Srsf1 and Elavl1 act antagonistically on neuronal fate choice in the developing neocortex by controlling TrkC receptor isoform expression.

The seat of higher-order cognitive abilities in mammals, the neocortex, is a complex structure, organized in several layers. The different subtypes of principal neurons are distributed in precise ratios and at specific positions in these layers and are generated by the same neural progenitor cells (NPCs), steered by a spatially and temporally specified combination of molecular cues that are incompletely understood. Recently, we discovered that an alternatively spliced isoform of the TrkC receptor lacking the kinase domain, TrkC-T1, is a determinant of the corticofugal projection neuron (CFuPN) fate. Here, we show that the finely tuned balance between TrkC-T1 and the better known, kinase domain-containing isoform, TrkC-TK+, is cell type-specific in the developing cortex and established through the antagonistic actions of two RNA-binding proteins, Srsf1 and Elavl1. Moreover, our data show that Srsf1 promotes the CFuPN fate and Elavl1 promotes the callosal projection neuron (CPN) fate in vivo via regulating the distinct ratios of TrkC-T1 to TrkC-TK+. Taken together, we connect spatio-temporal expression of Srsf1 and Elavl1 in the developing neocortex with the regulation of TrkC alternative splicing and transcript stability and neuronal fate choice, thus adding to the mechanistic and functional understanding of alternative splicing in vivo.

The impact of antibiotic stewardship interventions and patient related factors on antibiotic prescribing in a vascular surgical department.

PURPOSE: The development of guidelines tailored to the departments' needs and counselling during ward rounds are important antibiotic stewardship (AS) strategies. The aim was to analyse the impact of AS ward rounds and institutional guidelines as well as patient-related factors on antibiotic use in vascular surgical patients. METHODS: A retrospective prescribing-analysis of 3 months (P1, P2) before and after implementing weekly AS ward rounds and antimicrobial treatment guidelines was performed. Choice of systemic antibiotics, days of antibiotic therapy and clinical data were obtained from electronic patient records. RESULTS: During P2, the overall antibiotic consumption as well as the use of last-resort compounds like linezolid and fluoroquinolones decreased distinctly (overall: 47.0 days of therapy (DOT)/100 patient days (PD) vs. 35.3 DOT/100PD, linezolid: 3.7 DOT/100PD vs. 1.0 DOT/100PD, fluoroquinolones: 7.0 DOT/100PD vs. 3.2 DOT/100PD) while narrow-spectrum beta-lactams increased by 48.4%. Courses of antibiotics were de-escalated more often during P2 (30.5% vs. 12.1%, p = 0.011). Only in P2, an antibiotic therapy was initiated in patients suffering from more comorbidities (i.e. higher Charlson Comorbidity Index) more frequently. Other patient factors had no distinct impact on antibiotic prescribing. CONCLUSION: Weekly AS ward rounds improved adherence to institutional antibiotic treatment guidelines and antibiotic prescribing in vascular surgical patients. Clear patient-related determinants affecting choice of antibiotic therapies could not be identified.

Measurement of the α-Particle Monopole Transition Form Factor Challenges Theory: A Low-Energy Puzzle for Nuclear Forces?

We perform a systematic study of the α-particle excitation from its ground state 0_{1}^{+} to the 0_{2}^{+} resonance. The so-called monopole transition form factor is investigated via an electron scattering experiment in a broad Q^{2} range (from 0.5 to 5.0 fm^{-2}). The precision of the new data dramatically supersedes that of older sets of data, each covering only a portion of the Q^{2} range. The new data allow the determination of two coefficients in a low-momentum expansion, leading to a new puzzle. By confronting experiment to state-of-the-art theoretical calculations, we observe that modern nuclear forces, including those derived within chiral effective field theory that are well tested on a variety of observables, fail to reproduce the excitation of the α particle.

Imputation of precipitation data in northeast Brazil.

This article evaluates four statistical methods of multiple imputation to fill in the missing data of daily precipitation in Northeast Brazil (NEB). We used a daily database collected by 94 rain gauges distributed in NEB from January 1, 1986 to December 31, 2015. The methods were: random sampling from the observed values; predictive mean matching, Bayesian linear regression; and bootstrap expectation maximization algorithm (BootEm). To compare these methods, missing data from the original series were initially excluded. The next step was to create three scenarios for each method, in which 10\%, 20\% and 30\% of the data were removed at random. The BootEM method presented the best statistical results. With the average bias between the complete series and the imputed series values ranging between -0.91 and 1.30 mm/day. The values of the Pearson correlation ranging between 0.96, 0.91 and 0.86 respectively for 10\%, 20\% and 30\% missing data. We conclude that this is an adequate method for the reconstruction of historical precipitation data in NEB.

