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PubMed2004

Intraspecific mating with CzechII/Ei mice rescue lethality associated with loss of function mutations of the imprinted genes, Igf2r and Cdkn1c.

Maternal inheritance of targeted loss of function alleles encoding either the cyclin-dependent kinase inhibitor 1C (Cdkn1c) or the insulin-like growth factor 2 receptor (Igf2r) leads to fully penetrant perinatal lethality in C57BL/6J mice due to genomic imprinting. Here, we demonstrate that there is a marked enhancement in postnatal viability of F(1) mice carrying either the ablated Igf2r ( approximately 32%) or Cdkn1c ( approximately 83%) when the paternal genome was derived from the inbred Mus musculus musculus CzechII/Ei strain. Genetic and molecular analyses indicated that the increased viability was not caused by relaxation of imprinted gene expression, but is the consequence of unidentified polygenic modifiers that are not imprinted. In the course of this study, restriction-site polymorphisms between 129S1 and CzechII/Ei in 21 imprinted and 14 biallelically expressed genes were identified. These polymorphisms may prove useful in determining the effects of different mutant backgrounds on genomic imprinting.

Alleles↗
PubMed2025

Rare variants and survival of patients with idiopathic pulmonary fibrosis: analysis of a multicentre, observational cohort study with independent validation.

BACKGROUND: Rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in idiopathic pulmonary fibrosis (IPF). We aimed to assess whether rare qualifying variants in monogenic adult-onset pulmonary fibrosis genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in patients carrying the qualifying variants. METHODS: We identified qualifying variants in telomere and non-telomere genes using whole-genome sequences from individuals clinically diagnosed with IPF and enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFFPR), a large multicentre, observational cohort study (March 29, 2016 to June 15, 2018, n=888). We also derived a PRS for IPF (PRS-IPF) from known common sentinel IPF variants. The primary outcome was the association between qualifying variants and survival. The secondary outcome was the association between qualifying variants and PRS-IPF. We used logistic regression models adjusted for sex, age at diagnosis, and principal components of genetic heterogeneity to examine the mutual relationship of qualifying variants and PRS-IPF. The association between qualifying variants and PRS-IPF with survival was tested using Cox proportional hazard models adjusted for baseline confounders. Validation of the results was sought in data from an independent multicentre, prospective, observational cohort study of IPF in the UK (PROFILE, May 17, 2010 to Sept 5, 2017, n=472), and results were meta-analysed under a fixed-effects model. FINDINGS: We included 888 patients from PFFPR and 472 from PROFILE, totalling 1360 participants. In the PFFPR, carriers of qualifying variants in monogenic adult-onset pulmonary fibrosis genes were associated with lower PRS-IPF (odds ratio 1·79 [95% CI 1·15-2·81]; p=0·010) and shorter survival (hazard ratio 1·53 [1·12-2·10]; p=7·33 × 10-3). Individuals with the lowest PRS-IPF also had worse survival (1·61 [1·25-2·07]; p=1·87 × 10-4). These findings were validated in PROFILE and the meta-analysis of the results showed a consistent direction of effect across both cohorts. INTERPRETATION: We found non-additive effects between qualifying variants and common risk variants in IPF survival, suggesting distinct disease subtypes and raising the possibility of using PRS to guide sequencing prioritisation. Assessing the carrier status for qualifying variants and modelling PRS-IPF promises to further contribute to predicting disease progression among patients with IPF. FUNDING: Instituto de Salud Carlos III; Instituto Tecnológico y de Eenergías Renovables; Cabildo Insular de Tenerife; Fundación DISA; National Heart, Lung, and Blood Institute of the US National Institutes of Health; and UK Medical Research Council.

Humans↗
PubMed2026

Phenotypic and genotypic risk factors for uveal melanoma in a high ambient UV radiation environment.

