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PubMed2026

Genomic and epigenomic diversity of breast cancer across Western and MENA populations: implications for precision oncology.

Breast cancer is the most common malignancy in women worldwide and is increasingly recognized as a biologically diverse disease shaped by both molecular and ancestral context. Women from the Middle East and North Africa (MENA) populations, including Saudi Arabia, often present at a younger age and with more aggressive subtypes such as HER2-positive and triple-negative breast cancer (TNBC) compared with Western cohorts. These clinical patterns reflect a distinctive genomic background marked by high consanguinity, founder mutations in key susceptibility genes, and population-specific somatic alterations that are not fully captured in global reference datasets. This review brings together current evidence on somatic, germline, transcriptomic, and epigenomic diversity in breast cancer across Western and MENA populations, with a focus on Saudi cohorts. Drawing on a previously published systematic review of more than 2,500 MENA breast cancer cases, TP53 accounted for approximately 24% and PIK3CA for roughly 10% of curated somatic mutation records pooled across 44 studies (proportions of mutation calls, not per-patient prevalence); in a separate single-center Saudi cohort, only 3.7% of patients underwent BRCA testing, and 37.5% of this clinically selected, testing-referred subgroup carried a pathogenic variant, a figure that should not be read as general-population BRCA prevalence. Variants of uncertain significance exceeded 20% across several regional genomic studies. We summarize conserved driver events, such as recurrent TP53 and PIK3CA mutations, while highlighting regional features, including unique stop-gain and loss-of-function variants, a high copy-number burden, and early-onset disease linked to ancestral architecture. We also discuss emerging data on MENA-specific regulatory signatures, including immune-enriched and basal-myo transcriptomic clusters, CIMP-like methylation patterns, and non-coding RNA networks; these associations are numerically suggestive in available cohorts but have not reached statistical significance in existing studies and warrant validation in larger, dedicated MENA/Saudi cohorts before being considered established determinants of treatment response and resistance. Finally, we examine the clinical implications of this diversity for biomarker development, pharmacogenomics, and access to targeted therapies, and outline practical steps toward ancestry-aware precision oncology in the region.

BRCA↗
PubMed2025

Reproductive Isolation due to Divergent Ecological Selection Is Accompanied by Vast Genomic Instability in Experimentally Evolved Yeast Populations.

Populations evolving independently in divergent environments accumulate genetic differences and potentially evolve reproductive isolation as a by-product of divergence. The speed and mechanisms underlying this process are difficult to investigate because we rarely get the opportunity to witness them in natural settings, and histories of selection and gene flow between populations are often unknown. Here, we experimentally evolved yeast for 1000 generations of evolution in both divergent and parallel environments. At regular time points during experimental evolution, we made crosses between parallel- and divergent-evolving populations to measure postzygotic reproductive isolation (gamete viability). We used whole genome population sequencing to determine the mutational load, the number and types of structural variation, and other genomic features of the parent, F1 and F2 intraspecific hybrids. We found evidence for large-scale phenotypic and genome-wide differentiation in response to divergent laboratory selection. Divergent-selected populations produced hybrids with reduced gamete viability-a classic signature of postzygotic reproductive isolation in the form of hybrid breakdown. Parallel-selected populations, on the other hand, remained more reproductively compatible (with exceptions). We found that F2 hybrid genomes contained vast genomic instability, that is, new structural variants (especially insertions, deletions and interchromosomal translocations) that were not observed in parent and F1 genomes, which is likely a result of chromosome missegregation and recombination errors in hybrid meiosis. Our results provide phenotypic and genomic evidence that partial reproductive isolation evolved due to adaptation to divergent environments, consistent with predictions of ecological speciation theory.

Reproductive Isolation↗
PubMed2005

Genome analysis and gene expression profiling of neuroblastoma and ganglioneuroblastoma reveal differences between neuroblastic and Schwannian stromal cells.

