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Abstract Dogs interact with humans effectively and intimately. However, the neural underpinnings for such interspecies social communication are not understood. It is known that interbrain activity coupling, i.e., the synchronization of neural activity between individuals, represents the neural basis of social interactions. Here, previously unknown cross‐species interbrain activity coupling in interacting human–dog dyads is reported. By analyzing electroencephalography signals from both dogs and humans, it is found that mutual gaze and petting induce interbrain synchronization in the frontal and parietal regions of the human–dog dyads, respectively. The strength of the synchronization increases with growing familiarity of the human–dog dyad over five days, and the information flow analysis suggests that the human is the leader while the dog is the follower during human–dog interactions. Furthermore, dogs with Shank3 mutations, which represent a promising complementary animal model of autism spectrum disorders (ASD), show a loss of interbrain coupling and reduced attention during human–dog interactions. Such abnormalities are rescued by the psychedelic lysergic acid diethylamide (LSD). The results reveal previously unknown interbrain synchronizations within an interacting human–dog dyad which may underlie the interspecies communication, and suggest a potential of LSD for the amelioration of social impairment in patients with ASD.

Traumatic brain injury (TBI) caused by external mechanical forces is a major health burden worldwide, but the underlying mechanism in glia remains largely unclear. We report herein that Drosophila adults exhibit a defective blood–brain barrier, elevated innate immune responses, and astrocyte swelling upon consecutive strikes with a high-impact trauma device. RNA sequencing (RNA-seq) analysis of these astrocytes revealed upregulated expression of genes encoding PDGF and VEGF receptor-related (Pvr, a receptor tyrosine kinase), adaptor protein complex 1 (AP-1, a transcription factor complex of the c-Jun N-terminal kinase pathway) composed of Jun-related antigen (Jra) and kayak (kay), and matrix metalloproteinase 1 (Mmp1) following TBI. Interestingly, Pvr is both required and sufficient for AP-1 and Mmp1 upregulation, while knockdown of AP-1 expression in the background of Pvr overexpression in astrocytes rescued Mmp1 upregulation upon TBI, indicating that Pvr acts as the upstream receptor for the downstream AP-1–Mmp1 transduction. Moreover, dynamin-associated endocytosis was found to be an important regulatory step in downregulating Pvr signaling. Our results identify a new Pvr–AP-1–Mmp1 signaling pathway in astrocytes in response to TBI, providing potential targets for developing new therapeutic strategies for TBI.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is associated with a high prevalence of cancer-related deaths. The survival rates of patients are significantly lower in late-stage ccRCC than in early-stage ccRCC, due to the spread and metastasis of late-stage ccRCC, surgery has not reached the goal of radical cure, and the effect of traditional radiotherapy and chemotherapy is poor. Thus, it is crucial to accurately assess the prognosis and provide personalized treatment at an early stage in ccRCC. This study aims to develop an efficient nomogram model for stratifying and predicting the survival of ccRCC patients based on tumor stage. Methods We first analyzed the microarray expression data of ccRCC patients from the Gene Expression Omnibus (GEO) database and categorized them into two groups based on the disease stage (early and late stage). Subsequently, the GEO2R tool was applied to screen out the genes that were highly expressed in all GEO datasets. Finally, the clinicopathological data of the two patient groups were obtained from The Cancer Genome Atlas (TCGA) database, and the differences were compared between groups. Survival analysis was performed to evaluate the prognostic value of candidate genes (PSAT1, PRAME, and KDELR3) in ccRCC patients. Based on the screened gene PSAT1 and clinical parameters that were significantly associated with patient prognosis, we established a new nomogram model, which was further optimized to a single clinical variable-based model. The expression level of PSAT1 in ccRCC tissues was further verified by qRT-PCR, Western blotting, and immunohistochemical analysis. Results The datasets GSE73731, GSE89563, and GSE150404 identified a total of 22, 89, and 120 over-expressed differentially expressed genes (DEGs), respectively. Among these profiles, there were three genes that appeared in all three datasets based on different stage groups. The overall survival (OS) of late-stage patients was significantly shorter than that of early-stage patients. Among the three candidate genes (PSAT1, PRAME, and KDELR3), PSAT1 was shown to be associated with the OS of patients with late-stage ccRCC. Multivariate Cox regression analysis showed that age, tumor grade, neoadjuvant therapy, and PSAT1 level were significantly associated with patient prognosis. The concordance indices were 0.758 and 0.725 for the 3-year and 5-year OS, respectively. The new model demonstrated superior discrimination and calibration compared with the single clinical variable model. The enhancer PSAT1 used in the new model was shown to be significantly overexpressed in tissues from patients with late-stage ccRCC, as demonstrated by the mRNA level, protein level, and pathological evaluation. Conclusion The new prognostic prediction nomogram model of PSAT1 and clinicopathological variables combined was thus established, which may provide a new direction for individualized treatment for different-stage ccRCC patients.

