Traumatic dental injuries and molar incisor hypomineralization: a cross-sectional study of schoolchildren from southern Brazil.

PURPOSE: To describe the prevalence and the variables associated with TDIs in schoolchildren aged 8 to 14 years in Estância Velha city in southern Brazil, placing emphasis on molar incisor hypomineralization. METHODS: Students enrolled in public schools of a medium-sized city in the southern Brazil were selected using cluster random sampling. Clinical examinations assessed molar incisor hypomineralization-MIH (European Academy of Pediatric Dentistry criteria), dental caries (DMFT index), and TDIs (O'Brien's criteria). Socioeconomic and demographic variables were assessed using a standardized questionnaire. Prevalence ratios were estimated using Poisson regression (p < 0.05). RESULTS: 513 students (54.8% female), with a mean age of 11.6 (± 1.9) years, participated in the study. The prevalence of TDIs was 11.3%, with enamel fracture representing 90.4%. The high prevalence of traumatic dental injuries was associated with MIH (PR: 2.22 CI: 1.27; 3.87; p < 0.01) and overjet > 3 mm (PR: 2.03 CI 1.19; 3.45; p < 0.01). CONCLUSION: The sample of schoolchildren from southern Brazil had a low prevalence of traumatic dental injuries. Molar incisor hypomineralization and increased overjet were associated with the higher prevalence of traumatic dental injuries.

Investigating relationships between the host genome, rumen microbiome, and dairy cow feed efficiency using mediation analysis with structural equation modeling.

The rumen microbiome is crucial for converting feed into absorbable nutrients used for milk synthesis, and the efficiency of this process directly impacts the profitability and sustainability of the dairy industry. Recent studies have found that the rumen microbial composition explains part of the variation in feed efficiency traits, including dry matter intake, milk energy, and residual feed intake. The main goal of this study was to reveal relationships between the host genome, rumen microbiome, and dairy cow feed efficiency using structural equation models. Our specific objectives were to (i) infer the mediation effects of the rumen microbiome on feed efficiency traits, (ii) estimate the direct and total heritability of feed efficiency traits, and (iii) calculate the direct and total breeding values of feed efficiency traits. Data consisted of dry matter intake, milk energy, and residual feed intake records, SNP genotype data, and 16S rRNA rumen microbial abundances from 448 mid-lactation Holstein cows from 2 research farms. We implemented structural equation models such that the host genome directly affects the phenotype (GP → P) and the rumen microbiome (GM → P), while the microbiome affects the phenotype (M → P), partially mediating the effect of the host genome on the phenotype (G → M → P). We found that 7 to 30% of microbes within the rumen microbial community had structural coefficients different from zero. We classified these microbes into 3 groups that could have different uses in dairy farming. Microbes with heritability <0.10 but significant causal effects on feed efficiency are attractive for external interventions. On the other hand, 2 groups of microbes with heritability ≥0.10, significant causal effects, and genetic covariances and causal effects with the same or opposite sign to feed efficiency are attractive for selective breeding, improving or decreasing the trait heritability and response to selection, respectively. In general, the inclusion of the different microbes in genomic models tends to decrease the trait heritability rather than increase it, ranging from -15% to +5%, depending on the microbial group and phenotypic trait. Our findings provide more understanding to target rumen microbes that can be manipulated, either through selection or management interventions, to improve feed efficiency traits.

EDA-Graph: Graph Signal Processing of Electrodermal Activity for Emotional States Detection.

The continuous detection of emotional states has many applications in mental health, marketing, human-computer interaction, and assistive robotics. Electrodermal activity (EDA), a signal modulated by sympathetic nervous system activity, provides continuous insight into emotional states. However, EDA possesses intricate nonstationary and nonlinear characteristics, making the extraction of emotion-relevant information challenging. We propose a novel graph signal processing (GSP) approach to model EDA signals as graphical networks, termed EDA-graph. The GSP leverages graph theory concepts to capture complex relationships in time-series data. To test the usefulness of EDA-graphs to detect emotions, we processed EDA recordings from the CASE emotion dataset using GSP by quantizing and linking values based on the Euclidean distance between the nearest neighbors. From these EDA-graphs, we computed the features of graph analysis, including total load centrality (TLC), total harmonic centrality (THC), number of cliques (GNC), diameter, and graph radius, and compared those features with features obtained using traditional EDA processing techniques. EDA-graph features encompassing TLC, THC, GNC, diameter, and radius demonstrated significant differences (p<0.05) between five emotional states (Neutral, Amused, Bored, Relaxed, and Scared). Using machine learning models for classifying emotional states evaluated using leave-one-subject-out cross-validation, we achieved a five-class F1 score of up to 0.68.

