Human Lineage Research Articles

Morphological and evolutionary insights into the keystone element of the human foot’s medial longitudinal arch

The evolution of the medial longitudinal arch (MLA) is one of the most impactful adaptations in the hominin foot that emerged with bipedalism. When and how it evolved in the human lineage is still unresolved. Complicating the issue, clinical definitions of flatfoot in living Homo sapiens have not reached a consensus. Here we digitally investigate the navicular morphology of H. sapiens (living, archaeological, and fossil), great apes, and fossil hominins and its correlation with the MLA. A distinctive navicular shape characterises living H. sapiens with adult acquired flexible flatfoot, while the congenital flexible flatfoot exhibits a ‘normal’ navicular shape. All H. sapiens groups differentiate from great apes independently from variations in the MLA, likely because of bipedalism. Most australopith, H. naledi, and H. floresiensis navicular shapes are closer to those of great apes, which is inconsistent with a human-like MLA and instead might suggest a certain degree of arboreality. Navicular shape of OH 8 and fossil H. sapiens falls within the normal living H. sapiens spectrum of variation of the MLA (including congenital flexible flatfoot and individuals with a well-developed MLA). At the same time, H. neanderthalensis seem to be characterised by a different expression of the MLA.

Metabolic Remodeling during Early Cardiac Lineage Specification of Pluripotent Stem Cells.

Growing evidence indicates that metabolites and energy metabolism play an active rather than consequential role in regulating cellular fate. Cardiac development requires dramatic metabolic remodeling from relying primarily on glycolysis in pluripotent stem cells (PSCs) to oxidizing a wide array of energy substrates to match the high bioenergetic demands of continuous contraction in the developed heart. However, a detailed analysis of how remodeling of energy metabolism contributes to human cardiac development is lacking. Using dynamic multiple reaction monitoring metabolomics of central carbon metabolism, we evaluated temporal changes in energy metabolism during human PSC 3D cardiac lineage specification. Significant metabolic remodeling occurs during the complete differentiation, yet temporal analysis revealed that most changes occur during transitions from pluripotency to mesoderm (day 1) and mesoderm to early cardiac (day 5), with limited maturation of cardiac metabolism beyond day 5. Real-time metabolic analysis demonstrated that while hPSC cardiomyocytes (hPSC-CM) showed elevated rates of oxidative metabolism compared to PSCs, they still retained high glycolytic rates, confirming an immature metabolic phenotype. These observations support the opportunity to metabolically optimize the differentiation process to support lineage specification and maturation of hPSC-CMs.

Identification and characterization of human hematopoietic mesoderm.

The embryonic mesoderm comprises heterogeneous cell subpopulations with distinct lineage biases. It is unclear whether a bias for the human hematopoietic lineage emerges at this early developmental stage. In this study, we integrated single-cell transcriptomic analyses of human mesoderm cells from embryonic stem cells and embryos, enabling us to identify and define the molecular features of human hematopoietic mesoderm (HM) cells biased towards hematopoietic lineages. We discovered that BMP4 plays an essential role in HM specification and can serve as a marker for HM cells. Mechanistically, BMP4 acts as a downstream target of HDAC1, which modulates the expression of BMP4 by deacetylating its enhancer. Inhibition of HDAC significantly enhances HM specification and promotes subsequent hematopoietic cell differentiation. In conclusion, our study identifies human HM cells and describes new mechanisms for human hematopoietic development.

Comparative transcriptomics reveals human-specific cortical features.

The cognitive abilities of humans are distinctive among primates, but their molecular and cellular substrates are poorly understood. We used comparative single-nucleus transcriptomics to analyze samples of the middle temporal gyrus (MTG) from adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets to understand human-specific features of the neocortex. Human, chimpanzee, and gorilla MTG showed highly similar cell-type composition and laminar organization as well as a large shift in proportions of deep-layer intratelencephalic-projecting neurons compared with macaque and marmoset MTG. Microglia, astrocytes, and oligodendrocytes had more-divergent expression across species compared with neurons or oligodendrocyte precursor cells, and neuronal expression diverged more rapidly on the human lineage. Only a few hundred genes showed human-specific patterning, suggesting that relatively few cellular and molecular changes distinctively define adult human cortical structure.