Neuroblastic tumours are a group of paediatric cancers with marked morphological heterogeneity. Neuroblastoma (Schwannian stroma-poor) (NB-SP) is composed of undifferentiated neuroblasts. Ganglioneuroblastoma intermixed (Schwannian stroma-rich) (GNBi-SR) is predominantly composed of Schwannian stromal (SS) and neuroblastic (Nb) cells. There are contrasting reports suggesting that SS cells are non-neoplastic. In the present study, laser capture microdissection (LCM) was employed to isolate SS and Nb cells. Chromosome 1p36 deletion and MYCN gene amplification were found to be associated in two out of seven NB-SPs, whereas no abnormalities were observed in five GNBi-SRs. In some cases, loss of heterozygosity (LOH) at 1p36 loci was detected in Nb cells but not in the bulk tumour by LCM; furthermore, LOH was also identified in both SS and tumour tissue of a GNBi-SR. DNA gain and loss studied by comparative genomic hybridization were observed at several chromosome regions in NB-SP but in few regions of GNBi-SR. Finally, gene expression profiles studied using an oligo-microarray technique displayed two distinct signatures: in the first, 32 genes were expressed in NB-SP and in the second, 14 genes were expressed in GNBi-SR. The results show that NB-SP is composed of different morphologically indistinguishable malignant cell clones harbouring cryptic mutations that are detectable only after LCM. The degree of DNA imbalance is higher in NB-SP than in GNBi-SR. However, when the analysis of chromosome 1p36 is performed at the level of microdissection, LOH is also observed in SS cells. These data provide supportive evidence that SS cells have a less aggressive phenotype and play a role in tumour maturation.

Chromosomes, Human, Pair 1↗
PubMed2005

The endonuclease domain of bacteriophage terminases belongs to the resolvase/integrase/ribonuclease H superfamily: a bioinformatics analysis validated by a functional study on bacteriophage T5.

Bacteriophage terminases are essential molecular motors involved in the encapsidation of viral DNA. They are hetero-multimers whose large subunit encodes both ATPase and endonuclease activities. Although the ATPase domain is well characterized from sequence and functional analysis, the C-terminal region remains poorly defined. We describe sequence-structure comparisons of the endonuclease region of various bacteriophages that revealed new sequence similarities shared by this region and the Holliday junction resolvase RuvC and to a lesser extent the HIV integrase and the ribonuclease H. Extensive sequence comparison and motif refinement led to a common signature of terminases and resolvases with three conserved acidic residues engaged in catalytic activity. Sequence analyses were validated by in vivo and in vitro functional assays showing that the nuclease activity of the endonuclease domain of bacteriophage T5 terminase was abolished by mutation of any of the three predicted catalytic aspartates. Overall, these data suggest that the endonuclease domains of terminases operate autonomously and that they adopt a fold similar to that of resolvases and share the same divalent cation-dependent enzymatic mechanism.

Amino Acid Sequence↗
PubMed2005

Immunoglobulin gene diversification.

Three processes alter genomic sequence and structure at the immunoglobulin genes of B lymphocytes: gene conversion, somatic hypermutation, and class switch recombination. Though the molecular signatures of these processes differ, they occur by a shared pathway which is induced by targeted DNA deamination by a B cell-specific factor, activation induced cytidine deaminase (AID). Ubiquitous factors critical for DNA repair carry out all downstream steps, creating mutations and deletions in genomic DNA. This review focuses on the genetic and biochemical mechanisms of diversification of immunoglobulin genes.

Animals↗
PubMed2005

A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility.

A major goal of cancer research has been to identify genes that contribute to cancer formation. The similar pathology between zebrafish and human tumors, as well as the past success of large-scale genetic screens in uncovering human disease genes, makes zebrafish an ideal system in which to find such new genes. Here, we show that a zebrafish forward genetic screen uncovered multiple cell proliferation mutants including one mutant, crash&burn (crb), that represents a loss-of-function mutation in bmyb, a transcriptional regulator and member of a putative proto-oncogene family. crb mutant embryos have defects in mitotic progression and spindle formation, and exhibit genome instability. Regulation of cyclin B levels by bmyb appears to be the mechanism of mitotic accumulation in crb. Carcinogenesis studies reveal increased cancer susceptibility in adult crb heterozygotes. Gene-expression signatures associated with loss of bmyb in zebrafish are also correlated with conserved signatures in human tumor samples, and down-regulation of the B-myb signature genes is associated with retention of p53 function. Our findings show that zebrafish screens can uncover cancer pathways, and demonstrate that loss of function of bmyb is associated with cancer.