Shifts in uterine microbiome associated with pregnancy outcomes at first insemination and clinical cure in dairy cows with metritis.

Objectives were to assess differences in uterine microbiome associated with clinical cure and pregnancy outcomes in dairy cows treated for metritis. Cows with metritis (reddish-brownish, watery, and fetid vaginal discharge) were paired with cows without metritis based on parity and days postpartum. Uterine contents were collected through transcervical lavage at diagnosis, five days later following antimicrobial therapy (day 5), and at 40 days postpartum. Uterine microbiome was assessed by sequencing the V4 hypervariable region of the 16S rRNA gene. Although alpha-diversity based on Chao1, Shannon, and inverse Simpson indexes at diagnosis did not differ between cows with and without metritis, disease was associated with differences in beta-diversity. Prevalence of Porphyromonas, Bacteroides, and Veillonella was greater in cows with metritis. Streptococcus, Sphingomonas, and Ureaplasma were more prevalent in cows without metritis. Differences in beta-diversity between cows with and without metritis persisted on day 5. Uterine microbiome was not associated with clinical cure. Richness and alpha-diversity, but not beta-diversity, of uterine microbiome 40 days postpartum were associated with metritis and pregnancy. No relationship between uterine microbiome and pregnancy outcomes was observed. Results indicate that factors other than changes in intrauterine bacterial community underlie fertility loss and clinical cure in cows with metritis.

Clinical and Imaging Characteristics, Care Pathways, and Outcomes of Traumatic Epidural Hematomas: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Study.

BACKGROUND AND OBJECTIVES: Guideline recommendations for surgical management of traumatic epidural hematomas (EDHs) do not directly address EDHs that co-occur with other intracranial hematomas; the relative rates of isolated vs nonisolated EDHs and guideline adherence are unknown. We describe characteristics of a contemporary cohort of patients with EDHs and identify factors influencing acute surgery. METHODS: This research was conducted within the longitudinal, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury cohort study which prospectively enrolled patients with traumatic brain injury from 65 hospitals in 18 European countries from 2014 to 2017. All patients with EDH on the first scan were included. We describe clinical, imaging, management, and outcome characteristics and assess associations between site and baseline characteristics and acute EDH surgery, using regression modeling. RESULTS: In 461 patients with EDH, median age was 41 years (IQR 24-56), 76% were male, and median EDH volume was 5 cm3 (IQR 2-20). Concomitant acute subdural hematomas (ASDHs) and/or intraparenchymal hemorrhages were present in 328/461 patients (71%). Acute surgery was performed in 99/461 patients (21%), including 70/86 with EDH volume ≥30 cm3 (81%). Larger EDH volumes (odds ratio [OR] 1.19 [95% CI 1.14-1.24] per cm3 below 30 cm3), smaller ASDH volumes (OR 0.93 [95% CI 0.88-0.97] per cm3), and midline shift (OR 6.63 [95% CI 1.99-22.15]) were associated with acute surgery; between-site variation was observed (median OR 2.08 [95% CI 1.01-3.48]). Six-month Glasgow Outcome Scale-Extended scores ≥5 occurred in 289/389 patients (74%); 41/389 (11%) died. CONCLUSION: Isolated EDHs are relatively infrequent, and two-thirds of patients harbor concomitant ASDHs and/or intraparenchymal hemorrhages. EDHs ≥30 cm3 are generally evacuated early, adhering to Brain Trauma Foundation guidelines. For heterogeneous intracranial pathology, surgical decision-making is related to clinical status and overall lesion burden. Further research should examine the optimal surgical management of EDH with concomitant lesions in traumatic brain injury, to inform updated guidelines.

Anticonvulsant activity of Tetrahydrolinalool: behavioral, electrophysiological, and molecular docking approaches.