Perception and Risk Factors Associated with Tuberculosis in the Manyara Region, Tanzania

Tuberculosis (TB) results from infection with members of the Mycobacterium tuberculosis complex (MTBC) and represents a major global public health concern. We here sought to assess the perceptions of human and animal TB and the prevalence of circulating MTBCs lineages and associated risk factors through a cross-sectional survey of 335 individuals presenting with symptoms of pulmonary or extrapulmonary TB in the Manyara region of Tanzania. After the enrollment of participants, a questionnaire survey was conducted, samples were collected for bacterial culture, and real-time multiplex PCR was performed to differentiate amongst primary animal and human MTBC lineages. The results show poor TB awareness: 31.6% of the participants were not aware of human TB; 82.4% were unaware of animal TB and 95.2% lacked awareness of zoonotic TB (zTB) transmission. A total of 18 recovered specimens (5%; 95% CI: 3–8%) were positive by culture, all of which were typed as M. tuberculosis sensu stricto using a lineage-specific PCR assay. While no single risk factor was significantly associated with MTBC culture positivity, the survey revealed considerable self-reported high-risk practices for contracting zTB. Together, the results show that Manyara residents have poor knowledge of diseases caused by MTBCs and high evidence of risky practices for contracting zTB.

OR05-05 A Novel Model Of Prostate Cancer Suggests Enzalutamide Functions Through The Immune System To Diminish Castration Resistant And Metastatic Growth

Abstract Disclosure: S. Kregel: None. Background: There exists a tremendous need for establishing prostate cancer (PCa) murine models capable of recapitulating the progress of human PCa. By itself, the murine prostate does not form sporadic tumors and is anatomically and developmentally different from the human prostate. Engineered mouse models, however, lack the heterogeneity of human disease, are often driven in a contrived manner, and rarely (if ever) establish metastatic growth. Human xenografts represent an alternative, but they rely on tumor growth in an immunocompromised host, thus preventing the study of tumor-immune interactions and immunotherapies. Accordingly, we generated PCa xenograft models in a murine system with an intact human immune system (huNOG mice) to test the hypothesis that humanizing tumor-immune interactions would improve modeling of metastatic PCa as well as our ability to model the impact of hormonal and immunotherapies. Methods: Male huNOG and huNOG-EXL mice were produced at Taconic Biosciences by engrafting juvenile NOG mice with human CD34+ hematopoietic stem cells. These mice stably maintained multiple human cell lineages, including functional human T-cells. We utilized two human PCa xenograft cell line models transduced with luciferase to assay organ-specific metastatic growth. First, castrated and intact control mice were injected subcutaneously with 22Rv1 cells. When tumors reached >100 mm3, half of the castrated mice were treated with enzalutamide (enza), and tumor growth was then monitored to endpoint. Additionally, VCaP tumor-bearing mice were castrated when the tumors reached ∼200 mm3, and once the tumor grew back, they were randomized and treated with enza and/or the anti-PD-1 antibody, pembrolizumab (pembro) as well as with vehicle controls. At sacrifice, organs were ex vivo analyzed for metastatic growth, tumor infiltrating lymphocytes, and splenic immune reconstitution. Results: In 22Rv1 tumor-bearing mice, subcutaneous tumor size was not significantly altered across conditions. However, the extent and growth at the secondary sites differed markedly in castrate huNOG vs conventional NOG mice treated with enza. VCaP xenograft tumors showed marked decreases in growth with enza and pembro treatments in huNOG mice, while no effect was observed with either of these treatments in NOG mice. Furthermore, immune responses to enza treatment in huNOG and NOG mice were distinct, as enza treatment only increased intra-tumor CD3+ T-cells as well as CD3+ T-cell activation in huNOG mice. Conclusions: These results illustrate, to the best of our knowledge, the first model of human PCa that metastasizes to clinically relevant locations, has an intact human immune system, and responds to standard-of-care hormonal therapies in a manner similar to responses observed under clinical settings. Presentation: Thursday, June 15, 2023

Ohnologs and SSD Paralogs Differ in Genomic and Expression Features Related to Dosage Constraints.

