST tool. De-labelling was attempted at the tertiary allergy clinic atGroote Schuur Hospital. RESULTS: A total of 1 486 hospital inpatients were surveyed (1 166 adults and 320 children). Only 48 patients (3.2%) self-reported a BLA,with a higher rate in private than in government-funded hospitals (6.3% v. 2.8%; p=0.014). Using the PEN-FAST tool, only 10.4% (n=5/48)of self-reported BLA patients were classified as high risk for true penicillin hypersensitivity. Antibiotics were prescribed to 70.8% (n=34/48)of self-reported BLA patients, with 64.7% (n=22/34) receiving a beta-lactam. Despite three attempts to contact patients for de-labelling atthe allergy clinic, only 3/36 underwent in vivo testing, with no positive results, and 1 patient proceeded to a negative oral challenge. CONCLUSION: Unlike HICs, self-reported BLA is low among inpatients in SA. The majority of those who self-reported BLA were low risk fortype 1 hypersensitivity, but outpatient de-labelling efforts were largely unsuccessful.

High-Resolution Transcriptomic Landscape of the Human Submandibular Gland.

Saliva-secreting and transporting cells are part of the complex cellular milieu of the human salivary gland, where they play important roles in normal glandular physiology and diseased states. However, comprehensive molecular characterization, particularly at single-cell resolution, is still incomplete, in part due to difficulty in procuring normal human tissues. Here, we perform an in-depth analysis of male and female adult human submandibular gland (SMG) samples by bulk RNA sequencing (RNA-seq) and examine the molecular underpinnings of the heterogeneous cell populations by single-cell (sc) RNA-seq. Our results from scRNA-seq highlight the remarkable diversity of clusters of epithelial and nonepithelial cells that reside in the SMG that is also faithfully recapitulated by deconvolution of the bulk-RNA data sets. Our analyses reveal complex transcriptomic heterogeneity within both the ductal and acinar subpopulations and identify atypical SMG cell types, such as mucoacinar cells that are unique to humans and ionocytes that have been recently described in the mouse. We use CellChat to explore ligand-receptor interactome predictions that likely mediate crucial cell-cell communications between the various cell clusters. Finally, we apply a trajectory inference method to investigate specific cellular branching points and topology that offers insights into the dynamic and complex differentiation process of the adult SMG. The data sets and the analyses herein comprise an extensive wealth of high-resolution information and a valuable resource for a deeper mechanistic understanding of human SMG biology and pathophysiology.

Characteristics of ipsilateral, contralateral and bilateral masseter vestibular-evoked myogenic potential in healthy adults.

OBJECTIVE: This study aimed to characterise the ipsilateral, contralateral and bilateral masseter vestibular-evoked myogenic potential using clicks and 500 Hz tone burst stimuli in healthy adults. METHOD: Masseter vestibular-evoked myogenic potential was recorded from 20 healthy participants aged 19-28 years (11 males and 9 females). Masseter vestibular-evoked myogenic potential was recorded using 500 Hz tone burst and click stimuli in ipsilateral, contralateral and bilateral modes. RESULTS: A statistically significant difference was observed between ipsilateral and contralateral stimulation for p11 latency, n21 latency and p11-n21 amplitude for both click and 500 Hz tone burst stimuli. The amplitude of the p11-n21 complex was higher for ipsilateral, contralateral and bilateral stimulations for 500 Hz tone burst than for click stimulus. CONCLUSION: This study showed a significant difference for p11-n21 amplitude between click and 500 Hz tone burst evoked masseter vestibular-evoked myogenic potential. In addition, bilateral stimulation elicited a larger response than ipsilateral and contralateral stimulation.

Genetic Study of Elf5 and Ehf in the Mouse Salivary Gland.

Salivary gland (SG) development, maturation, and homeostasis require coordinated roles of transcription factors (TFs) that dictate specific cell identities and fate. The ETS family of proteins are important transcriptional drivers of diverse cell lineages, tissue development, and differentiation programs and hence are also likely to play an important role in the SG. Here we have leveraged genomic and epigenomic data of the SG to examine the expression profile of ETS genes and identified 2 closely related paralogs, Elf5 and Ehf, that are highly expressed in distinct epithelial subpopulations. By using a well-defined mouse knockout model of Elf5, we show that Elf5, despite its enriched expression in the acinar cells, is functionally dispensable for maintaining the homeostatic state of the adult SG epithelium. The lack of a discernible phenotype of the Elf5-null SG might be due to possible functional redundancy with Ehf or other ETS factors. To probe this possibility and to examine the specific consequences of Ehf loss in the SG, we used CRISPR-Cas9 to generate mice in which the DNA-binding ETS domain of Ehf is disrupted due to an insertion mutation. We demonstrate that the Ehf mutant (EhfMut) mice exhibit a distinct cellular phenotype with decreased granular convoluted tubules that are accompanied by an increased accumulation of the intercalated Sox9-positive ductal cell population. Interestingly, the ductal phenotype of the EhfMut animals is highly pronounced in males, reaffirming the established sexual dimorphism of the SG that exists in rodents. Our results show that unlike Elf5, Ehf plays a nonredundant role in directing ductal cell differentiation of the SG and highlights the phenotypic subtlety in mutant mice of closely related TFs and the importance of careful consideration of cell type-specific studies.