Tetrahydrolinalool (THL) is an acyclic monoterpene alcohol, produced during linalol metabolism and also a constituent of essential oils. As described in the literature, many monoterpenes present anticonvulsant properties, and thus we became interested in evaluating the anticonvulsant activity of Tetrahydrolinalool using in mice model as well as in silico approaches. Our results demonstrated that THL increased latency to seizure onset and also reduced the mortality, in picrotoxin induced seizure tests. The results may be related to GABAergic regulation, which was also suggested in seizure testing induced by 3-mercapto-propionic acid. In the strychnine-induced seizure testing, none of the groups pretreated with THL modulated the parameters indicative of anticonvulsant effect. The electrophysiological results revealed that THL treatment reduces seizures induced by pentylenetetrazole. The in silico molecular docking studies showed that the interaction between THL and a GABAA receptor model formed a stable complex, in comparison to the crystaligraphic structure of diazepam, a structurally related ligand. In conclusion, all the evidences showed that THL presents effective anticonvulsant activity related to the GABAergic pathway, being a candidate for treatment of epileptic syndromes.

Early versus delayed cranioplasty after decompressive craniectomy in traumatic brain injury: a multicenter observational study within CENTER-TBI and Net-QuRe.

OBJECTIVE: The aim of this study was to compare the outcomes of early (≤ 90 days) and delayed (> 90 days) cranioplasty following decompressive craniectomy (DC) in patients with traumatic brain injury (TBI). METHODS: The authors analyzed participants enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) and the Neurotraumatology Quality Registry (Net-QuRe) studies who were diagnosed with TBI and underwent DC and subsequent cranioplasty. These prospective, multicenter, observational cohort studies included 5091 patients enrolled from 2014 to 2020. The effect of cranioplasty timing on functional outcome was evaluated with multivariable ordinal regression and with propensity score matching (PSM) in a sensitivity analysis of functional outcome (Glasgow Outcome Scale-Extended [GOSE] score) and quality of life (Quality of Life After Brain Injury [QOLIBRI] instrument) at 12 months following DC. RESULTS: Among 173 eligible patients, 73 (42%) underwent early cranioplasty and 100 (58%) underwent delayed cranioplasty. In the ordinal logistic regression and PSM, similar 12-month GOSE scores were found between the two groups (adjusted odds ratio [aOR] 0.87, 95% CI 0.61-1.21 and 0.88, 95% CI 0.48-1.65, respectively). In the ordinal logistic regression, early cranioplasty was associated with a higher risk for hydrocephalus than that with delayed cranioplasty (aOR 4.0, 95% CI 1.2-16). Postdischarge seizure rates (early cranioplasty: aOR 1.73, 95% CI 0.7-4.7) and QOLIBRI scores (ß -1.9, 95% CI -9.1 to 9.6) were similar between the two groups. CONCLUSIONS: Functional outcome and quality of life were similar between early and delayed cranioplasty in patients who had undergone DC for TBI. Neurosurgeons may consider performing cranioplasty during the index admission (early) to simplify the patient's chain of care and prevent readmission for cranioplasty but should be vigilant for an increased possibility of hydrocephalus. Clinical trial registration nos.: CENTER-TBI, NCT02210221 (clinicaltrials.gov); Net-QuRe, NTR6003 (trialsearch.who.int) and NL5761 (onderzoekmetmensen.nl).

Scattering of partially coherent electromagnetic beams by a sphere.

We examine the scattering of a partially coherent, partially polarized electromagnetic beam by a homogeneous sphere (Mie scattering). The degree of polarization and the Stokes parameters in the far zone are found to be strongly dependent on the state of coherence and polarization of the incident beam. In particular, we demonstrate the emergence of polarization singularities and show that partial spatial coherence gives rise to significant depolarization effects. In addition we explore the symmetry properties of the scattered field.

Detecting Psychological Interventions Using Bilateral Electromyographic Wearable Sensors.

This study investigated the impact of auditory stimuli on muscular activation patterns using wearable surface electromyography (EMG) sensors. Employing four key muscles (Sternocleidomastoid Muscle (SCM), Cervical Erector Muscle (CEM), Quadricep Muscles (QMs), and Tibialis Muscle (TM)) and time domain features, we differentiated the effects of four interventions: silence, music, positive reinforcement, and negative reinforcement. The results demonstrated distinct muscle responses to the interventions, with the SCM and CEM being the most sensitive to changes and the TM being the most active and stimulus dependent. Post hoc analyses revealed significant intervention-specific activations in the CEM and TM for specific time points and intervention pairs, suggesting dynamic modulation and time-dependent integration. Multi-feature analysis identified both statistical and Hjorth features as potent discriminators, reflecting diverse adaptations in muscle recruitment, activation intensity, control, and signal dynamics. These features hold promise as potential biomarkers for monitoring muscle function in various clinical and research applications. Finally, muscle-specific Random Forest classification achieved the highest accuracy and Area Under the ROC Curve for the TM, indicating its potential for differentiating interventions with high precision. This study paves the way for personalized neuroadaptive interventions in rehabilitation, sports science, ergonomics, and healthcare by exploiting the diverse and dynamic landscape of muscle responses to auditory stimuli.