BACKGROUND: Most evidence regarding risk factors for uveal melanoma (UM) derives from case-control studies prone to recall bias, and its rarity has limited prospective research. To address these gaps, we applied a population-based case-control design incorporating polygenic risk scores and Mendelian randomization to explore genetic and phenotypic determinants of UM risk. METHODS: The study was conducted in Queensland, Australia. Incident UM cases diagnosed between 2011 and 2022 were recruited through specialist ocular oncology clinics. Controls were participants in the QSkin Sun and Health Study, a prospective cohort of 43,794 adults aged 40-69 at baseline (2010-2011). Demographic, phenotypic, and sun exposure factors were harmonized across studies. Polygenic risk scores were calculated for pigmentation traits and nevi characteristics using genome-wide association study datasets, and Mendelian randomization was used to assess potential causal relationships with UM risk. RESULTS: Among 485 UM cases and 43,724 controls, several phenotypic traits were strongly associated with UM risk: male sex, blue or light eye color, inability to tan, freckling, and high nevus density. A family history of cutaneous melanoma and a personal history of keratinocyte cancer were also associated with higher risk. Polygenic risk score analyses confirmed significant associations for eye color and freckling. Mendelian randomization analyses supported causal relationships between lighter eye color, freckling propensity, reduced tanning ability and UM risk. CONCLUSIONS: These findings provide genetic evidence supporting a causal role for pigmentation-related traits in UM susceptibility. IMPACT: This evidence may help refine risk assessment and inform counselling for individuals with suspicious ocular lesions.

Journal Article↗
PubMed2005

The emergence of a new paradigm of pharmacogenomics.

A series of qualitatively new properties of the complex polygenic systems are transforming the dominant, genome-centric approach of pharmacogenomics towards a more integrative, holistic paradigm. The recent concepts of interposition of regulatory networks between genotype and phenotype, and the emergence of epigenotype as the locus of integration of genetic background with nutritional and lifestyle influences, render problematic any prediction of the consequences of individual gene alterations. In addition, the redefinition of the traditional boundaries of clinical phenotypes, with the promotion of the endophenotypes as methodological strategy, and the initiative of the phenome elucidation, reshape both the research, as well as the application, of pharmacogenomics. These concepts and developments can explain some of the complexity, and the multifactorial nature, of most drug responses and imply another understanding of education in the field, which aims at stimulating a critical reflection on these major shifts prior to a practical training on the immediate application of pharmacogenomics.

Humans↗
PubMed2005

Genetic basis of hybrid male sterility among three closely related species of Drosophila.

The genetic basis of hybrid male sterility among three closely related species, Drosophila bipectinata, D. parabipectinata and D. malerkotliana has been investigated by using backcross analysis methods. The role of Y chromosome, major hybrid sterility (MHS) genes (genetic factors) and cytoplasm (non-genetic factor) have been studied in the hybrids of these three species. In the species pair, bipectinata--parabipectinata, Y chromosome introgression of parabipectinata in the genomic background of bipectinata and the reciprocal Y chromosome introgression were unsuccessful as all males in second backcross generation were sterile. Neither MHS genes nor cytoplasm was found important for sterility. This suggests the involvement of X-Y, X-autosomes or polygenic interactions in hybrid male sterility. In bipectinata--malerkotliana and parabipectinata--malerkotliana species pairs, Y chromosome substitution in reciprocal crosses did not affect male fertility. Backcross analyses also show no involvement of MHS genes or cytoplasm in hybrid male sterility in these two species pairs. Therefore, X- autosome interaction or polygenic interaction is supposed to be involved in hybrid male sterility in these two species pairs. These findings also provide evidence that even in closely related species, genetic interactions underlying hybrid male sterility may vary.

Animals↗
PubMed2006

Chromosome 2 locus Nidd5 has a potent effect on adiposity in the TSOD mouse.

We previously reported a quantitative trait locus for body weight, non-insulin-dependent diabetes 5 (Nidd5), on Chromosome 2 in the TSOD (Tsumura, Suzuki, Obese Diabetes) mouse, a model of polygenic obese type 2 diabetes. To find the gene responsible for a specific component of the pathogenesis, we used a marker-assisted selection protocol to produce congenic strains. These mice are designed to carry a control BALB/cA-derived genomic interval and a TSOD background to look for loss of phenotype. One of the strains with the widest congenic interval, D2Mit297-D2Mit304, showed reductions in both body weight and adiposity compared with TSOD mice. The phenotypic analyses of other congenic strains further narrowed the locus in a 9.4-Mb interval between D2Mit433 and D2Mit91, around which numerous loci for body weight and adiposity have been mapped previously. Although the locus showed a relatively modest effect on body weight, it had a major influence on fat mass that explains approximately 60% of the difference in the adipose index between parental TSOD and BALB/cA mice. Furthermore, the congenic strain with a minimal BALB/cA-derived region showed significantly smaller cell sizes of white and brown adipocytes compared with the control littermates. However, the locus did not primarily affect food consumption, general activity, or rectal temperature after cold exposure, although there are clear differences in these traits between the parental strains. The present work physically delineates the major locus for adiposity in the TSOD mouse.

Adipose Tissue↗
PubMed2004

Idd1 and Idd3 are necessary but not sufficient for development of type 1 diabetes in NOD mouse.