Non-surgical organ preservation in laryngeal and hypopharyngeal cancers: an audit from the clinic.

BACKGROUND: There is increasing concern regarding efficacy of organ preservation protocol in laryngeal and hypopharyngeal cancers. METHOD: This study retrospectively assessed disease-related and functional outcomes of 191 patients with non-metastatic laryngeal or hypopharyngeal squamous cell carcinoma treated with curative intent (radiotherapy with or without chemotherapy). RESULTS: Seventy-six patients (39.8 per cent) had a primary cancer in the larynx, and 115 patients (60.2 per cent) had a primary cancer in the hypopharynx. The median follow up was 39 months. The 3-year time to progression, overall survival, local control and laryngectomy free survival was 56.2 per cent, 76.3 per cent, 73.2 per cent and 67.2 per cent, respectively. At the time of analysis, 83 patients (43.5 per cent) were alive and disease free at their last follow up and did not require tube feeding or tracheostomy. The laryngo-oesophageal dysfunction-free survival was 61 per cent at 3 years. CONCLUSION: Organ conservation protocols remain the standard of treatment in appropriately selected patients with laryngeal and hypopharyngeal cancers.

Creating superconductivity in WB2 through pressure-induced metastable planar defects.

High-pressure electrical resistivity measurements reveal that the mechanical deformation of ultra-hard WB2 during compression induces superconductivity above 50 GPa with a maximum superconducting critical temperature, Tcof 17 K at 91 GPa. Upon further compression up to 187 GPa, the Tcgradually decreases. Theoretical calculations show that electron-phonon mediated superconductivity originates from the formation of metastable stacking faults and twin boundaries that exhibit a local structure resembling MgB2 (hP3, space group 191, prototype AlB2). Synchrotron x-ray diffraction measurements up to 145 GPa show that the ambient pressure hP12 structure (space group 194, prototype WB2) continues to persist to this pressure, consistent with the formation of the planar defects above 50 GPa. The abrupt appearance of superconductivity under pressure does not coincide with a structural transition but instead with the formation and percolation of mechanically-induced stacking faults and twin boundaries. The results identify an alternate route for designing superconducting materials.

Insights from Magnetic Evoked Field Analysis in Patients with Wilson's Disease.

Aims: To study the latency, amplitude, and source localization of magnetic evoked field (MEF) responses to visual, auditory, and somatosensory stimuli in Wilson's disease (WD) using magnetoencephalography (MEG) and compare it with "healthy" controls, and correlate the observations with disease severity and brain MRI. Methods: MEF of 28 patients with neurological WD (age: 22.82 ± 5.8 years; M:F = 12:16) and 21 matched controls (age: 25.0 ± 4.6 years; M:F = 10:11) were recorded using MEG. Source localization was performed using standard models on the components of M100, M20, and M100 for visual, somatosensory, and auditory evoked fields, respectively and its latency/amplitude was correlated with disease severity. Results: There were significant differences in source location between control and WD during visual evoked field (VEF) and auditory evoked field (AEF) studies. Latencies of M20 (right-p = 0.02; left-p = 0.04) and M32 (right-p = 0.01) components of SSEF were significantly prolonged. The amplitude of M20 was significantly reduced in patients bilaterally (P = 0.001). There was a trend for the prolonged latency of M100 of VEF in patients (P = 0.09). Five patients had reduced right M145 compared to 8 controls. The left somatosensory evoked fields (SSEF) latency correlated with disease severity (P = 0.04). There was no significant correlation between major components of other MEF with disease severity or MRI score. Conclusions: This study, first of its kind to use MEF analysis in a large cohort of patients with WD, detected subclinical but a variable degree of abnormalities, most consistently of SSEF. It provides valuable insights of functioning and localization of various pathways in a disease known to have protean clinical manifestations and widespread MRI changes.

The fluctuation-dissipation measurement instrument at the Linac Coherent Light Source.

The development of new modes at x-ray free electron lasers has inspired novel methods for studying fluctuations at different energies and timescales. For closely spaced x-ray pulses that can be varied on ultrafast time scales, we have constructed a pair of advanced instruments to conduct studies targeting quantum materials. We first describe a prototype instrument built to test the proof-of-principle of resonant magnetic scattering using ultrafast pulse pairs. This is followed by a description of a new endstation, the so-called fluctuation-dissipation measurement instrument, which was used to carry out studies with a fast area detector. In addition, we describe various types of diagnostics for single-shot contrast measurements, which can be used to normalize data on a pulse-by-pulse basis and calibrate pulse amplitude ratios, both of which are important for the study of fluctuations in materials. Furthermore, we present some new results using the instrument that demonstrates access to higher momentum resolution.

Metabolic transitions define spermatogonial stem cell maturation.