Abstract Background SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. Methods We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. Results We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. Limitations Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. Conclusions Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research.

Abstract Treatment of castration‐resistant prostate cancer (CRPC) is a long‐standing clinical challenge. Traditionally, CRPC drugs work by either reducing dihydrotestosterone biosynthesis or blocking androgen receptor (AR) signaling. Here it is demonstrated that AR inhibitor treatment gives rise to a drug‐tolerant persister (DTP) state. The thioredoxin/peroxiredoxin pathway is up‐regulated in DTP cells. Peroxiredoxin 5 (PRDX5) promotes AR inhibitor resistance and CRPC development. Inhibition of PRDX5 suppresses DTP cell proliferation in culture, dampens CRPC development in animal models, and stabilizes PSA progression and metastatic lesions in patients. Therefore, the study provides a novel mechanism and potential target for the management of castration‐resistant prostate cancer.

Abstract Due to the complexity and incomplete understanding of the crosstalk between liver and adipose tissue, especially the processes of hepatic lipogenesis and adipogenic differentiation, there are currently no effective drugs for the treatment of nonalcoholic fatty liver disease (NAFLD). Stearoyl-coenzyme A desaturase 1 (SCD1), which is abundantly expressed in liver and adipose tissue, may mediate the cross-talk between liver and adipose tissue. Thus, it is essential to develop specific SCD1 inhibitors that target the liver-adipose axis. Herein, we identified a novel SCD1 inhibitor, E6446, through a high-throughput virtual screen. E6646 significantly inhibited adipogenic differentiation and hepatic lipogenesis via SCD1-ATF3 signaling. The SPR results showed that E6446 had a strong interaction ability with SCD1 (KD:4.61 μM). Additionally, E6646 significantly decreased hepatic steatosis, hepatic lipid droplet accumulation and insulin resistance in high-fat diet (HFD)-fed mice. Taken together, our findings not only suggest that E6446 can serve as a new, safe and highly effective anti-NAFLD agent for future clinical use but also provide a molecular basis for the future development of SCD1 inhibitors that inhibit both adipogenic differentiation and hepatic lipogenesis. Video Abstract

Aegilops tauschii is the donor of the D subgenome of hexaploid wheat and an important genetic resource. The reference-quality genome sequence Aet v4.0 for Ae. tauschii acc. AL8/78 was therefore an important milestone for wheat biology and breeding. Further advances in sequencing acc. AL8/78 and release of the Aet v5.0 sequence assembly are reported here. Two new optical maps were constructed and used in the revision of pseudomolecules. Gaps were closed with Pacific Biosciences long-read contigs, decreasing the gap number by 38,899. Transposable elements and protein-coding genes were reannotated. The number of annotated high-confidence genes was reduced from 39,635 in Aet v4.0 to 32,885 in Aet v5.0. A total of 2245 biologically important genes, including those affecting plant phenology, grain quality, and tolerance of abiotic stresses in wheat, was manually annotated and disease-resistance genes were annotated by a dedicated pipeline. Disease-resistance genes encoding nucleotide-binding site domains, receptor-like protein kinases, and receptor-like proteins were preferentially located in distal chromosome regions, whereas those encoding transmembrane coiled-coil proteins were dispersed more evenly along the chromosomes. Discovery, annotation, and expression analyses of microRNA (miRNA) precursors, mature miRNAs, and phasiRNAs are reported, including miRNA target genes. Other small RNAs, such as hc-siRNAs and tRFs, were characterized. These advances enhance the utility of the Ae. tauschii genome sequence for wheat genetics, biotechnology, and breeding.