Gene duplication is recognized as a critical process in genome evolution; however, many questions about this process remain unanswered. Although gene duplicability has been observed to differ by duplication mechanism and evolutionary rate, there is so far no broad characterization of its determinants. Many features correlate with this difference in duplicability; however, our ability to exploit these observations to advance our understanding of the role of duplication in evolution is hampered by limitations within existing work. In particular, the existence of methodological differences across studies impedes meaningful comparison. Here, we use consistent definitions of duplicability in the human lineage to explore these associations, allow resolution of the impact of confounding factors, and define the overall relevance of individual features. Using a classifier approach and controlling for the confounding effect of duplicate longevity, we find a subset of gene features important in differentiating genes duplicable by small-scale duplication from those duplicable by whole-genome duplication, revealing critical roles for gene dosage and expression costs in duplicability. We further delve into patterns of functional enrichment and find a lack of constraint on duplicate retention in any context for genes duplicable by small-scale duplication.

MYTHOLOGICAL INTERTEXTUALITY IN THE CYCLE "LEGENDS OF OLD KYIV" BY NATALENA KOROLEVA

The article reveals that in the literary reception of Natalena Koroleva, there is a predominance of researches dedicated to religious-philosophical issues, the interpretation of evangelical themes. The analysis of her particular protagonist is of homo religious character. The writer's interest in historiosophical themes is driven by the aesthetics of neo-romanticism and neoclassicism, lyrical-impressionistic storytelling and a desire for the heroic and the sublime things. When delineating the intertextuality of the writer's works, literary scholars primarily focus on the Gospel intertext, while somewhat less attention is given to the analysis of mythological intertextuality that is realized in "The Legends of Old Kyiv." It has been revealed that in her cycle, the writer has recreated various ideological systems. They move by different means towards one goal such as faith in the spiritual power of humanity. It has been established that the narratives of Herodotus' history are skillfully interwoven in the author's legends incorporating ancient Greek mythologems. As mythological prototypes, the writer utilizes plots involving Zeus and Apollo/Phoebus. In the literary realm of "The Scythian Treasure" legends, Zeus is portrayed as the primordial ancestor because the human lineage along the banks of the Dnieper River traces its origins to Targiotas, the son of Zeus and Lartis, the daughter of Borysthenes. In the legend of "Melusine," he appears as the one who determines the fate of humanity. The chronotope of Natalia Koroleva's legends is imbued with "traces" of Apollo. It is depicted that in the "Scythian Treasure" and "On Delos," the effect of the god's presence is achieved through literary details being his attribute characteristics: bow and arrows, swan, discus throwing, the art of prophecy. The Apollo context in the legend "On Delos" is complemented by "The Borysthenian code" (Lada, Dadzy-Bog, Yar-Bog, Khors) in the writer's work. It is noted that while describing the presence of other peoples in the history of Ukraine, the writer focused on the history of Kyivan Rus allowing her to incorporate Scandinavian codes into the cycle of texts ("Swan Gild Princess," "Stuhna"). Owing to her mythological thinking, Natalena Koroleva managed to achieve a symbiosis of different cultures and demonstrate the resilience of Ukrainian identity.

Progress with induction of HIV broadly neutralizing antibodies in the Duke Consortia for HIV/AIDS Vaccine Development.

Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather HIV bnAbs are disfavored by a number of virus and host factors. The purpose of the review is to discuss recent progress made in the design and use of immunogens capable of inducing HIV bnAbs in the Duke Consortia for HIV/AIDS Vaccine Development. New immunogens capable of binding with high affinity to unmutated common ancestors (UCAs) of bnAb B cell lineages have been designed and strategies for stabilization of HIV Env in its prefusion state are being developed. Success is starting to be translated from preclinical studies of UCA-targeting immunogens in animals, to success of initiating bnAb lineages in humans. Recent progress has been made in both immunogen design and in achieving bnAb B cell lineage induction in animal models and now in human clinical trials. With continued progress, a practical HIV/AIDS vaccine may be possible. However, host constraints on full bnAb maturation remain as potential roadblocks for full maturation of some types of bnAbs.

Phylogenomic analysis of a global collection of Escherichia coli ST38: evidence of interspecies and environmental transmission?