The value of honey dressings in pilonidal cyst healing: a prospective randomized single-center trial.

BACKGROUND: Honey is described as a wound healing agent. Many virtues have been attributed to it, in particular, antibacterial properties. The aim of our study was to evaluate its value in healing of wounds after wide excision on pilonidal cyst healing. METHODS: A prospective randomized trial was conducted from March 2016 to February 2022 which included patients with a persistent non healed wound which required packing 6 weeks after pilonidal cyst excision. Patients were randomly allocated to simple alginate wick dressings or the same design plus honey. RESULTS: Fifty patients were included in each arm. There were 57 men and 43 women. The median age was 22 years (range 19-28 years). The mean healing time was 61 (± 44) days in the wick + honey group compared to 78 (± 55) days in the simple alginate wick group (p = 0.094). There was no significant difference between the two groups in terms of time off work and time without physical activity The VQ-Dermato quality of life score was equivalent in both groups. CONCLUSIONS: Tolerability for honey dressings is good and is equivalent to that of alginate dressings in cavity wound care. This trial did not reach a significant difference in its primary endpoint but it shows the value of honey in this indication, although its use requires further study. TRIAL REGISTRATION NUMBER: CLINICAL TRIALS: NCT02485860 and EUDRACT: 2015-A00452-47 (10/03/2015).

Cartilage repair strategies in the knee according to Dutch Orthopedic Surgeons: a survey study.

BACKGROUND: This study surveyed Dutch orthopedic surgeons on the management of cartilage defects in the knee and the adherence to the recently updated Dutch knee cartilage repair consensus statement (DCS). METHODS: A web-based survey was sent to 192 Dutch knee specialists. RESULTS: The response rate was 60%. Microfracture, debridement and osteochondral autografts are performed by the majority, 93%, 70% and 27% of respondents, respectively. Complex techniques are used by < 7%. Microfracture is mainly considered in defects 1-2 cm2 (by > 80%) but also in 2-3 cm2 (by > 40%). Concomitant procedures, e.g., malalignment corrections, are performed by 89%. Twenty-one percent of surgeons treat patients aged 40-60 years. Microfracture, debridement and autologous chondrocyte implantation are not considered to be highly affected by age > 40 years by any of the respondents (0-3%). Moreover, for the middle-aged there is a large spread in treatments considered. In case of loose bodies, the majority (84%) only performs refixation in the presence of attached bone. CONCLUSION: Small cartilage defects in ideal patients may be well treated by general orthopedic surgeons. The matter becomes complicated in older patients, or in case of larger defects or malalignment. The current study reveals some knowledge gaps for these more complex patients. Referral to tertiary centers might be indicated, as is stated by the DCS, and this centralization should enhance knee joint preservation. Since the data from present study are subjective, registration of all separate cartilage repair cases should fuel objective analysis of clinical practice and adherence to the DCS in the future.

The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc.

Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual disability, developmental delays, microcephaly, and characteristic dysmorphisms. Biallelic mutations of UBE3B, encoding for a ubiquitin ligase E3B are causative for KOS. In this report, we characterize neuronal functions of its murine ortholog Ube3b and show that Ube3b regulates dendritic branching in a cell-autonomous manner. Moreover, Ube3b knockout (KO) neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology, and changes in hippocampal circuit activity. Dorsal forebrain-specific Ube3b KO animals show impaired spatial learning, altered social interactions, and repetitive behaviors. We further demonstrate that Ube3b ubiquitinates the catalytic γ-subunit of calcineurin, Ppp3cc, the overexpression of which phenocopies Ube3b loss with regard to dendritic spine density. This work provides insights into the molecular pathologies underlying intellectual disability-like phenotypes in a genetically engineered mouse model.

TrkC-T1, the Non-Catalytic Isoform of TrkC, Governs Neocortical Progenitor Fate Specification by Inhibition of MAP Kinase Signaling.