Application of DIY Electrodermal Activity Wristband in Detecting Stress and Affective Responses of Students.

This paper describes the analysis of electrodermal activity (EDA) in the context of students' scholastic activity. Taking a multidisciplinary, citizen science and maker-centric approach, low-cost, bespoken wearables, such as a mini weather station and biometric wristband, were built. To investigate both physical health as well as stress, the instruments were first validated against research grade devices. Following this, a research experiment was created and conducted in the context of students' scholastic activity. Data from this experiment were used to train machine learning models, which were then applied to interpret the relationships between the environment, health, and stress. It is hoped that analyses of EDA data will further strengthen the emerging model describing the intersections between local microclimate and physiological and neurological stress. The results suggest that temperature and air quality play an important role in students' physiological well-being, thus demonstrating the feasibility of understanding the extent of the effects of various microclimatic factors. This highlights the importance of thermal comfort and air ventilation in real-life applications to improve students' well-being. We envision our work making a significant impact by showcasing the effectiveness and feasibility of inexpensive, self-designed wearable devices for tracking microclimate and electrodermal activity (EDA). The affordability of these wearables holds promising implications for scalability and encourages crowd-sourced citizen science in the relatively unexplored domain of microclimate's influence on well-being. Embracing citizen science can then democratize learning and expedite rapid research advancements.

The structure of a C. neoformans polysaccharide motif recognized by protective antibodies: A combined NMR and MD study.

Cryptococcus neoformans is a fungal pathogen responsible for cryptococcosis and cryptococcal meningitis. The C. neoformans' capsular polysaccharide and its shed exopolysaccharide function both as key virulence factors and to protect the fungal cell from phagocytosis. Currently, a glycoconjugate of these polysaccharides is being explored as a vaccine to protect against C. neoformans infection. In this study, NOE and J-coupling values from NMR experiments were consistent with a converged structure of the synthetic decasaccharide, GXM10-Ac3, calculated from MD simulations. GXM10-Ac3 was designed as an extension of glucuronoxylomannan (GXM) polysaccharide motif (M2) which is common in the clinically predominant serotype A strains and is recognized by protective forms of GXM-specific monoclonal antibodies. The M2 motif is a hexasaccharide with a three-residue α-mannan backbone, modified by ß-(1→2)-xyloses (Xyl) on the first two mannoses (Man) and a ß-(1→2)-glucuronic acid (GlcA) on the third Man. Combined NMR and MD analyses reveal that GXM10-Ac3 adopts an extended structure, with Xyl/GlcA branches alternating sides along the α-mannan backbone. O-acetyl esters also alternate sides and are grouped in pairs. MD analysis of a twelve M2-repeating unit polymer supports the notion that the GXM10-Ac3 structure is uniformly represented throughout the polysaccharide. This derived GXM model displays high flexibility while maintaining a structural identity, yielding insights to further explore intermolecular interactions between polysaccharides, interactions with anti-GXM mAbs, and the cryptococcal polysaccharide architecture.

Detecting Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder Using Multimodal Time-Frequency Analysis with Machine Learning Using the Electroretinogram from Two Flash Strengths.

PURPOSE: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are conditions that similarly alter cognitive functioning ability and challenge the social interaction, attention, and communication skills of affected individuals. Yet these are distinct neurological conditions that can exhibit diverse characteristics which require different management strategies. It is desirable to develop tools to assist with early distinction so that appropriate early interventions and support may be tailored to an individual's specific requirements. The current diagnostic procedures for ASD and ADHD require a multidisciplinary approach and can be lengthy. This study investigated the potential of electroretinogram (ERG), an eye test measuring retinal responses to light, for rapid screening of ASD and ADHD. METHODS: Previous studies identified differences in ERG amplitude between ASD and ADHD, but this study explored time-frequency analysis (TFS) to capture dynamic changes in the signal. ERG data from 286 subjects (146 control, 94 ASD, 46 ADHD) was analyzed using two TFS techniques. RESULTS: Key features were selected, and machine learning models were trained to classify individuals based on their ERG response. The best model achieved 70% overall accuracy in distinguishing control, ASD, and ADHD groups. CONCLUSION: The ERG to the stronger flash strength provided better separation and the high frequency dynamics (80-300 Hz) were more informative features than lower frequency components. To further improve classification a greater number of different flash strengths may be required along with a discrimination comparison to participants who meet both ASD and ADHD classifications and carry both diagnoses.