Type 1 diabetes in the NOD mouse is under polygenic control, with a major susceptibility gene, Idd1, in the major histocompatibility complex (MHC). To investigate the contribution of the NOD MHC to type 1 diabetes susceptibility, a B6.NOD-H-2 congenic strain, in which the NOD MHC was introgressed onto the genetic background of the C57BL/6 strain, was established. Despite possession of the diabetogenic MHC from the NOD mouse, none of the B6.NOD-H-2 mice developed type 1 diabetes, indicating that the NOD MHC alone is not sufficient for type 1 diabetes and that non-MHC genes are also necessary. One of the strongest non-MHC genes is Idd3, and Il2 which encodes interleukin 2, is a candidate gene for Idd3. To test whether a combination of the NOD MHC with the NOD allele of Il2 is sufficient for type 1 diabetes, B6.NOD-H-2 mice were crossed with C3H mice, which possess the NOD allele at Il2, and F2 mice homozygous for NOD alleles at both the MHC and Il2 were produced. None of the F2 mice developed type 1 diabetes, suggesting that NOD alleles at MHC (Idd1) and Il2 (Idd3) are not sufficient for type 1 diabetes in the NOD mouse.

Amino Acid Sequence↗
PubMed2006

SNP-SNP interactions in breast cancer susceptibility.

BACKGROUND: Breast cancer predisposition genes identified to date (e.g., BRCA1 and BRCA2) are responsible for less than 5% of all breast cancer cases. Many studies have shown that the cancer risks associated with individual commonly occurring single nucleotide polymorphisms (SNPs) are incremental. However, polygenic models suggest that multiple commonly occurring low to modestly penetrant SNPs of cancer related genes might have a greater effect on a disease when considered in combination. METHODS: In an attempt to identify the breast cancer risk conferred by SNP interactions, we have studied 19 SNPs from genes involved in major cancer related pathways. All SNPs were genotyped by TaqMan 5'nuclease assay. The association between the case-control status and each individual SNP, measured by the odds ratio and its corresponding 95% confidence interval, was estimated using unconditional logistic regression models. At the second stage, two-way interactions were investigated using multivariate logistic models. The robustness of the interactions, which were observed among SNPs with stronger functional evidence, was assessed using a bootstrap approach, and correction for multiple testing based on the false discovery rate (FDR) principle. RESULTS: None of these SNPs contributed to breast cancer risk individually. However, we have demonstrated evidence for gene-gene (SNP-SNP) interaction among these SNPs, which were associated with increased breast cancer risk. Our study suggests cross talk between the SNPs of the DNA repair and immune system (XPD-[Lys751Gln] and IL10-[G(-1082)A]), cell cycle and estrogen metabolism (CCND1-[Pro241Pro] and COMT-[Met108/158Val]), cell cycle and DNA repair (BARD1-[Pro24Ser] and XPD-[Lys751Gln]), and within carcinogen metabolism (GSTP1-[Ile105Val] and COMT-[Met108/158Val]) pathways. CONCLUSION: The importance of these pathways and their communication in breast cancer predisposition has been emphasized previously, but their biological interactions through SNPs have not been described. The strategy used here has the potential to identify complex biological links among breast cancer genes and processes. This will provide novel biological information, which will ultimately improve breast cancer risk management.

Adult↗
PubMed2026

B cell pathways implicate shared genetic architecture between schizophrenia and immune-mediated diseases.

BACKGROUND: Schizophrenia and immune-mediated diseases are globally prevalent and highly heritable conditions that frequently co-occur, posing major public health burdens. However, their shared genetic architecture remains poorly understood. METHODS: We applied the bivariate causal mixture model (MiXeR) to investigate the polygenic overlap between schizophrenia and eight common immune-mediated diseases, using genome-wide association study summary statistics comprising 2,489 to 67,323 cases and 9,066 to 497,622 controls. Shared loci were identified through conditional/conjunctional false discovery rate (cond/conjFDR), local genetic correlation (LAVA), and colocalization analyses. Subsequently, gene mapping, functional annotation, expression-trait association, and drug-gene interaction analyses were performed to explore shared genes and enriched pathways, and genetic risk scores (GRS) from the UK Biobank were used to validate the findings. RESULTS: MiXeR estimated substantial polygenic overlap between schizophrenia and immune-mediated diseases, and conjFDR identified 133 shared loci, with eight prioritized through local genetic correlation and colocalization signals. These eight loci were mapped to 85 protein-coding genes enriched in pathways essential for B cell function. Among them, S-PrediXcan analyses identified 14 genes whose expression in brain tissues or blood was associated with both diseases. These genes also interact with immunomodulatory or antihypertensive drugs. Additionally, 11 of the 14 genes were linked to innate immunity and/or cognitive traits. Using UK Biobank data, we further confirmed that overall, shared gene, and B cell activation and receptor signaling pathway–specific genetic risk for schizophrenia is associated with immune-mediated disease susceptibility. CONCLUSIONS: These findings underscore the shared genetic architecture of schizophrenia and immune-mediated diseases, advancing insights at the interface of psychiatric genetics and immunology.