Animals↗
PubMed2004

hnRNP H binding at the 5' splice site correlates with the pathological effect of two intronic mutations in the NF-1 and TSHbeta genes.

We have recently reported a disease-causing substitution (+5G > C) at the donor site of NF-1 exon 3 that produces its skipping. We have now studied in detail the splicing mechanism involved in analyzing RNA-protein complexes at several 5' splice sites. Characteristic protein patterns were observed by pulldown and band-shift/super-shift analysis. Here, we show that hnRNP H binds specifically to the wild-type GGGgu donor sequence of the NF-1 exon 3. Depletion analyses shows that this protein restricts the accessibility of U1 small nuclear ribonucleoprotein (U1snRNA) to the donor site. In this context, the +5G > C mutation abolishes both U1snRNP base pairing and the 5' splice site (5'ss) function. However, exon recognition in the mutant can be rescued by disrupting the binding of hnRNP H, demonstrating that this protein enhances the effects of the +5G > C substitution. Significantly, a similar situation was found for a second disease-causing +5G > A substitution in the 5'ss of TSHbeta exon 2, which harbors a GGgu donor sequence. Thus, the reason why similar nucleotide substitutions can be either neutral or very disruptive of splicing function can be explained by the presence of specific binding signatures depending on local contexts.

Binding Sites↗
PubMed2022

Signatures for viral infection and inflammation in the proximal olfactory system in familial Alzheimer's disease.

Alzheimer's disease (AD) is characterized by deficits in olfaction and olfactory pathology preceding diagnosis of dementia. Here we analyzed differential gene and protein expression in the olfactory bulb (OB) and tract (OT) of familial AD (FAD) individuals carrying the autosomal dominant presenilin 1 E280A mutation. Compared to control, FAD OT had increased immunostaining for β-amyloid (Aβ) and CD68 in high and low myelinated regions, as well as increased immunostaining for Iba1 in the high myelinated region. In FAD samples, RNA sequencing showed: (1) viral infection in the OB; (2) inflammation in the OT that carries information via entorhinal cortex from the OB to hippocampus, a brain region essential for learning and memory; and (3) decreased oligodendrocyte deconvolved transcripts. Interestingly, spatial proteomic analysis confirmed altered myelination in the OT of FAD individuals, implying dysfunction of communication between the OB and hippocampus. These findings raise the possibility that viral infection and associated inflammation and dysregulation of myelination of the olfactory system may disrupt hippocampal function, contributing to acceleration of FAD progression.

Humans↗
PubMed2003

Large-scale analysis of the meningococcus genome by gene disruption: resistance to complement-mediated lysis.

The biologic role of a majority of the Neisseria meningitidis 2100 predicted coding regions is still to be assigned or experimentally confirmed. Determining the phenotypic effect of gene disruption being a fundamental approach to understanding gene function, we used high-density signature-tagged transposon mutagenesis, followed by a large-scale sequencing of the transposon insertion sites, to construct a genome-wide collection of mutants. The sequencing results for the first half of the 4548 mutants composing the library suggested that we have mutations in 80%-90% of N. meningitidis nonessential genes. This was confirmed by a whole-genome identification of the genes required for resistance to complement-mediated lysis, a key to meningococcal virulence. We show that all the genes we identified, including four previously uncharacterized, were important for the synthesis of the polysialic acid capsule or the lipooligosaccharide (LOS), suggesting that these are likely to be the only meningococcal attributes necessary for serum resistance. Our work provides a valuable and lasting resource that may lead to a global map of gene function in N. meningitidis.