NORAD-Regulated Signaling Pathways in Breast Cancer Progression.

Long non-coding RNA activated by DNA damage (NORAD) has recently been associated with pathologic mechanisms underlying cancer progression. Due to NORAD's extended range of interacting partners, there has been contradictory data on its oncogenic or tumor suppressor roles in BC. This review will summarize the function of NORAD in different BC subtypes and how NORAD impacts crucial signaling pathways in this pathology. Through the preferential binding to pumilio (PUM) proteins PUM1 and PUM2, NORAD has been shown to be involved in the control of cell cycle, angiogenesis, mitosis, DNA replication and transcription and protein translation. More recently, NORAD has been associated with PUM-independent roles, accomplished by interacting with other ncRNAs, mRNAs and proteins. The intricate network of NORAD-mediated signaling pathways may provide insights into the potential design of novel unexplored strategies to overcome chemotherapy resistance in BC treatment.

An artificial intelligence approach of feature engineering and ensemble methods depicts the rumen microbiome contribution to feed efficiency in dairy cows.

Genetic selection has remarkably helped U.S. dairy farms to decrease their carbon footprint by more than doubling milk production per cow over time. Despite the environmental and economic benefits of improved feed and milk production efficiency, there is a critical need to explore phenotypical variance for feed utilization to advance the long-term sustainability of dairy farms. Feed is a major expense in dairy operations, and their enteric fermentation is a major source of greenhouse gases in agriculture. The challenges to expanding the phenotypic database, especially for feed efficiency predictions, and the lack of understanding of its drivers limit its utilization. Herein, we leveraged an artificial intelligence approach with feature engineering and ensemble methods to explore the predictive power of the rumen microbiome for feed and milk production efficiency traits, as rumen microbes play a central role in physiological responses in dairy cows. The novel ensemble method allowed to further identify key microbes linked to the efficiency measures. We used a population of 454 genotyped Holstein cows in the U.S. and Canada with individually measured feed and milk production efficiency phenotypes. The study underscored that the rumen microbiome is a major driver of residual feed intake (RFI), the most robust feed efficiency measure evaluated in the study, accounting for 36% of its variation. Further analyses showed that several alpha-diversity metrics were lower in more feed-efficient cows. For RFI, [Ruminococcus] gauvreauii group was the only genus positively associated with an improved feed efficiency status while seven other taxa were associated with inefficiency. The study also highlights that the rumen microbiome is pivotal for the unexplained variance in milk fat and protein production efficiency. Estimation of the carbon footprint of these cows shows that selection for better RFI could reduce up to 5 kg of diet consumed per cow daily, potentially reducing up to 37.5% of CH4. These findings shed light that the integration of artificial intelligence approaches, microbiology, and ruminant nutrition can be a path to further advance our understanding of the rumen microbiome on nutrient requirements and lactation performance of dairy cows to support the long-term sustainability of the dairy community.

Exploring structural determinants of neuroprotection bias on novel glypromate conjugates with bioactive amines.

Neurodegenerative disorders of the central nervous system (CNS) such as Alzheimer's and Parkinson's diseases, afflict millions globally, posing a significant public health challenge. Despite extensive research, a critical hurdle in effectively treating neurodegenerative diseases is the lack of neuroprotective drugs that can halt or reverse the underlying disease processes. In this work, we took advantage of the neuroprotective properties of the neuropeptide glycyl-l-prolyl-l-glutamic acid (Glypromate) for the development of new peptidomimetics using l-pipecolic acid as a proline surrogate and exploring their chemical conjugation with relevant active pharmaceutical ingredients (API) via a peptide bond. Together with prolyl-based Glypromate conjugates, a total of 36 conjugates were toxicologically and biologically evaluated. In this series, the results obtained showed that a constrained ring (l-proline) at the central position of the peptide motif accounts for enhanced toxicological profiles and biological effects using undifferentiated and differentiated human neuroblastoma SH-SY5Y cells. Additionally, it was shown that biased biological responses are API-dependent. Conjugation with (R)-1-aminoindane led to a 38-43% reduction of protein aggregation induced by Aß25-35 (10 µM), denoting a 3.2-3.6-fold improvement in comparison with the parent neuropeptide, with no significative difference between functionalization at α and γ-carboxyl ends. On the other hand, the best-performing neuroprotective conjugate against the toxicity elicited by 6-hydroxydopamine (6-OHDA, 125 µM) was obtained by conjugation with memantine at the α-carboxyl end, resulting in a 2.3-fold improvement of the neuroprotection capacity in comparison with Glypromate neuropeptide. Altogether, the chemical strategy explored in this work shows that the neuroprotective capacity of Glypromate can be modified and fine-tuned, opening a new avenue for the development of biased neurotherapeutics for CNS-related disorders.