STUDY QUESTION: Do spermatogonia, including spermatogonial stem cells (SSCs), undergo metabolic changes during prepubertal development? SUMMARY ANSWER: Here, we show that the metabolic phenotype of prepubertal human spermatogonia is distinct from that of adult spermatogonia and that SSC development is characterized by distinct metabolic transitions from oxidative phosphorylation (OXPHOS) to anaerobic metabolism. WHAT IS KNOWN ALREADY: Maintenance of both mouse and human adult SSCs relies on glycolysis, while embryonic SSC precursors, primordial germ cells (PGCs), exhibit an elevated dependence on OXPHOS. Neonatal porcine SSC precursors reportedly initiate a transition to an adult SSC metabolic phenotype at 2 months of development. However, when and if such a metabolic transition occurs in humans is ambiguous. STUDY DESIGN, SIZE, DURATION: To address our research questions: (i) we performed a meta-analysis of publicly available and newly generated (current study) single-cell RNA sequencing (scRNA-Seq) datasets in order to establish a roadmap of SSC metabolic development from embryonic stages (embryonic week 6) to adulthood in humans (25 years of age) with a total of ten groups; (ii) in parallel, we analyzed single-cell RNA sequencing datasets of isolated pup (n = 3) and adult (n = 2) murine spermatogonia to determine whether a similar metabolic switch occurs; and (iii) we characterized the mechanisms that regulate these metabolic transitions during SSC maturation by conducting quantitative proteomic analysis using two different ages of prepubertal pig spermatogonia as a model, each with four independently collected cell populations. PARTICIPANTS/MATERIALS, SETTING, METHODS: Single testicular cells collected from 1-year, 2-year and 7-year-old human males and sorted spermatogonia isolated from 6- to 8-day (n = 3) and 4-month (n = 2) old mice were subjected to scRNA-Seq. The human sequences were individually processed and then merged with the publicly available datasets for a meta-analysis using Seurat V4 package. We then performed a pairwise differential gene expression analysis between groups of age, followed by pathways enrichment analysis using gene set enrichment analysis (cutoff of false discovery rate < 0.05). The sequences from mice were subjected to a similar workflow as described for humans. Early (1-week-old) and late (8-week-old) prepubertal pig spermatogonia were analyzed to reveal underlying cellular mechanisms of the metabolic shift using immunohistochemistry, western blot, qRT-PCR, quantitative proteomics, and culture experiments. MAIN RESULTS AND THE ROLE OF CHANCE: Human PGCs and prepubertal human spermatogonia show an enrichment of OXPHOS-associated genes, which is downregulated at the onset of puberty (P < 0.0001). Furthermore, we demonstrate that similar metabolic changes between pup and adult spermatogonia are detectable in the mouse (P < 0.0001). In humans, the metabolic transition at puberty is also preceded by a drastic change in SSC shape at 11 years of age (P < 0.0001). Using a pig model, we reveal that this metabolic shift could be regulated by an insulin growth factor-1 dependent signaling pathway via mammalian target of rapamycin and proteasome inhibition. LARGE SCALE DATA: New single-cell RNA sequencing datasets obtained from this study are freely available through NCBI GEO with accession number GSE196819. LIMITATIONS, REASONS FOR CAUTION: Human prepubertal tissue samples are scarce, which led to the investigation of a low number of samples per age. Gene enrichment analysis gives only an indication about the functional state of the cells. Due to limited numbers of prepubertal human spermatogonia, porcine spermatogonia were used for further proteomic and in vitro analyses. WIDER IMPLICATIONS OF THE FINDINGS: We show that prepubertal human spermatogonia exhibit high OXHPOS and switch to an adult-like metabolism only after 11 years of age. Prepubescent cancer survivors often suffer from infertility in adulthood. SSC transplantation could provide a powerful tool for the treatment of infertility; however, it requires high cell numbers. This work provides key insight into the dynamic metabolic requirements of human SSCs across development that would be critical in establishing ex vivo systems to support expansion and sustained function of SSCs toward clinical use. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the NIH/NICHD R01 HD091068 and NIH/ORIP R01 OD016575 to I.D. K.E.O. was supported by R01 HD100197. S.K.M. was supported by T32 HD087194 and F31 HD101323. The authors declare no conflict of interest.

Quantum transitions, ergodicity, and quantum scars in the coupled top model.

We consider an interacting collective spin model known as coupled top (CT), exhibiting a rich variety of phenomena related to quantum transitions, ergodicity, and formation of quantum scars, discussed in our previous work [Mondal, Sinha, and Sinha, Phys. Rev. E 102, 020101(R) (2020)2470-004510.1103/PhysRevE.102.020101]. In this work, we present a detailed analysis of the different type of transitions in the CT model, and find their connection with the underlying collective spin dynamics. Apart from the quantum scarring phenomena, we also identify another source of deviation from ergodicity due to the presence of nonergodic multifractal states. The degree of ergodicity of the eigenstates across the energy band is quantified from the relative entanglement entropy as well as multifractal dimensions, which can be probed from nonequilibrium dynamics. Finally, we discuss the detection of nonergodic behavior and different types of quantum scars using "out-of-time-order correlators," which has relevance in the recent experiments.