Abstract Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that affects social interaction and behavior. Mutations in the gene encoding chromodomain helicase DNA-binding protein 8 (CHD8) lead to autism symptoms and macrocephaly by a haploinsufficiency mechanism. However, studies of small animal models showed inconsistent findings about the mechanisms for CHD8 deficiency-mediated autism symptoms and macrocephaly. Using the nonhuman primate as a model system, we found that CRISPR/Cas9-mediated CHD8 mutations in the embryos of cynomolgus monkeys led to increased gliogenesis to cause macrocephaly in cynomolgus monkeys. Disrupting CHD8 in the fetal monkey brain prior to gliogenesis increased the number of glial cells in newborn monkeys. Moreover, knocking down CHD8 via CRISPR/Cas9 in organotypic monkey brain slices from newborn monkeys also enhanced the proliferation of glial cells. Our findings suggest that gliogenesis is critical for brain size in primates and that abnormal gliogenesis may contribute to ASD.

Retinoic acid (RA), a bioactive metabolite of vitamin A, has shown therapeutic effects in liver disease, and its effect in improving non-alcoholic fatty liver disease (NAFLD) is associated with the inhibition of adipogenesis in the white adipose tissue (WAT) and fatty acid oxidation induction in the liver. However, the major target organ of RA is unknown. We performed chronic administration of RA in high-fat diet (HFD)-induced NAFLD mice. Further, hepatic and adipose cells were used to study the direct effect of RA on lipid metabolism. In addition, qRT-PCR was performed to examine differential gene expression in mouse adipose tissue. RA administration ameliorated NAFLD in HFD-induced obese mice and increased mouse energy expenditure. Although RA had therapeutic effects on liver histology and lipid accumulation, it did not directly affect lipid metabolism in HepG2 cells. In contrast, RA reduced the weight of several adipose tissues and improved lipid accumulation in OP9 cells. In addition, RA upregulated genes responsible for fatty acid oxidation and thermogenesis in three different WATs. Our work suggests that the liver may not be the main target organ of RA during NAFLD treatment. WAT browning induced by RA may be the primary contributor towards the amelioration of NAFLD in HFD-induced obese mice.

Social isolation (SI) exerts diverse adverse effects on brain structure and function in humans. To gain an insight into the mechanisms underlying these effects, we conducted a systematic analysis of multiple brain regions from socially isolated and group-housed dogs, whose brain and behavior are similar to humans. Our transcriptomic analysis revealed reduced expression of myelin-related genes specifically in the white matter of prefrontal cortex (PFC) after SI during the juvenile stage. Despite these gene expression changes, myelin fiber organization in PFC remained unchanged. Surprisingly, we observed more mature oligodendrocytes and thicker myelin bundles in the somatosensory parietal cortex in socially isolated dogs, which may be linked to an increased expression of ADORA2A, a gene known to promote oligodendrocyte maturation. Additionally, we found a reduced expression of blood-brain barrier (BBB) structural components Aquaporin-4, Occludin, and Claudin1 in both PFC and parietal cortices, indicating BBB disruption after SI. In agreement with BBB disruption, myelin-related sphingolipids were increased in cerebrospinal fluid in the socially isolated group. These unexpected findings show that SI induces distinct alterations in oligodendrocyte development and shared disruption in BBB integrity in different cortices, demonstrating the value of dogs as a complementary animal model to uncover molecular mechanisms underlying SI-induced brain dysfunction.