We performed a comprehensive phylogenomic analysis of 925 extraintestinal pathogenic Escherichia coli (ExPEC) ST38 genomes from 38 countries and diverse hosts and sources. The phylogeny resolved two broad clades: A (593 strains; 91% human) and B (332 isolates; 42% human), each with distinct ST38 clusters linked to the carriage of specific bla CTX-M alleles, often in association with other antibiotic resistance genes, class 1 integrons and specific plasmid replicon types. Co-carriage of fyuA and irp2 virulence genes, a reliable proxy for carriage of the Yersinia high-pathogenicity island, featured in 580 (62.7%) genomes. ST38 lineages carrying combinations of ExPEC and intestinal pathogenic Escherichia coli virulence factors were also identified. The F plasmid replicon was identified in 536 (58%) genomes, and 112 of these (21%) carry cjrABC-senB, a virulence operon frequently identified in pandemic ExPEC sequence types. Most (108; 96.4%) cjrABC-senB+ ST38 isolates were from human and other sources, except food animals, and were associated with F5:A-:B10 (41 isolates), F1:A2:B20 (20 isolates), and F24:A-:B1 (15 isolates) F replicon types. ST38 genomes that were inferred to carry a ColV-F virulence plasmid (69; 7.4%) were mostly from human (12; 17.4%), avian (26; 37.7%), or poultry (10; 6.9%) sources. We identified multiple examples of putative inter-host and host-environment transmission events, where genomes differed by <35 SNPs. This work emphasizes the importance of adopting a One Health approach for phylogenomic studies that seek to improve understanding of antimicrobial resistance and pathogen evolution. IMPORTANCE Extraintestinal pathogenic Escherichia coli (ExPEC) sequence type (ST) 38 is one of the top 10 human pandemic lineages. Although a major cause of urinary tract and blood stream infections, ST38 has been poorly characterized from a global phylogenomic perspective. A comprehensive genome-scale analysis of 925 ST38 isolate genomes identified two broad ancestral clades and linkage of discrete ST38 clusters with specific bla CTX-M variants. In addition, the clades and clusters carry important virulence genes, with diverse but poorly characterized plasmids. Numerous putative interhost and environment transmission events were identified here by the presence of ST38 clones (defined as isolates with ≤35 SNPs) within humans, companion animals, food sources, urban birds, wildlife, and the environment. A small cluster of international ST38 clones from diverse sources, likely representing progenitors of a hospital outbreak that occurred in Brisbane, Australia, in 2017, was also identified. Our study emphasizes the importance of characterizing isolate genomes derived from nonhuman sources and geographical locations, without any selection bias.

Downclimbing and the evolution of ape forelimb morphologies.

The forelimbs of hominoid primates (apes) are decidedly more flexible than those of monkeys, especially at the shoulder, elbow and wrist joints. It is tempting to link the greater mobility of these joints to the functional demands of vertical climbing and below-branch suspension, but field-based kinematic studies have found few differences between chimpanzees and monkeys when comparing forelimb excursion angles during vertical ascent (upclimbing). There is, however, a strong theoretical argument for focusing instead on vertical descent (downclimbing), which motivated us to quantify the effects of climbing directionality on the forelimb kinematics of wild chimpanzees (Pan troglodytes) and sooty mangabeys (Cercocebus atys). We found that the shoulders and elbows of chimpanzees and sooty mangabeys subtended larger joint angles during bouts of downclimbing, and that the magnitude of this difference was greatest among chimpanzees. Our results cast new light on the functional importance of downclimbing, while also burnishing functional hypotheses that emphasize the role of vertical climbing during the evolution of apes, including the human lineage.