Neocortical projection neurons are generated by neural progenitor cells (NPCs) within the ventricular and subventricular zone. While early NPCs can give rise to both deep and upper layer neurons, late progenitors are restricted to upper layer neurogenesis. The molecular mechanisms controlling the differentiation potential of early versus late NPCs are unknown. Here, we report a novel function for TrkC-T1, the non-catalytic isoform of the neurotrophin receptor TrkC, that is distinct from TrkC-TK+, the full-length isoform. We provide direct evidence that TrkC-T1 regulates the switch in NPC fate from deep to upper layer neuron production. Elevated levels of TrkC-T1 in early NPCs promote the generation of deep layer neurons. Conversely, downregulation of TrkC-T1 in these cells promotes upper layer neuron fate. Furthermore, we show that TrkC-T1 exerts this control by interaction with the signaling adaptor protein ShcA. TrkC-T1 prevents the phosphorylation of Shc and the downstream activation of the MAP kinase (Erk1/2) pathway. In vivo manipulation of the activity of ShcA or Erk1/2, directly affects cortical neuron cell fate. We thus show that the generation of upper layer neurons by late progenitors is dependent on the downregulation of TrkC-T1 in late progenitor cells and the resulting activation of the ShcA/Erk1/2 pathway.

Peripheral isolation and demographic stability are reflected in the genetic diversity of the populations of the Helmeted Manakin: a bird endemic to the gallery forests.

The Cerrado encompasses a complex network of hydrographic basins, which is responsible for the formation and maintenance of the riparian and gallery forests. Alterations in the vegetation resulting from the paleoclimatic changes that occurred during the Pleistocene influenced the current distribution of these humid forests. To understand of the evolutionary dynamics of this landscape on the population structure of the associated organisms, we studied the population genetics of the Antilophia galeata (Pipridae), a bird endemic to the gallery forests of the Cerrado. For this, we evaluated the variability of the mitochondrial control region of 71 A. galeata specimens from 18 localities distributed throughout the Cerrado. The results indicated the existence of significant substructure among the populations located in the peripheral areas of the Cerrado, in comparison with the populations found in the central portion, reflecting historical changes in the environment. We also found high levels of diversity in all the populations, while the analysis of the demographic history revealed a scenario of stability. Overall, then, these findings indicate that the historical modifications of the gallery forest distribution may have been most accentuated in the peripheral zones, with a greater stability and connectivity persisting in the central portion of the biome.

Cladribine modifies functional properties of microglia.

Cladribine (CdA), an oral prodrug approved for the treatment of relapsing multiple sclerosis, selectively depletes lymphocytes. CdA passes the blood-brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. We examined if CdA modifies the phenotype and function of naive and activated primary mouse microglia, when applied in the concentrations 0·1-1 µM that putatively overlap human cerebrospinal fluid (CSF) concentrations. Primary microglia cultures without stimulation or in the presence of proinflammatory lipopolysaccharide (LPS) or anti-inflammatory interleukin (IL)-4 were treated with different concentrations of CdA for 24 h. Viability was assessed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Phagocytotic ability and morphology were examined by flow cytometry and random migration using IncuCyte Zoom and TrackMate. Change in gene expression was examined by quantitative polymerase chain reaction (qPCR) and protein secretion by Meso Scale Discovery. We found that LPS and IL-4 up-regulated deoxycytidine kinase (DCK) expression. Only activated microglia were affected by CdA, and this was unrelated to viability. CdA 0·1-1 µM significantly reduced granularity, phagocytotic ability and random migration of activated microglia. CdA 10 µM increased the IL-4-induced gene expression of arginase 1 (Arg1) and LPS-induced expression of IL-1ß, tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS) and Arg1, but protein secretion remained unaffected. CdA 10 µM potentiated the increased expression of anti-inflammatory TNF receptor 2 (TNF-R2) but not TNF-R1 induced by LPS. This suggests that microglia acquire a less activated phenotype when treated with 0·1-1 µM CdA that putatively overlaps human CSF concentrations. This may be related to the up-regulated gene expression of DCK upon activation, and suggests a potential alternative mechanism of CdA with direct effect on CNS resident cells.

Cubic Rashba Effect in the Surface Spin Structure of Rare-Earth Ternary Materials.