Wheat is one of the most important cereal crops for the global food security. Due to its narrow genetic base, modern bread wheat cultivars face challenges from increasing abiotic and biotic stresses. Since genetic improvement is the most sustainable approach, finding novel genes and alleles is critical for enhancing the genetic diversity of wheat. The tertiary gene pool of wheat is considered a gold mine for genetic diversity as novel genes and alleles can be identified and transferred to wheat cultivars. Aegilops geniculata and Ae. umbellulata are the key members of the tertiary gene pool of wheat and harbor important genes against abiotic and biotic stresses. Homoeologous-group five chromosomes (5Uu and 5Mg) have been extensively studied from Ae. geniculata and Ae. umbellulata as they harbor several important genes including Lr57, Lr76, Yr40, Yr70, Sr53 and chromosomal pairing loci. In the present study, using chromosome DNA sequencing and RNAseq datasets, we performed comparative analysis to study homoeologous gene evolution in 5Mg, 5Uu, and group 5 wheat chromosomes. Our findings highlight the diversity of transcription factors and resistance genes, resulting from the differential expansion of the gene families. Both the chromosomes were found to be enriched with the “response to stimulus” category of genes providing resistance against biotic and abiotic stress. Phylogenetic study positioned the M genome closer to the D genome, with higher proximity to the A genome than the B genome. Over 4000 genes were impacted by SNPs on 5D, with 4-5% of those genes displaying non-disruptive variations that affect gene function.

Fatty acid elongases play crucial roles in synthesizing long-chain polyunsaturated fatty acids. Identifying more efficient elongases is essential for enhancing oleaginous microorganisms to produce high yields of target products. We characterized three elongases that were identified with distinct specificities: McELO from Mucor circinelloides, PrELO from Phytophthora ramorum, and PsELO from Phytophthora sojae. Heterologous expression in Saccharomyces cerevisiae showed that McELO preferentially elongates C16 to C18 fatty acids, PrELO targets Δ6 polyunsaturated fatty acids, and PsELO uses long chain saturated fatty acids as substrates. McELO and PrELO exhibited more homology, potentially enabling fatty acid composition remodeling and enhanced LC-PUFAs production in oleaginous microorganisms. Site-directed mutagenesis of conserved amino acids across elongase types identified residues essential for activity, supported by molecular docking. Alanine substitution of conserved polar residues led to enzyme inactivation, underscoring their importance in the condensation reaction. Our findings offer promising elongase candidates for polyunsaturated fatty acid production, contributing to the bioindustry’s sustainable development.

GrainGenes (https://wheat.pw.usda.gov or https://graingenes.org) is an international centralized repository for curated, peer-reviewed datasets useful to researchers working on wheat, barley, rye and oat. GrainGenes manages genomic, genetic, germplasm and phenotypic datasets through a dynamically generated web interface for facilitated data discovery. Since 1992, GrainGenes has served geneticists and breeders in both the public and private sectors on six continents. Recently, several new datasets were curated into the database along with new tools for analysis. The GrainGenes homepage was enhanced by making it more visually intuitive and by adding links to commonly used pages. Several genome assemblies and genomic tracks are displayed through the genome browsers at GrainGenes, including the Triticum aestivum (bread wheat) cv. 'Chinese Spring' IWGSC RefSeq v1.0 genome assembly, the Aegilops tauschii (D genome progenitor) Aet v4.0 genome assembly, the Triticum turgidum ssp. dicoccoides (wild emmer wheat) cv. 'Zavitan' WEWSeq v.1.0 genome assembly, a T. aestivum (bread wheat) pangenome, the Hordeum vulgare (barley) cv. 'Morex' IBSC genome assembly, the Secale cereale (rye) select 'Lo7' assembly, a partial hexaploid Avena sativa (oat) assembly and the Triticum durum cv. 'Svevo' (durum wheat) RefSeq Release 1.0 assembly. New genetic maps and markers were added and can be displayed through CMAP. Quantitative trait loci, genetic maps and genes from the Wheat Gene Catalogue are indexed and linked through the Wheat Information System (WheatIS) portal. Training videos were created to help users query and reach the data they need. GSP (Genome Specific Primers) and PIECE2 (Plant Intron Exon Comparison and Evolution) tools were implemented and are available to use. As more small grains reference sequences become available, GrainGenes will play an increasingly vital role in helping researchers improve crops.