Anatomically modern human in the Châtelperronian hominin collection from the Grotte du Renne (Arcy-sur-Cure, Northeast France)

Around 42,000 years ago, anatomically modern humans appeared in Western Europe to the detriment of indigenous Neanderthal groups. It is during this period that new techno-cultural complexes appear, such as the Châtelperronian that extends from northern Spain to the Paris Basin. The Grotte du Renne (Arcy-sur-Cure) is a key site for discussing the biological identity of its makers. This deposit has yielded several Neanderthal human remains in its Châtelperronian levels. However, the last inventory of the paleoanthropological collection attributed to this techno-complex allowed the identification of an ilium belonging to a neonate (AR-63) whose morphology required a thorough analysis to assess its taxonomic attribution. Using geometric morphometrics, we quantified its morphology and compared it to that of 2 Neanderthals and 32 recent individuals deceased during the perinatal period to explore their morphological variation. Our results indicate a morphological distinction between the ilia of Neanderthals and anatomically modern neonates. Although AR-63 is slightly outside recent variability, it clearly differs from the Neanderthals. We propose that this is due to its belonging to an early modern human lineage whose morphology differs slightly from present-day humans. We also explore different hypotheses about the presence of this anatomically modern neonate ilium among Neanderthal remains.

An in vitro model of human hematopoiesis identifies a regulatory role for the aryl hydrocarbon receptor

AbstractIn vitro models to study simultaneous development of different human immune cells and hematopoietic lineages are lacking. We identified and characterized, using single-cell methods, an in vitro stromal cell–free culture system of human hematopoietic stem and progenitor cell (HSPC) differentiation that allows concurrent development of multiple immune cell lineages. The aryl hydrocarbon receptor (AHR) is a ligand–activated transcription factor influencing many biological processes in diverse cell types. Using this in vitro model, we found that AHR activation by the highly specific AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, drives differentiation of human umbilical cord blood–derived CD34+ HSPCs toward monocytes and granulocytes with a significant decrease in lymphoid and megakaryocyte lineage specification that may lead to reduced immune competence. To our knowledge, we also discovered for the first time, using single-cell modalities, that AHR activation decreased the expression of BCL11A and IRF8 in progenitor cells, which are critical genes involved in hematopoietic lineage specification processes at both transcriptomic and protein levels. Our in vitro model of hematopoiesis, coupled with single-cell tools, therefore allows for a better understanding of the role played by AHR in modulating hematopoietic differentiation.

Tamoxifen/montmorillonite as a controlled release oral system

Drugs have been incorporated into clay minerals to obtain a controlled-release system. In the present study, tamoxifen citrate (TMX) was loaded in pharmaceutical montmorillonite (VHS) at pH 3.0, 4.0, and 5.0 and released in vitro under simulated stomach and intestinal conditions to evaluate the cytotoxic activity of TMX/VHS systems. The systems were characterized using structural (X-ray diffractometry and Fourier transform infrared spectroscopy) and thermal (thermogravimetric analysis and differential calorimetry) techniques. TMX was loaded in VHS via a reaction between 1660 mg L−1 TMX methanol solutions and 0.1 g of VHS at pH 3.0 (VHS/TMX/pH3), 4.0 (VHS/TMX/pH4), and 5.0 (VHS/TMX/pH5) for 12 h at 200 rpm and 25 °C. The release of TMX was evaluated with dispersed amounts of loaded TMX systems in a simulated medium at pH 1.2 and 6.8, and TXM was quantified by high-performance liquid chromatography. Cytotoxicity tests were performed in vitro using the MTT assay for human tumor cell lineages. Characterization results indicated the intercalation of TMX in the clay mineral, and the amounts of TMX were 344.7, 347.1, and 374.4 mg per gram of VHS for the systems prepared at pH 3, 4, and 5, respectively. Releases of 8.40% (VHS/TMX/pH3), 8.68% (VHS/TMX/pH4), and 11.15% (VHS/TMX/pH5) occurred at pH 1.2, whereas at pH 6.8, the release of TMX increased to 21.21% (VHS/TMX/pH3), 24.85% (VHS/TMX/pH4), and 39.27% (VHS/TMX/pH5). The VHS/TMX systems exhibited cytotoxicity with increasing concentrations for all cells, with increased cytotoxic activity with IC50 of 54.57 μg mL−1 (TMX 20.10 μg mL−1) for the VHS/TMX/pH5 for glioblastoma lineages. Therefore, the TMX/VHS systems presented drug release control and, depending on the concentration, could exert cytotoxic activity without causing damage to normal cells, thus reducing adverse effects.