Spin-orbit interaction and structure inversion asymmetry in combination with magnetic ordering is a promising route to novel materials with highly mobile spin-polarized carriers at the surface. Spin-resolved measurements of the photoemission current from the Si-terminated surface of the antiferromagnet TbRh_{2}Si_{2} and their analysis within an ab initio one-step theory unveil an unusual triple winding of the electron spin along the fourfold-symmetric constant energy contours of the surface states. A two-band k·p model is presented that yields the triple winding as a cubic Rashba effect. The curious in-plane spin-momentum locking is remarkably robust and remains intact across a paramagnetic-antiferromagnetic transition in spite of spin-orbit interaction on Rh atoms being considerably weaker than the out-of-plane exchange field due to the Tb 4f moments.

Comparative population genomics in animals uncovers the determinants of genetic diversity.

Genetic diversity is the amount of variation observed between DNA sequences from distinct individuals of a given species. This pivotal concept of population genetics has implications for species health, domestication, management and conservation. Levels of genetic diversity seem to vary greatly in natural populations and species, but the determinants of this variation, and particularly the relative influences of species biology and ecology versus population history, are still largely mysterious. Here we show that the diversity of a species is predictable, and is determined in the first place by its ecological strategy. We investigated the genome-wide diversity of 76 non-model animal species by sequencing the transcriptome of two to ten individuals in each species. The distribution of genetic diversity between species revealed no detectable influence of geographic range or invasive status but was accurately predicted by key species traits related to parental investment: long-lived or low-fecundity species with brooding ability were genetically less diverse than short-lived or highly fecund ones. Our analysis demonstrates the influence of long-term life-history strategies on species response to short-term environmental perturbations, a result with immediate implications for conservation policies.

Rise of nations: Why do empires expand and fall?

We consider centralized networks composed of multiple satellites arranged around a few dominating super-egoistic centers. These so-called empires are organized using a divide and rule framework enforcing strong center-satellite interactions while keeping the pairwise interactions between the satellites sufficiently weak. We present a stochastic stability analysis, in which we consider these dynamical systems as stable if the centers have sufficient resources while the satellites have no value. Our model is based on a Hopfield type network that proved its significance in the field of artificial intelligence. Using this model, it is shown that the divide and rule framework provides important advantages: it allows for completely controlling the dynamics in a straight-forward way by adjusting center-satellite interactions. Moreover, it is shown that such empires should only have a single ruling center to provide sufficient stability. To survive, empires should have switching mechanisms implementing adequate behavior models by choosing appropriate local attractors in order to correctly respond to internal and external challenges. By an analogy with Bose-Einstein condensation, we show that if the noise correlations are negative for each pair of nodes, then the most stable structure with respect to noise is a globally connected network. For social systems, we show that controllability by their centers is only possible if the centers evolve slowly. Except for short periods when the state approaches a certain stable state, the development of such structures is very slow and negatively correlated with the size of the system's structure. Hence, increasing size eventually ends up in the "control trap."

[Molecular tumor diagnostics-current methods, examples of application and future]. / Molekulare Tumordiagnostik ­ aktuelle Methoden, Anwendungsbeispiele und Ausblick.

Molecular tumor diagnostics is rapidly evolving, driven by technological advances in high-throughput sequencing and bioinformatics, and paralleled by the emergence of novel therapeutic approaches, not least in the field of immune oncology. Molecular stratification of common tumor entities such as colorectal carcinoma and the discovery of paradigmatic molecular changes such as NTRK fusions illustrate how molecular pathological investigations can be performed under diagnostic or predictive conditions and can also provide prognostic information. Promising recent developments include "liquid biopsy" and tumor agnostic strategies. A functioning interdisciplinary cooperation between oncology, bioinformatics and molecular pathology is prerequisite for modern oncological diagnostics based on the current state-of-the-art knowledge and decisive for optimal care of oncological patients.

Recruitment of activated neutrophils correlates with disease severity in adult Crohn's disease.