Abstract Castration-resistance of prostate cancer is one of the most challenging clinical problems. In the present study, we have performed proteomics and glycomics using LNCaP model. Growth differentiation factor-15 (GDF15) level is increased in androgen receptor (AR) inhibitor-resistant cells and the inhibitory effect of GDF15 on epithelial growth factor receptor (EGFR) pathway is relieved by GDF15 N70 glycosylation. Interference of GDF15 (siRNA or N70Q dominant negative) or EGFR pathway (inhibitor or siRNA for EGFR, SRC or ERK) decreases the resistant-cell survival in culture and tumor growth in mice. Our study reveals a novel regulatory mechanism of prostate cancer AR inhibitor resistance, raises the possibility of AR/SRC dual-targeting of castration-resistance of prostate cancer, and lays foundation for the future development of selective inhibitors of GDF15 glycosylation.

Keypoints The structure of the Δ6 fatty acid desaturase and substrate complex is modeled. The substrate tunnel and key residues of MpFADS6 catalytic activity are determined. The new insights to determine the mechanism of the membrane-bound desaturases.

Nitrogen (N) and phosphorus (P) enrichment from the surrounding landscape can enhance the growth and abundance of algal assemblages, both suspended in the water column and occurring as benthic biofilms in the receiving waters of resident stream ecosystems. However, it is unclear how enhanced levels of dissolved organic carbon (DOC) might mediate the response of algae to nutrients. In this study, we aim to understand the relationship between N and P enrichment in stream reaches with varying levels of DOC within a common watershed. Both suspended and benthic algal assemblages were exposed to increasing (low, moderate, high) levels of N and P in an in situ 3 × 3 factorial experimental design. Experiments were carried out simultaneously at three sites of varying DOC concentration, the results of which, showed that both assemblages responded very differently to enrichment. For suspended algae, biomass was enhanced following enrichment with both N and P singularly and in combination, particularly at the highest concentrations levels for both nutrients (3-way ANOVA interactions; p < 0.05). This pattern was consistent at all levels of DOC at the three sites (3-way ANOVA Nutrient-site interaction; F = 1.4, p = 0.228). In contrast, benthic algal biomass progressively increased with enhanced concentration of both N and P, but only at the lowest level of DOC (3-way ANOVA site term; F = 84.2, p = 0.0001). No appreciable biomass accumulation was observed under moderate or high DOC conditions and this pattern was likely attributed to low light penetration at these two sites (ANOVA). Our results indicate that eutrophication is likely to manifest itself in a complex manner throughout watersheds where loading of N and P interacts with DOC.

Dogs interact with humans effectively and intimately. However, the neural underpinnings for such interspecies social communication are not understood. It is known that interbrain activity coupling, i.e., the synchronization of neural activity between individuals, represents the neural basis of social interactions. Here, previously unknown cross‐species interbrain activity coupling in interacting human–dog dyads is reported. By analyzing electroencephalography signals from both dogs and humans, it is found that mutual gaze and petting induce interbrain synchronization in the frontal and parietal regions of the human–dog dyads, respectively. The strength of the synchronization increases with growing familiarity of the human–dog dyad over five days, and the information flow analysis suggests that the human is the leader while the dog is the follower during human–dog interactions. Furthermore, dogs with Shank3 mutations, which represent a promising complementary animal model of autism spectrum disorders (ASD), show a loss of interbrain coupling and reduced attention during human–dog interactions. Such abnormalities are rescued by the psychedelic lysergic acid diethylamide (LSD). The results reveal previously unknown interbrain synchronizations within an interacting human–dog dyad which may underlie the interspecies communication, and suggest a potential of LSD for the amelioration of social impairment in patients with ASD. [ABSTRACT FROM AUTHOR]