Antigens, Bacterial↗
PubMed2025

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72, 38 GRN, and 25 MAPT) and 55 symptomatic (27 C9orf72, 17 GRN, and 11 MAPT) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer's disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.

Humans↗
PubMed2005

Multiple gene segments control the temperature sensitivity and attenuation phenotypes of ca B/Ann Arbor/1/66.

Cold-adapted (ca) B/Ann Arbor/1/66 is the influenza B virus strain master donor virus for FluMist, a live, attenuated, influenza virus vaccine licensed in 2003 in the United States. Each FluMist vaccine strain contains six gene segments of the master donor virus; these master donor gene segments control the vaccine's replication and attenuation. These gene segments also express characteristic biological traits in model systems. Unlike most virulent wild-type (wt) influenza B viruses, ca B/Ann Arbor/1/66 is temperature sensitive (ts) at 37 degrees C and attenuated (att) in the ferret model. In order to define the minimal genetic components of these phenotypes, the amino acid sequences of the internal genes of ca B/Ann Arbor/1/66 were aligned to those of other influenza B viruses. These analyses revealed eight unique amino acids in three proteins: two in the polymerase subunit PA, two in the M1 matrix protein, and four in the nucleoprotein (NP). Using reverse genetics, these eight wt amino acids were engineered into a plasmid-derived recombinant of ca B/Ann Arbor/1/66, and these changes reverted both the ts and the att phenotypes. A detailed mutational analysis revealed that a combination of two sites in NP (A114 and H410) and one in PA (M431) controlled expression of ts, whereas these same changes plus two additional residues in M1 (Q159 and V183) controlled the att phenotype. Transferring this genetic signature to the divergent wt B/Yamanashi/166/98 strain conferred both the ts and the att phenotypes on the recombinant, demonstrating that this small, complex, genetic signature encoded the essential elements for these traits.

Adaptation, Physiological↗
PubMed2001

Molecular evolution of the homeodomain family of transcription factors.

The homeodomain family of transcription factors plays a fundamental role in a diverse set of functions that include body plan specification, pattern formation and cell fate determination during metazoan development. Members of this family are characterized by a helix-turn-helix DNA-binding motif known as the homeodomain. Homeodomain proteins regulate various cellular processes by specifically binding to the transcriptional control region of a target gene. These proteins have been conserved across a diverse range of species, from yeast to human. A number of inherited human disorders are caused by mutations in homeodomain-containing proteins. In this study, we present an evolutionary classification of 129 human homeodomain proteins. Phylogenetic analysis of these proteins, whose sequences were aligned based on the three-dimensional structure of the homeodomain, was performed using a distance matrix approach. The homeodomain proteins segregate into six distinct classes, and this classification is consistent with the known functional and structural characteristics of these proteins. An ancestral sequence signature that accurately describes the unique sequence characteristics of each of these classes has been derived. The phylogenetic analysis, coupled with the chromosomal localization of these genes, provides powerful clues as to how each of these classes arose from the ancestral homeodomain.

Amino Acid Sequence↗
PubMed2026

Proteogenomic features define subtypes of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a biologically heterogeneous B-cell malignancy. Although genomics and transcriptomics have delineated parts of the MCL disease spectrum, proteomics remains largely unexplored. Here, we conducted a comprehensive proteogenomic analysis integrating genomics, transcriptomics, and proteomics on peripheral blood samples from 27 patients with MCL and 4 healthy donors to investigate the translational and posttranslational dimensions of MCL. Our study identified 1296 downregulated and 468 upregulated proteins in MCL cells. The splicing pathways were significantly upregulated at both the mRNA and protein levels, suggesting a critical role for aberrant RNA splicing in MCL pathogenesis. Integration of proteomic data with genetic aberrations revealed immunoglobulin heavy chain variable mutational status and CCND1 mutation are associated with distinctive transcriptomic and proteomic profiles, which correspond to significant differences in clinical outcomes. A multiomics molecular stratification model incorporating proteomic data showed superior predictive power for patient survival compared with single-omics models (concordance index, 0.83 vs 0.74). This study provides, to our knowledge, the first comprehensive proteogenomic profile of MCL, offering novel insights into its molecular mechanisms and clinical behavior. The identification of molecular subtypes and prognostic protein signatures underscores the potential of proteomics to guide precision medicine strategies for MCL.