Neutrophils are detected in inflamed colon in Crohn's disease (CD). However, whether the frequency and/or activation of circulating or gut tissue neutrophils correlate with endoscopic severity remains to be investigated. A cohort of 73 CD patients was prospectively enrolled according to endoscopic severity and treatment history. Individuals with active disease were stratified using the Montreal classification. Harvey-Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn's Disease (SES-CD) were performed at the time of ileocolonoscopy. Frequency of neutrophils and their expression of CD66b and CD64 were assessed in paired blood and colonic biopsies using flow cytometry. The percentage of neutrophils increased in inflamed colon and correlated with SES-CD in the entire cohort of patients examined, as well as in the subgroup with inflammatory (B1) active disease. SES-CD further correlated with neutrophil CD66b expression in mucosa but not blood and, conversely, with neutrophil CD64 expression in blood but not mucosa. However, the evaluation of neutrophil activation in mucosa when compared to blood reflected disease activity more clearly. Finally, a neutrophil activation power index (CD66b in mucosa X CD64 in blood) that correlated with SES-CD discriminated between patients with mild and severe disease. In conclusion, the frequency and activation of colonic neutrophils correlated with SES-CD, highlighting that mucosal neutrophils are associated with disease severity in CD.

New Insight in the Q

Virtual Compton scattering on the proton has been investigated at three yet unexplored values of the four-momentum transfer Q^{2}: 0.10, 0.20, and 0.45 GeV^{2}, at the Mainz Microtron. Fits performed using either the low-energy theorem or dispersion relations allowed the extraction of the structure functions P_{LL}-P_{TT}/ε and P_{LT}, as well as the electric and magnetic generalized polarizabilities α_{E1}(Q^{2}) and ß_{M1}(Q^{2}). These new results show a smooth and rapid falloff of α_{E1}(Q^{2}), in contrast to previous measurements at Q^{2}=0.33 GeV^{2}, and provide for the first time a precise mapping of ß_{M1}(Q^{2}) in the low-Q^{2} region.

Arabidopsis species deploy distinct strategies to cope with drought stress.

BACKGROUND AND AIMS: Water limitation is an important determinant of the distribution, abundance and diversity of plant species. Yet, little is known about how the response to limiting water supply changes among closely related plant species with distinct ecological preferences. Comparison of the model annual species Arabidopsis thaliana with its close perennial relatives A. lyrata and A. halleri, can help disentangle the molecular and physiological changes contributing to tolerance and avoidance mechanisms, because these species must maintain tolerance and avoidance mechanisms to increase long-term survival, but they are exposed to different levels of water stress and competition in their natural habitat. METHODS: A dry-down experiment was conducted to mimic a period of missing precipitation. The covariation of a progressive decrease in soil water content (SWC) with various physiological and morphological plant traits across a set of representative genotypes in A. thaliana, A. lyrata and A. halleri was quantified. Transcriptome changes to soil dry-down were further monitored. KEY RESULTS: The analysis of trait covariation demonstrates that the three species differ in the strategies they deploy to respond to drought stress. Arabidopsis thaliana showed a drought avoidance reaction but failed to survive wilting. Arabidopsis lyrata efficiently combined avoidance and tolerance mechanisms. In contrast, A. halleri showed some degree of tolerance to wilting but it did not seem to protect itself from the stress imposed by drought. Transcriptome data collected just before plant wilting and after recovery corroborated the phenotypic analysis, with A. lyrata and A. halleri showing a stronger activation of recovery- and stress-related genes, respectively. CONCLUSIONS: The response of the three Arabidopsis species to soil dry-down reveals that they have evolved distinct strategies to face drought stress. These strategic differences are in agreement with the distinct ecological priorities of the stress-tolerant A. lyrata, the competitive A. halleri and the ruderal A. thaliana.

A retrospective clinical and microbial analysis of 32 patients with bilomas.

BACKGROUND: Bilomas are defined collections of bile fluids mainly caused by iatrogenic injuries of the bile duct system. Owing to the infrequency of this disease, studies addressing bilomas are rare. METHODS: By using an endoscopic database, this retrospective study identified 32 patients with bilomas treated between 2004 to 2015, in order to analyse aetiology, clinical presentation, spectrum of pathogens, and resolution rate of bilomas. RESULTS: 65.6% of the study population (21/32) developed bilomas after surgery and 21.9% (7/32) after endoscopic retrograde cholangiography (ERC). Icterus, fever, and abdominal pain were the leading symptoms. 93.9% (46/49) of microbiological bile cultures revealed a positive microbiology. The predominant microorganisms were the group of Enterobacteriaceae (43.0%, 52/121), followed by Enterococcus spp. (32.2%, 39/121), and Candida spp. (9.1%, 11/121). Multiresistant bacteria like Enterobacteriaceae were isolated from one quarter of all patients. Single or multimodal treatment resulted in an overall complication rate of 4.8% (9/188). Clinical follow-up analysis showed a complete resolution rate of 78.3% for interventional therapy and 80% in the non-interventional group. CONCLUSIONS: Pathogen spectrum of bilomas mainly comprises the group of Enterobacteriacae and Enterococcus spp., with a high proportion of multiresistant bacteria. Different interventional approaches are available for biloma drainage, which seem to be safe and effective for most patients. TRIAL REGISTRATION: German Clinical Trials Register DRKS00015208 , retrospectively registered.