How Mitochondrial DNA Can Write Pre-History: Kinship and Culture in Duero Basin (Spain) during Chalcolithic and Bronze Age

The chronological period from the beginning of the Chalcolithic Age to the end of the Bronze Age on the Iberian northern sub-plateau of the Iberic Peninsula involves interesting social and cultural phenomena, such as the appearance of the Bell Beaker and, later, the Cogotas I cultures. This work constructs a genetic characterisation of the maternal lineages of the human population that lived on the northern sub-plateau between 5000 and 3000 years ago through an analysis of mitochondrial DNA (mtDNA), a kind of genetic marker that is inherited through maternal lineages, unaltered from generation to generation. Population and cultural questions are investigated through mtDNA analyses. This study intends to shed light on the following questions. Were individuals who were buried together in multiple or collective burials biologically related through their maternal lineages? Were there distinct maternal human lineages in the same or different geographical areas if different material cultures (Bell Beaker and Cogotas I) were associated with the arrival of new human populations who established close biological relationships with the endogenous populations? Or could this be the result of the transmission of knowledge without human populations mixing? Another important question is whether the material cultures were related to the female populations. We analysed 91 individuals from 28 different archaeological sites of the Iberian northern sub-plateau from four different chrono-cultural periods (Pre-Bell Beaker, Bell Beaker, Proto-Cogotas I, and Cogotas I), from the end of the Chalcolithic Age up to the Bronze Age. There were two historical moments of new populations arriving: the first during the Pre-Bell Beaker period, associated with the K mtDNA haplogroup, and the second during the Proto-Cogotas I culture, with new lineages of the H, HVO, and T haplogroups. Neither of these new population flows were directly associated with the maximum development of the two main material cultures Bell Beaker and Cogotas I, so they must have occurred immediately beforehand, during the Pre-Bell Beaker and Proto-Cogotas I periods, respectively. However, we cannot discard an association between the populations and material cultures. Curiously, it has also been observed that there was also a tendency towards multiple burials, in which the individuals who were buried together belonged to the same maternal lineage, during these two periods of population change. This study has shed some light on the populational changes that occurred through these different periods in this specific geographical area of the northern sub-plateau of the Iberian Peninsula.

Transcriptomic landscape reveals germline potential of porcine skin-derived multipotent dermal fibroblast progenitors.

According to estimations, approximately about 15% of couples worldwide suffer from infertility, in which individuals with azoospermia or oocyte abnormalities cannot be treated with assisted reproductive technology. The skin-derived stem cells (SDSCs) differentiation into primordial germ cell-like cells (PGCLCs) is one of the major breakthroughs in the field of stem cells intervention for infertility treatment in recent years. However, the cellular origin of SDSCs and their dynamic changes in transcription profile during differentiation into PGCLCs in vitro remain largely undissected. Here, the results of single-cell RNA sequencing indicated that porcine SDSCs are mainly derived from multipotent dermal fibroblast progenitors (MDFPs), which are regulated by growth factors (EGF/bFGF). Importantly, porcine SDSCs exhibit pluripotency for differentiating into three germ layers and can effectively differentiate into PGCLCs through complex transcriptional regulation involving histone modification. Moreover, this study also highlights that porcine SDSC-derived PGCLCs specification exhibit conservation with the human primordial germ cells lineage and that its proliferation is mediated by the MAPK signaling pathway. Our findings provide substantial novel insights into the field of regenerative medicine in which stem cells differentiate into germ cells in vitro, as well as potential therapeutic effects in individuals with azoospermia and/or defective oocytes.

Dissecting peri-implantation development using cultured human embryos and embryo-like assembloids

Studies of cultured embryos have provided insights into human peri-implantation development. However, detailed knowledge of peri-implantation lineage development as well as underlying mechanisms remains obscure. Using 3D-cultured human embryos, herein we report a complete cell atlas of the early post-implantation lineages and decipher cellular composition and gene signatures of the epiblast and hypoblast derivatives. In addition, we develop an embryo-like assembloid (E-assembloid) by assembling naive hESCs and extraembryonic cells. Using human embryos and E-assembloids, we reveal that WNT, BMP and Nodal signaling pathways synergistically, but functionally differently, orchestrate human peri-implantation lineage development. Specially, we dissect mechanisms underlying extraembryonic mesoderm and extraembryonic endoderm specifications. Finally, an improved E-assembloid is developed to recapitulate the epiblast and hypoblast development and tissue architectures in the pre-gastrulation human embryo. Our findings provide insights into human peri-implantation development, and the E-assembloid offers a useful model to disentangle cellular behaviors and signaling interactions that drive human embryogenesis.