Schizophrenia↗
PubMed2006

[The genetics of obesity].

Obesity is a major health problem. It increases the risk of cardiovascular diseases, 2-type diabetes mellitus, cancers, and premature mortality. Apart from some monogenic forms, it's a polygenic disorder, the result of interaction of genes and environmental factors. Genetic variants of proteins taking part in the regulation of food intake or thermogenesis and tissue mediators produced by the adipose tissue are responsible the genetic components of obesity. Identification of the genetic background of the obesity will help to understand the exact molecular mechanism of the pathogenesis, make possible the prevention, as well as individual therapeutic interventions.

Animals↗
PubMed1990

Genetic aspects of juvenile chronic arthritis.

Immunogenetic studies in the past decade have confirmed the theory of an association between one's immunogenetic background and the manifestation of several forms of juvenile chronic arthritis (JCA), in particular pauciarticular-onset JCA. Considerable work has been done at the serologic level to demonstrate disease association with the major histocompatibility Class II antigens in pauciarticular-onset JCA. The polygenic nature of JCA is best illustrated by the findings in this particularly well-defined clinical subgroup. Evidence is now emerging that analysis of the DNA sequence, the derived protein sequence, and the structure of Class II molecules will yield significant insight into the genetic predisposition to JCA.

Arthritis, Juvenile↗
PubMed2005

Gene expression microarray studies in polygenic psychiatric disorders: applications and data analysis.

Gene expression microarrays have become a mainstream technology that can provide valuable insight into psychiatric disorders. Gene expression studies in post mortem brain samples of schizophrenia and bipolar disorder have the potential to yield novel clues about the pathophysiology of these complex trait disorders. In the present review, a short introduction of the genetic and molecular background of schizophrenia and bipolar disorder is followed by a discussion of the basic concept and limits of gene expression microarray technology, and the complexities surrounding the analysis of thousands of gene transcripts. Although this review is intended for use in most platforms, it has a particular focus on the commercially available Affymetrix system. Various computer programs and their principal features are discussed, and it is shown how these programs can be applied to reveal a biological context of microarray findings. I will demonstrate how the programs can help to judge the results rather than focus on their statistical principles. The strength of gene array experiments is their emphasis on broad, biological themes, rather than on specific genes, and proper biostatistical approaches are important to ensure reproducibility of the findings. All results should be verified by independent means. This review is intended to help brain researchers who want to apply gene expression microarray technology to conceptualize research strategies and sample analysis.

Biomedical Research↗
PubMed1976

The genetic variability of third chromosomes in a local population of Drosophila melanogaster.

Five hundred and two third chromosomes were extracted from a large cage population of Drosophila melanogaster initiated two months after collection of the progenitors near Raleigh, North Carolina in 1970.---Salivary gland chromosomes of 489 chromosome lines were examined and 54 chromosomes were found to carry inversions. The inversions were classified into three polymorphic types [In (3L)P, In (3R)P, and In (3R)C] and two unique types. The polymorphic inversions were found in frequencies of 0.012, 0.88, and 0.010, respectively.--Viabilities of homozygotes and heterozygotes were examined. Chromosomes with lethals occurred with a frequency of 0.495: 0.537 in the group of inversion-carrying chromosomes and 0.490 in the group of inversion-free chromosomes. The average homozygote viability computed on the basis of an average heterozygote viability of 1.0000 was 0.3235 if lethal lines were included and 0.6290 if they were excluded. The detrimental load to lethal load ratio (D:L ratio) was 0.70 (=0.4636-0.6650). The average viability of lethal heterozygotes was significantly larger than that of lethal-free heterozygotes. It appears, however, that lethal genes in heterozygotes have deleterious effects on fitness as a whole.--The average degree of dominance for viability polygenes was estimated to be about 0.3-0.4 in lethal-free individuals and nearly zero in lethal heterozygotes. Overdominance or some form of balancing selection was suggested at some loci. The difference between the values obtained for average degree of dominance due to genetic backgrounds and superior vibaility of lethal heterozygotes (but not fitness as a whole) suggest that some epistasis or coadaptation occurs.--The results described above are similar to those obtained for the second chromosomes.