Early Clinical Experience with Double Ring Implantation for Aortic and Mitral Valve Repair.

Reconstruction of cardiac valves is associated with reduced mortality, including in multiple valve surgery. However, multiple valve repair is still considered a challenge, even with established techniques. Recently, internal aortic ring annuloplasty has been introduced and could simplify multiple valve reconstruction. This study reports early results with double ring aortic and mitral valve repair. Three patients with bivalvular degenerative regurgitation were managed with combined aortic and mitral valve repair using double rings. Mean (±SD) age was 41 ± 21 years, preoperative left ventricular end-diastolic volume was 119 ± 53 mL/m2, and ejection fraction was 0.50 ± 0.07. Mean aortic ring diameter was 21 mm, and mitral rings averaged 32 mm. No operative mortalities or major complications were observed. No valve-related events occurred. Postoperative echo showed complete resolution of mitral and aortic regurgitation. Postoperative left ventricular end-diastolic volume decreased to 98 ± 10 mL/m2; no left ventricular outflow tract obstruction or significant transvalvular gradients were observed. Postoperative cardiac CTs showed an optimal three-dimensional configuration of aortic and mitral annuloplasty devices. This initial series demonstrated the feasibility and safety of combined aortic and mitral repair with double rings. Clinical and hemodynamic results were promising. Increasing application and more clinical experience with combined aortic and mitral double ring repair seems indicated.

Hepatic transcript profiling in early-lactation dairy cows fed rumen-protected niacin during the transition from late pregnancy to lactation.

In dairy cows, administration of high dosages of niacin (nicotinic acid, NA) was found to cause antilipolytic effects, which are mediated by the NA receptor hydroxyl-carboxylic acid receptor 2 (HCAR2) in white adipose tissue (WAT), and thereby an altered hepatic lipid metabolism. However, almost no attention has been paid to possible direct effects of NA in cattle liver, despite evidence that HCAR2 is also expressed in the liver and is even more abundant than in WAT. Because of this, we hypothesized that feeding a high dosage of rumen-protected NA to dairy cows influences critical metabolic or signaling pathways in the liver by inducing changes in the hepatic transcriptome. To identify these pathways, we applied genome-wide transcript profiling in liver biopsies obtained at d 7 postpartum (p.p.) from dairy cows used in our recent study; cows received either no NA (control group, n = 9) or 79 mg of rumen-protected NA/kg of body weight daily (NA group, n = 9) from 21 d before calving until 3 wk p.p. Hepatic transcript profiling revealed that 487 transcripts were differentially expressed (filter criteria: fold change >1.2 or <-1.2 and P < 0.05) in the liver at d 7 p.p. between cows fed NA and control cows. Substantially more transcripts were downregulated (n = 338), whereas only 149 transcripts were upregulated by NA in the liver of cows. Gene set enrichment analysis for the upregulated transcripts revealed that the most-enriched gene ontology biological process terms were exclusively related to immune processes, such as leukocyte differentiation, immune system process, activation of immune response, and acute inflammatory response. Gene set enrichment analysis of the downregulated transcripts showed that the most-enriched biological process terms were related to metabolic processes, such as cellular metabolic process, small molecule metabolic process, lipid catabolic process, organic cyclic compound metabolic process, small molecule biosynthetic process, and cellular lipid catabolic process. In conclusion, hepatic transcriptome analysis showed that rumen-protected NA induces genes that are involved mainly in immune processes, including acute phase response and stress response, in dairy cows at d 7 p.p. Thus, supplementation of a high dosage of rumen-protected NA to dairy cows in the periparturient period may induce or amplify the systemic inflammation-like condition that is typically observed in the liver of high-yielding dairy cows in the p.p. period.