The excessive accumulation of saturated fatty acids and cholesterol have been linked to prostate cancer (Pca). Here, we found that lipoproteins, apolipoproteins, triglycerides and free fatty acids are significantly higher in the peripheral blood of prostate cancer patients than in non-cancer patients. Furthermore, the expression of ACC1, FASN and HMGCR is significantly higher in prostate cancer tissues than that in non-cancer tissues, and positively correlated with the gleason score. Using genetically engineered mouse models, we found that in a mouse model of high grade prostatic intraneoplasia (HGPIN), a combination of fatty acid synthase (FASN) overexpression and cholesterol efflux pump (Abca1) knockout resulted in the progression of prostatic intraneoplasia (PIN) to invasive PCa with 100% penetrance, as well as an increase in prostate cancer stem cell (PCSC)population, accompanied by activation of PGE2 and TGF-β signaling pathway. Our study suggests that the steady rise in prostate cancer incidence and mortality among Chinese population during the last several decades may be attribute to a combinational effect of fatty acid and cholesterol, and reduction in dietary fat and cholesterol intake could slow down the progression from occult lesions to prostate cancer.

Abstract Background A comprehensive understanding of the molecular mechanisms of adipogenesis is a critically important strategy for identifying new targets for obesity intervention. Methods Transcriptomic and lipidomic approaches were used to explore the functional genes regulating adipogenic differentiation and their potential mechanism of action in OP9 cells and adipose-derived stem cells. Oil Red O staining was used to detect oil droplets in adipocytes. Results RNA sequencing (RNA-seq) showed that Slc25a5 expression was significantly upregulated in adipogenic differentiation. Depletion of Slc25a5 led to the suppressed expression of adipogenesis-related genes, reduced the accumulation of triglycerides, and inhibited PPARγ protein expression. Moreover, the knockdown of Slc25a5 resulted in significant reduction of oxidative phosphorylation (OXPHOS) protein expression (ATP5A1, CQCRC2, and MTCO1) and ATP production. The RNA-seq and real-time quantitative polymerase chain reaction (RT–qPCR) results suggested that adipogenic differentiation is possibly mediated by ERK1/2 phosphorylation, and this hypothesis was confirmed by intervention with PD98059 (an ERK 1/2 inhibitor). Conclusions This study indicates that Slc25a5 inhibits adipogenesis and might be a new therapeutic target for the treatment of obesity.

Key messageComparison of genome sequences of wild emmer wheat and Aegilops tauschii suggests a novel scenario of the evolution of rearranged wheat chromosomes 4A, 5A, and 7B. Past research suggested that wheat chromosome 4A was subjected to a reciprocal translocation T(4AL;5AL)1 that occurred in the diploid progenitor of the wheat A subgenome and to three major rearrangements that occurred in polyploid wheat: pericentric inversion Inv(4AS;4AL)1, paracentric inversion Inv(4AL;4AL)1, and reciprocal translocation T(4AL;7BS)1. Gene collinearity along the pseudomolecules of tetraploid wild emmer wheat (Triticum turgidum ssp. dicoccoides, subgenomes AABB) and diploid Aegilops tauschii (genomes DD) was employed to confirm these rearrangements and to analyze the breakpoints. The exchange of distal regions of chromosome arms 4AS and 4AL due to pericentric inversion Inv(4AS;4AL)1 was detected, and breakpoints were validated with an optical Bionano genome map. Both breakpoints contained satellite DNA. The breakpoints of reciprocal translocation T(4AL;7BS)1 were also found. However, the breakpoints that generated paracentric inversion Inv(4AL;4AL)1 appeared to be collocated with the 4AL breakpoints that had produced Inv(4AS;4AL)1 and T(4AL;7BS)1. Inv(4AS;4AL)1, Inv(4AL;4AL)1, and T(4AL;7BS)1 either originated sequentially, and Inv(4AL;4AL)1 was produced by recurrent chromosome breaks at the same breakpoints that generated Inv(4AS;4AL)1 and T(4AL;7BS)1, or Inv(4AS;4AL)1, Inv(4AL;4AL)1, and T(4AL;7BS)1 originated simultaneously. We prefer the latter hypothesis since it makes fewer assumptions about the sequence of events that produced these chromosome rearrangements.