Animals↗
PubMed2026

Divergent autoimmune genetic landscapes in diabetic and non-diabetic individuals.

BACKGROUND: Type 2 diabetes (T2D) and autoimmune diseases are complex disorders shaped by genetic, immunological, and environmental factors. However, differences in genetic susceptibility to autoimmune disorders between diabetic and non-diabetic individuals remain poorly understood, particularly within the Indian population. This study aimed to compare polygenic susceptibility to multiple autoimmune diseases between individuals with and without T2D from Gujarat, India. RESULTS: Polygenic risk scores were evaluated for eleven autoimmune diseases in 474 individuals, including 99 diabetics and 375 non-diabetics. Significant differences were observed for systemic lupus erythematosus and rheumatoid arthritis. Individuals with diabetes showed a higher genetic risk for systemic lupus erythematosus, whereas non-diabetic individuals exhibited a higher genetic risk for rheumatoid arthritis. Pathway enrichment analysis of disease-associated genetic variants revealed significant involvement of immune-related pathways, including antigen processing and presentation, T-helper cell differentiation, and immune responses to viral infections. CONCLUSIONS: The findings reveal disease-specific differences in genetic susceptibility to autoimmune disorders between diabetic and non-diabetic individuals. These results highlight the complex immunogenetic relationship between type 2 diabetes and autoimmune diseases and provide insight into shared and distinct immune pathways within an Indian population. Such information may support future efforts in risk stratification and precision medicine approaches for immune-related comorbidities in diabetes.

Humans↗
PubMed2004

Phenotypic and molecular evaluation of a recurrent selection program for a polygenic resistance to Phytophthora capsici in pepper.

'Criollo de Morelos 334' (CM334) is one of the most promising sources of resistance to Phytophthora capsici in pepper. This Mexican accession is distantly related to bell pepper and its resistance displays a complex inheritance. The QTLs involved in resistance to P. capsici were previously mapped. In order to transfer the resistance factors from CM334 into a bell pepper genetic background, a modified, recurrent breeding scheme was initiated. The breeding population was divided into three sub-populations which were screened by distinct phenotypic tests of increasing severity. The plants from the first sub-population were screened with low-severity tests and backcrossed to the susceptible bell pepper; the plants from the second and third sub-populations were screened by more severe resistance tests and crossed with the plants from the first and second sub-populations, respectively. In this study, the phenotypic data for the three sub-populations during five screening/intermating cycles were analysed. In parallel, the changes in allelic frequencies at molecular markers linked to the resistance QTLs were reported. The resistance phenotype and allelic frequencies strongly depended on the sub-population and screening severity. Regarding allelic frequency changes across the selection cycles, a loss of resistant QTL alleles was observed in the first sub-population, particularly for the low-effect QTLs, whereas a better conservation of the resistant QTL alleles was observed in the two other sub-populations. The same trend was observed in the phenotypic data with an increasing resistance level from the first to the third sub-populations. The changes in the allelic frequencies of loci not linked to resistance QTLs and for horticultural traits across the breeding process indicated that the recovery of the recipient parent genome was not significantly affected by the selection for resistance.

Analysis of Variance↗
PubMed2005

Chromosome-wise dissection of the genome of the extremely big mouse line DU6i.

The extreme high-body-weight-selected mouse line DU6i is a polygenic model for growth research, harboring many small-effect QTL. We dissected the genome of this line into 19 autosomes and the Y chromosome by the construction of a new panel of chromosome substitution strains (CSS). The DU6i chromosomes were transferred to a DBA/2 mice genetic background by marker-assisted recurrent backcrossing. Mitochondria and the X chromosome were of DBA/2 origin in the backcross. During the construction of these novel strains, >4000 animals were generated, phenotyped, and genotyped. Using these data, we studied the genetic control of variation in body weight and weight gain at 21, 42, and 63 days. The unique data set facilitated the analysis of chromosomal interaction with sex and parent-of-origin effects. All analyzed chromosomes affected body weight and weight gain either directly or in interaction with sex or parent of origin. The effects were age specific, with some chromosomes showing opposite effects at different stages of development.

Age Distribution↗
PubMed2001

Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain.

Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.

Alleles↗
PubMed2006

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures.

BACKGROUND: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. OBJECTIVE: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. METHODS AND RESULTS: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. CONCLUSION: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

Animals↗