Humans↗
PubMed2003

Functional importance of polar and charged amino acid residues in transmembrane helix 14 of multidrug resistance protein 1 (MRP1/ABCC1): identification of an aspartate residue critical for conversion from a high to low affinity substrate binding state.

Human multidrug resistance protein 1 (MRP1) confers resistance to many chemotherapeutic agents and transports diverse conjugated organic anions. We previously demonstrated that Glu1089 in transmembrane (TM) 14 is critical for the protein to confer anthracycline resistance. We have now assessed the functional importance of all polar and charged amino acids in this TM helix. Asn1100, Ser1097, and Lys1092, which are all predicted to be on the same face of the helix as to Glu1089, are involved in determining the substrate specificity of the protein. Notably, elimination of the positively charged side chain of Lys1092, increased resistance to the cationic drugs vincristine and doxorubicin, but not the electroneutral drug etoposide (VP-16). In addition, mutations S1097A and N1100A selectively decreased transport of 17beta-estradiol 17-(beta-d-glucuronide) (E217betaG) but not cysteinyl leukotriene 4 (LTC4), demonstrating the importance of multiple residues in this helix in determining substrate specificity. In contrast, mutations of Asp1084 that eliminate the carboxylate side chain markedly decreased resistance to all drugs tested, as well as transport of both E217betaG and LTC4, despite the fact that LTC4 binding was unaffected. We show that these mutations prevent the ATP-dependent transition of the protein from a high to low affinity substrate binding state and drastically diminish ADP trapping at nucleotide binding domain 2. Based on results presented here and crystal structures of prokaryotic ATP binding cassette transporters, Asp1084 may be critical for interaction between the cytoplasmic loop connecting TM13 and TM14 and a region of nucleotide binding domain 2 between the conserved Walker A and ABC signature motifs.

Adenosine Diphosphate↗
PubMed2026

A machine learning-derived and functionally validated circadian rhythm signature predicts clinical outcomes and in silico drug sensitivity in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) displays considerable heterogeneity in clinical outcomes, highlighting the need for reliable prognostic biomarkers. While the aberrant expression of circadian rhythm-related genes has been implicated in cancer pathogenesis, its comprehensive role in CRC progression and predicted therapeutic vulnerabilities remains inadequately characterized. METHODS: Bulk and single-cell RNA-sequencing data were integrated from multiple CRC cohorts. A circadian rhythm signature (CRS) was developed through machine learning algorithms and validated for prognostic value. Comprehensive analyses of tumor microenvironment, genomic alterations, and drug sensitivity were performed. Furthermore, the biological function of the core gene, BHLHE40, was validated in CRC cell lines through CCK-8, EdU, and wound healing assays. RESULTS: Single-cell analysis demonstrated an elevated expression signature of circadian rhythm-related genes in dendritic cells. The optimized CRS, comprising 14 circadian rhythm-related genes, successfully categorized patients into high- and low-risk groups. Patients with a high CRS showed markedly poorer overall survival and computationally inferred immunosuppressive features, including reduced CD8+ T cell infiltration and increased M2 macrophage polarization. Genomic analysis revealed enhanced mutation burden in TP53 and alterations in RTK-RAS/WNT pathways. Notably, in vitro assays confirmed that BHLHE40 is significantly overexpressed in CRC cells. Knockdown of BHLHE40 markedly inhibited tumor cell proliferation and migration. Drug sensitivity profiling identified bexarotene and SMER-3 as potential therapeutic options for high-CRS patients. A nomogram integrating CRS with clinical parameters demonstrated superior predictive accuracy for 1-, 3-, and 5-year survival. CONCLUSIONS: The CRS represents a promising prognostic biomarker that reflects tumor immune status and genomic features, providing valuable insights for personalized treatment strategies in CRC.