Selective Internal Radiation Therapy Using Y-90 Resin Microspheres for Metastatic Colorectal Cancer: An Updated Systematic Review and Network Meta-Analysis.

INTRODUCTION: This literature review and exploratory network meta-analysis (NMA) aimed to compare the clinical effectiveness and tolerability of selective internal radiation therapy (SIRT) using yttrium-90 (Y-90) resin microspheres, regorafenib (REG), trifluridine-tipiracil (TFD/TPI), and best supportive care (BSC) in adult patients with chemotherapy-refractory or chemotherapy-intolerant metastatic colorectal cancer (mCRC). METHODS: In light of recently published data, the literature was searched to complement and update a review published in 2018. Studies up to December 2022 comparing two or more of the treatments and reporting overall survival (OS), progression-free survival (PFS), or incidence of adverse events (AE) were included. The NMA compared hazard ratios (HRs) for OS and PFS using Markov chain Monte Carlo techniques. RESULTS: Fifteen studies were included, with eight studies added (none addressing SIRT). All active treatments improved OS in relation to BSC. SIRT had the longest OS among all treatments, although without statistically significant differences (HR [95% credible interval] for SIRT, 0.48 [0.27, 0.87]; TFD/TPI, 0.62 [0.46, 0.83]; REG, 0.78 [0.57, 1.05]) in a fixed effects model. Information regarding SIRT was insufficient for PFS analysis, and TFD/TPI was the best intervention (HR 2.26 [1.6, 3.18]). One SIRT study reported radioembolization-induced liver disease in > 10% of the sample; this was symptomatically managed. Non-haematological AEs (hand-foot skin reaction, fatigue, diarrhoea, hypertension, rash or desquamation) were more common with REG, while haematological events (neutropoenia, leukopenia, and anaemia) were more common with TFD/TPI. CONCLUSION: Current evidence supports SIRT treatment in patients with chemotherapy-refractory or chemotherapy-intolerant mCRC compared to newer oral agents, with comparable OS and low incidence of AEs.

Insights on trends in the management of metrological analysis of devices in blood and transfusion medicine services: Verification based on their fitness for purpose and suitability for their respective applications.

In the field of blood and transfusion medicine, European Directorate for the Quality of Medicines & HealthCare recommends practices for metrological devices. Monitoring and measurement resources, as well as their permitted metrological limits, must be considered in this regard. We must understand variables such as metrological domains, the International System of Units, metrological traceability, and metrological requirements and controls in the field of transfusions in order to understand these metrological devices. An approach to metrological analysis and subsequent actions was constructed using flowcharts. As part of this methodology, a metrological device was selected, along with regulatory and normative requirements. A calibration and a test were conducted to demonstrate the application of the figure based on current recommendations. Current recommendations are consistent with the suggested ROC approach. The metrological devices must be verified based on their suitability for their respective applications (fitness-for-purpose).

Host and rumen microbiome contributions to feed efficiency traits in Holstein cows.

