The knowledge about the contribution of the innate immune system to health and disease is expanding. However, to obtain reliable results, it is critical to select appropriate mouse models for in vivo studies. Data on genetic and phenotypic changes associated with different mouse strains can assist in this task. Such data can also facilitate our understanding of how specific polymorphisms and genetic alterations affect gene function, phenotypes, and disease outcomes. Extensive information is available on genetic changes in all major mouse strains. However, comparatively little is known about their impact on immune response and in particular on innate immunity. Here, we analyzed a mouse model of chronic multifocal osteomyelitis (CMO), an autoinflammatory disease driven exclusively by the innate immune system, which is caused by an inactivating mutation in the Pstpip2 gene. We investigated how the genetic background of BALB/c, C57BL/6J, and C57BL/6NCrl strains alters the molecular mechanisms controlling disease progression. While all mice developed the disease, symptoms were significantly milder in BALB/c and partially also in C57BL/6J when compared to C57BL/6NCrl. Disease severity correlated with the number of infiltrating neutrophils and monocytes and with the production of chemokines attracting these cells to the site of inflammation. It also correlated with increased expression of genes associated with autoinflammation, rheumatoid arthritis, neutrophil activation, and degranulation, resulting in altered neutrophil activation in vivo. Together, our data demonstrate striking effects of genetic background on multiple parameters of neutrophil function and activity influencing the onset and course of the CMO disease.

Mineral element accumulation in plants is influenced by soil conditions and varietal factors. We investigated the dynamic accumulation of 12 elements in straw at the flowering stage and in grains at the mature stage in eight rice varieties with different genetic backgrounds (Japonica, Indica, and admixture) and flowering times (early, middle, and late) grown in soil with various pH levels. In straw, Cd, As, Mn, Zn, Ca, Mg, and Cu accumulation was influenced by both soil pH and varietal factors, whereas P, Mo, and K accumulation was influenced by pH, and Fe and Ni accumulation was affected by varietal factors. In grains, Cd, As, Mn, Cu, Ni, Mo, Ca, and Mg accumulation was influenced by both pH and varietal factors, whereas Zn, Fe, and P accumulation was affected by varietal factors, and K accumulation was not altered. Only As, Mn, Ca and Mg showed similar trends in the straw and grains, whereas the pH responses of Zn, P, K, and Ni differed between them. pH and flowering time had synergistic effects on Cd, Zn, and Mn in straw and on Cd, Ni, Mo, and Mn in grains. Soil pH is a major factor influencing mineral uptake in rice straw and grains, and genetic factors, flowering stage factors, and their interaction with soil pH contribute in a combined manner.

Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knock-out on the development of intestinal polyps using collaborative cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knock-out mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knock-out males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knock-out, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-nearest neighbors and linear regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides new information on understanding the intricate genetic interplay in the context of Smad4 knock-out, offering valuable insights that could inform the identification of potential therapeutic targets for juvenile polyposis and related diseases.

OBJECTIVE: Patients with mutations in SCN5A encoding NaV1.5 often display variable severity of electrical and structural alterations, but the underlying mechanisms are not fully elucidated. We here investigate the combined modulatory effect of genetic background and age on disease severity in the Scn5a1798insD/+ mouse model.
RESULTS: In vivo electrocardiogram and echocardiograms, ex vivo electrical and optical mapping, and histological analyses were performed in adult (2-7 months) and aged (8-28 months) wild-type (WT) and Scn5a1798insD/+ (mutant, MUT) mice from the FVB/N and 129P2 inbred strains. Atrio-ventricular (AV) conduction, ventricular conduction, and ventricular repolarization are modulated by strain, genotype, and age. An aging effect was present in MUT mice, with aged MUT mice of both strains showing prolonged QRS interval and right ventricular (RV) conduction slowing. 129P2-MUT mice were severely affected, with adult and aged 129P2-MUT mice displaying AV and ventricular conduction slowing, prolonged repolarization, and spontaneous arrhythmias. In addition, the 129P2 strain appeared particularly susceptible to age-dependent electrical, functional, and structural alterations including RV conduction slowing, reduced left ventricular (LV) ejection fraction, RV dilatation, and myocardial fibrosis as compared to FVB/N mice. Overall, aged 129P2-MUT mice displayed the most severe conduction defects, RV dilatation, and myocardial fibrosis, in addition to the highest frequency of spontaneous arrhythmia and inducible arrhythmias.
CONCLUSIONS: Genetic background and age both modulate disease severity in Scn5a1798insD/+ mice and hence may explain, at least in part, the variable disease expressivity observed in patients with SCN5A mutations. Age- and genetic background-dependent development of cardiac structural alterations furthermore impacts arrhythmia risk. Our findings therefore emphasize the importance of continued assessment of cardiac structure and function in patients carrying SCN5A mutations.