Circadian rhythm↗
PubMed2000

Genes and the physics of the DNA double-helix.

The processing of the genetic information stored in the double-helical DNA implies the separation of the two strands, the physics of which is described by the helix-coil transition model. Is there a relationship between genetic maps and DNA physical stability maps that plot the sequence-specific propensity for the thermal disruption of the double-helix? Here, with appropriate methodological formulations, such maps are derived for a large set of sequences, including complete genomes. The superposition of the two maps leads to a contrasted picture with correlations ranging between two extremes: from almost perfect (with the genes precisely delineated as stable regions) to more or less complete unrelatedness. The simplest explanation for the results is that the observed striking correlations correspond to the relics of a primeval organisation of the genetic message, with the physics of DNA playing a role in the delimitation of coding regions. In order to trace the evolutionary fate of this signal further, a detailed study of the yeast complete genome is performed. In this study, the superposition of the genetic and physical stability maps is examined in the light of information concerning gene duplication. On the basis of this analysis it is concluded that the 'signature' associated with the supposed archaic signal is in the process of being erased, most probably because the underlying feature is no longer under selective pressure. There are many evolutionary implications for the results presented and for their proposed interpretations, notably concerning models of mutational dynamics in relation to erasure processes.

Algorithms↗
PubMed2005

Insights into the quaternary association of proteins through structure graphs: a case study of lectins.

The unique three-dimensional structure of both monomeric and oligomeric proteins is encoded in their sequence. The biological functions of proteins are dependent on their tertiary and quaternary structures, and hence it is important to understand the determinants of quaternary association in proteins. Although a large number of investigations have been carried out in this direction, the underlying principles of protein oligomerization are yet to be completely understood. Recently, new insights into this problem have been gained from the analysis of structure graphs of proteins belonging to the legume lectin family. The legume lectins are an interesting family of proteins with very similar tertiary structures but varied quaternary structures. Hence they have become a very good model with which to analyse the role of primary structures in determining the modes of quaternary association. The present review summarizes the results of a legume lectin study as well as those obtained from a similar analysis carried out here on the animal lectins, namely galectins, pentraxins, calnexin, calreticulin and rhesus rotavirus Vp4 sialic-acid-binding domain. The lectin structure graphs have been used to obtain clusters of non-covalently interacting amino acid residues at the intersubunit interfaces. The present study, performed along with traditional sequence alignment methods, has provided the signature sequence motifs for different kinds of quaternary association seen in lectins. Furthermore, the network representation of the lectin oligomers has enabled us to detect the residues which make extensive interactions ('hubs') across the oligomeric interfaces that can be targetted for interface-destabilizing mutations. The present review also provides an overview of the methodology involved in representing oligomeric protein structures as connected networks of amino acid residues. Further, it illustrates the potential of such a representation in elucidating the structural determinants of protein-protein association in general and will be of significance to protein chemists and structural biologists.

Amino Acid Sequence↗
PubMed2005

Molecular mechanisms in cancer: what should clinicians know?

Normal cells are influenced by a variety of environmental and host influences that can produce pro-carcinogenic mutations. Either a single or a series of mutations might result in cellular transformation. Like normal cells, most cancer cells use multiple redundant intracellular signaling pathways to ensure the maintenance and viability of functions critical to their survival. Thus, cellular pathways that are integral to cell function, survival, proliferation, and receptor expression are potential targets for therapeutic intervention. One example of this is the epidermal growth factor receptor signaling pathway. Other potential targets are molecules that mediate processes through which tumors produce angiogenic and invasion factors that stimulate host blood vessel growth into tumors and allow tumor growth and metastasis, such as the vascular endothelial growth factor. Targeting of downstream events that result in cellular apoptosis is another potential strategy. Continued investigations may result in the development of proteomic profiling databases through which a patient might be matched with molecular signatures in a library and upon which individualized cancer therapies might be selected. In this way, clinicians might recommend combinations of molecularly targeted agents and other therapies on the basis of an individual patient's proteomic profile.

Humans↗