It is now widely accepted that dairy cow performance is influenced by both the host genome and rumen microbiome composition. The contributions of the genome and the microbiome to the phenotypes of interest are quantified by heritability (h2) and microbiability (m2), respectively. However, if the genome and microbiome are included in the model, then the h2 reflects only the contribution of the direct genetic effects quantified as direct heritability (hd2), and the holobiont effect reflects the joint action of the genome and the microbiome, quantified as the holobiability (ho2). The objectives of this study were to estimate h2, hd2,m2, and ho2 for dry matter intake, milk energy, and residual feed intake; and to evaluate the predictive ability of different models, including genome, microbiome, and their interaction. Data consisted of feed efficiency records, SNP genotype data, and 16S rRNA rumen microbial abundances from 448 mid-lactation Holstein cows from 2 research farms. Three kernel models were fit to each trait: one with only the genomic effect (model G), one with the genomic and microbiome effects (model GM), and one with the genomic, microbiome, and interaction effects (model GMO). The model GMO, or holobiont model, showed the best goodness-of-fit. The hd2 estimates were always 10% to 15% lower than h2 estimates for all traits, suggesting a mediated genetic effect through the rumen microbiome, and m2 estimates were moderate for all traits, and up to 26% for milk energy. The ho2 was greater than the sum of hd2 and m2, suggesting that the genome-by-microbiome interaction had a sizable effect on feed efficiency. Kernel models fitting the rumen microbiome (i.e., models GM and GMO) showed larger predictive correlations and smaller prediction bias than the model G. These findings reveal a moderate contribution of the rumen microbiome to feed efficiency traits in lactating Holstein cows and strongly suggest that the rumen microbiome mediates part of the host genetic effect.

Stapling Amantadine to Melanostatin Neuropeptide: Discovery of Potent Positive Allosteric Modulators of the D2 Receptors.

This work describes the synthesis and pharmacological and toxicological evaluation of melanostatin (MIF-1) bioconjugates with amantadine (Am) via a peptide linkage. The data from the functional assays at human dopamine D2 receptors (hD2R) showed that bioconjugates 1 (EC50 = 26.39 ± 3.37 nM) and 2 (EC50 = 17.82 ± 4.24 nM) promote a 3.3- and 4.9-fold increase of dopamine potency, respectively, at 0.01 nM, with no effect on the efficacy (Emax = 100%). In this assay, MIF-1 was only active at the highest concentration tested (EC50 = 23.64 ± 6.73 nM, at 1 nM). Cytotoxicity assays in differentiated SH-SY5Y cells showed that both MIF-1 (94.09 ± 5.75%, p < 0.05) and carbamate derivative 2 (89.73 ± 4.95%, p < 0.0001) exhibited mild but statistical significant toxicity (assessed through the MTT reduction assay) at 200 µM, while conjugate 1 was found nontoxic at this concentration.

Changes in Uterine Metabolome Associated with Metritis Development and Cure in Lactating Holstein Cows.

The objective of this study was to identify alterations in the vaginal discharge (VD) metabolome and potential biomarkers to predict metritis development and a cure in dairy cows. This prospective cohort study was conducted on two dairies located in CA and TX. Vaginal discharge was evaluated and collected using the Metricheck® device. Cows were examined for metritis at 4, 7, and 9 days in milk (DIM). Cows with a fetid, watery, and reddish-brown uterine discharge were classified as having metritis and randomized to receive ceftiofur (n = 10) or remain untreated (n = 7). A cure was defined as the absence of a fetid, watery, reddish-brown uterine discharge at 14 d after enrollment. Vaginal discharge samples were collected from 86 cows within 6 h after parturition, at 4 and 7 DIM, at metritis diagnosis, and at 4 and 7 days after metritis diagnosis. Cows with metritis (MET; n = 17) were paired with counterparts without metritis (HTH) of a similar DIM and parity (n = 34). The uterine metabolome was evaluated using untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). Metabolomic data were analyzed using the MetaboAnalyst 5.0. Data were log-transformed and auto-scaled for normalization. Univariate analyses, including the fold-change, were performed to identify the metabolites linked to metritis development and its cure and principal component analysis and partial least squares discriminant analysis were performed to explain metabolite variance between animals developing or not developing metritis and being cured or not being cured of metritis. Comparing HTH with MET cows at calving, 12 metabolites were upregulated, and one was downregulated. At four and seven DIM, 51 and 74 metabolites, respectively, were altered between MET and HTH cows. After metritis development, three and five metabolites were upregulated in cows that were cured and in cows that received treatment and were cured, respectively. In all scenarios, the metabolites lignoceric, malic, and maleic acids, ornithine, and hypotaurine, which are associated with arginine/aminoacyl-tRNA biosynthesis and taurine/purine metabolism, were upregulated in HTH cows. Metritis was associated with changes in the uterine metabolome. Cows not being cured of metritis had changes in the uterus metabolome independent of receiving ceftiofur or remaining untreated. Metabolome analysis may be an important tool to understand the vaginal discharge changes during postpartum and the dynamics of metritis development and cures and help to identify biomarkers to predict metritis being cured.