About half of the world population carries at least one allele of the Ala92-DIO2, which slows down the activity of the type 2 deiodinase (D2), the enzyme that activates T4 to T3. Carrying the Ala92-DIO2 allele has been associated with increased body mass index and insulin resistance, but this has not been reproduced in all populations. To test if the genetic background affects the impact of this polymorphism, here we studied the genetically distant C57Bl/6J (B6) and FVB/N (FVB) mice carrying the Ala92-Dio2 allele as compared to control mice carrying the Thr92-Dio2 allele. Whereas B6-Ala92-Dio2 and B6-Thr92-Dio2 mice-fed chow or high-fat diet-behaved metabolically similar in studies using indirect calorimetry, glucose- and insulin tolerance tests, and measuring white adipose tissue (WAT) weight and liver steatosis, major differences were observed between FVB-Ala92-Dio2 and FVB-Thr92-Dio2 mice: carrying the Ala92-Dio2 allele (on a chow diet) resulted in hypercholesterolemia, smaller WAT pads, hepatomegaly, steatosis, and transcriptome changes in the interscapular brown adipose tissue (iBAT) typical of ER stress and apoptosis. Acclimatization at thermoneutrality (30 °C) eliminated most of the metabolic phenotype, indicating that impaired adaptive (BAT) thermogenesis can be involved. In conclusion, the metabolic impact of carrying the Ala92-Dio2 allele depends greatly on the genetic background of the mouse, varying from no phenotype in B6 mice to a major phenotype in FVB mice. These results will help the planning of future clinical trials studying the Thr92Ala-DIO2 polymorphism and may explain why some clinical studies performed in different populations across the globe have obtained inconsistent results.

The FZP gene plays a critical role in the formation of lateral branches and spikelets in rice panicle architecture. This study investigates the qSBN7 allele, a hypomorphic variant of FZP, and its influence on panicle architectures in different genetic backgrounds. We evaluated two backcross inbred lines (BILs), BC5_TCS10sbn and BC3_TCS10sbn, each possessing the homozygous qSBN7 allele but demonstrating differing degrees of spikelet degeneration. Our analysis revealed that BC5_TCS10sbn had markedly low FZP expression, which corresponded with an increase in axillary branches and severe spikelet degeneration. Conversely, BC3_TCS10sbn exhibited significantly elevated FZP expression, leading to fewer secondary and tertiary branches, and consequently decreased spikelet degeneration. Compared to BC5_TCS10sbn, BC3_TCS10sbn carries three additional chromosomal substitution segments from its donor parent, IR65598-112-2. All three segments significantly enhance the expression of FZP and reduce the occurrence of tertiary branch and spikelet degeneration. These findings enhance our understanding of the mechanisms regulating FZP and aid rice breeding efforts.

In this study, BC3F2 convergent population [(K343*3/RML22 × K343*3/DHMAS) × K343] was constructed by marker-assisted backcross breeding using K343 as the recurrent parent. DHMAS and RML22 were used as donor parents for the rice blast resistance genes Pi54 and Pi9, respectively. The population was first characterized using GGT 2.0 software, which showed 96.7% of the recurrent genome recovery covering 13953.6 cM, while DHMAS and RML22 showed 1.6% (235.5 cM) and 1.2% (177.1 cM) introgression respectively. The chromosomal segment substitution lines (CSSLs) were then identified using CSSL Finder software. A total of 36 CSSLs were identified, including 22 for DHMAS/K343 and 14 for RML22/K343. Introgression rates for donor substituted segments in DHMAS/K343 CSSLs ranged from 0.54% to 5.99%, with donor coverage of 44.5%, while in RML22/K343 CSSLs, introgression rates ranged from 0.54% to 4.75%, with donor coverage of 24.5%. The identified CSSLs would be a valuable genetic pool and could be used as genomic resources for the discovery and mapping of important genes and QTLs in rice genetic improvement.

BACKGROUND: Patients with nonischemic dilated cardiomyopathy (DCM), severe left ventricular (LV) dysfunction, and complete left bundle branch block benefit from cardiac resynchronization therapy (CRT). However, a large heterogeneity of response to CRT is described. Several predictors of response to CRT have been identified, but the role of the underlying genetic background is still poorly explored.
OBJECTIVE: In the present study, the authors sought to define differences in LV remodeling and outcome prediction after CRT when stratifying patients according to the presence or absence of DCM-causing genetic background.
METHODS: From our center, 74 patients with DCM subjected to CRT and available genetic testing were retrospectively enrolled. Carriers of causative monogenic variants in validated DCM-causing genes, and/or with documented family history of DCM, were classified as affected by genetically determined disease (GEN+DCM) (n = 25). Alternatively, by idiopathic dilated cardiomyopathy (idDCM) (n = 49). The primary outcome was long-term LV remodeling and prevalence of super response to CRT (evaluated at 24-48 months after CRT); the secondary outcome was heart failure-related death/heart transplant/LV assist device.
RESULTS: GEN+DCM and idDCM patients were homogeneous at baseline with the exception of QRS duration, longer in idDCM. The median follow-up was 55 months. Long-term LV reverse remodeling and the prevalence of super response were significantly higher in the idDCM group (27% in idDCM vs 5% in GEN+DCM; P = 0.025). The heart failure-related death/heart transplant/LV assist device outcome occurred more frequently in patients with GEN+DCM (53% vs 24% in idDCM; P = 0.028).
CONCLUSIONS: Genotyping contributes to the risk stratification of patients with DCM undergoing CRT implantation in terms of LV remodeling and outcomes.

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