Mitochondrial Replacement Therapy: An Islamic Perspective.

Mitochondrial replacement technology (MRT) is an emerging and complex bioethical issue. This treatment aims to eliminate maternal inherited mitochondrial DNA (mtDNA) disorders. For Muslims, its introduction affects every aspect of human life, especially the five essential interests of human beings-namely, religion, life, lineage, intellect, and property. Thus, this technology must be assessed using a comprehensive and holistic approach addressing these human essential interests. Consequently, this article analyses and assesses tri-parent baby technology from the perspective of Maqasidic bioethics-that is, Islamic bioethics based on the framework of Maqasid al-Shariah. Using this analysis, this article suggests that tri-parent baby technology should not be permitted for Muslims due to the existence of third-party cell gametes which lead to lineage mixing and due to the uncertain safety of the therapy itself and because the major aim of the technology is to fulfil the affected couples interest to conceive their own genetically healthy child, not to treat and cure mtDNA disorders sufferers.

Integrative analysis of single-cell embryo data reveals transcriptome signatures for the human pre-implantation inner cell mass.

As the source of embryonic stem cells (ESCs), inner cell mass (ICM) can form all tissues of the embryo proper, however, its role in early human lineage specification remains controversial. Although a stepwise differentiation model has been proposed suggesting the existence of ICM as a distinct developmental stage, the underlying molecular mechanism remains unclear. In the present study, we perform an integrated analysis on the public human preimplantation embryonic single-cell transcriptomic data and apply a trajectory inference algorithm to measure the cell plasticity. In our results, ICM population can be clearly discriminated on the dimension-reduced graph and confirmed by compelling evidences, thus validating the two-step hypothesis of lineage commitment. According to the branch probabilities and differentiation potential, we determine the precise time points for two lineage segregations. Further analysis on gene expression dynamics and regulatory network indicates that transcription factors including GSC, PRDM1, and SPIC may underlie the decisions of ICM fate. In addition, new human ICM marker genes, such as EPHA4 and CCR8 are discovered and validated by immunofluorescence. Given the potential clinical applications of ESCs, our analysis provides a further understanding of human ICM cells and facilitates the exploration of more unique characteristics in early human development.

The importance of gene flow in human evolution

By the latter half of the 20th century, there were three dominant models of human evolution. All three accepted an African origin of humans at the Homo erectus stage, with H. erectus expanding out of Africa and colonizing Eurasia near the beginning of the Pleistocene. The candelabra model had H. erectus splitting into mostly isolated geographical lineages that independently evolved into the modern African, European and Asian “races”. The out-of-Africa replacement model starts out like the candelabra model, but then posits that Homo sapiens first evolved in Africa and then expanded out of Africa in the late Pleistocene and replaced all of the archaic Eurasian populations without interbreeding with them. Neither of these models assign an important role to gene flow (genetic interchange). In contrast, the multiregional model regarded the human populations in Africa and Eurasia as experiencing gene flow throughout the Pleistocene and evolving as a single human lineage with some local differentiation. Studies on mitochondrial DNA in the 1980’s claimed to support the out-of-Africa replacement model and to falsify both the candelabra and multiregional models by mistakenly equating the two. In fact, the mitochondrial DNA studies were fully compatible with both the replacement and multiregional models. The first statistically significant discrimination between these two models appeared in 2002 and revealed a hybrid model in which there was a mid-Pleistocene and a late Pleistocene expansion of humans out of Africa that resulted in limited genetic interchange with Eurasians rather than complete replacement. Moreover, significant gene flow and population movements led to genetic interchange throughout the mid-Pleistocene to the present. Studies on genomic data and ancient DNA have strongly confirmed these inferences. Moreover, our modern species of humans was forged in an African multiregional metapopulation rather than arising from one local area of Africa. Thus, gene flow has played a dominant role in human evolution since the mid-Pleistocene whereas splits and isolation have not. This undercuts the idea that human races are biologically real categories or separate branches on an evolutionary tree.