Structurally divergent and recurrently mutated regions of primate genomes.

We sequenced and assembled using multiple long-read sequencing technologies the genomes of chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, owl monkey, and marmoset. We identified 1,338,997 lineage-specific fixed structural variants (SVs) disrupting 1,561 protein-coding genes and 136,932 regulatory elements, including the most complete set of human-specific fixed differences. We estimate that 819.47 Mbp or ∼27% of the genome has been affected by SVs across primate evolution. We identify 1,607 structurally divergent regions wherein recurrent structural variation contributes to creating SV hotspots where genes are recurrently lost (e.g., CARD, C4, and OLAH gene families) and additional lineage-specific genes are generated (e.g., CKAP2, VPS36, ACBD7, and NEK5 paralogs), becoming targets of rapid chromosomal diversification and positive selection (e.g., RGPD gene family). High-fidelity long-read sequencing has made these dynamic regions of the genome accessible for sequence-level analyses within and between primate species.

Rapid and inexpensive bedside diagnosis of RAN binding protein 2-associated acute necrotizing encephalopathy.

Acute necrotizing encephalopathy 1 (ANE1) is a very rare disorder associated with a dominant heterozygous mutation in the RANBP2 (RAN binding protein 2) gene. ANE1 is frequently triggered by a febrile infection and characterized by serious and irreversible neurological damage. Although only a few hundred cases have been reported, mutations in RANBP2 are only partially penetrant and can occur de novo, suggesting that their frequency may be higher in some populations. Genetic diagnosis is a lengthy process, potentially delaying definitive diagnosis. We therefore developed a rapid bedside qPCR-based tool for early diagnosis and screening of ANE1 mutations. Primers were designed to specifically assess RANBP2 and not RGPD (RANBP2 and GCC2 protein domains) and discriminate between wild-type or mutant RANBP2. Nasal epithelial cells were obtained from two individuals with known RANBP2 mutations and two healthy control individuals. RANBP2-specific reverse transcription followed by allele-specific primer qPCR amplification confirmed the specific detection of heterozygously expressed mutant RANBP2 in the ANE1 samples. This study demonstrates that allele-specific qPCR can be used as a rapid and inexpensive diagnostic tool for ANE1 using preexisting equipment at local hospitals. It can also be used to screen non-hospitalized family members and at risk-population to better establish the frequency of non-ANE-associated RANBP2 mutations, as well as possible tissue-dependent expression patterns. Systematic review registration: The protocol was registered in the international prospective register of systematic reviews (PROSPERO- CRD42023443257).

RANBP2 evolution and human disease.

Ran-binding protein 2 (RANBP2)/Nup358 is a nucleoporin and a key component of the nuclear pore complex. Through its multiple functions (e.g., SUMOylation, regulation of nucleocytoplasmic transport) and subcellular localizations (e.g., at the nuclear envelope, kinetochores, annulate lamellae), it is involved in many cellular processes. RANBP2 dysregulation or mutation leads to the development of human pathologies, such as acute necrotizing encephalopathy 1, cancer, neurodegenerative diseases, and it is also involved in viral infections. The chromosomal region containing the RANBP2 gene is highly dynamic, with high structural variation and recombination events that led to the appearance of a gene family called RANBP2 and GCC2 Protein Domains (RGPD), with multiple gene loss/duplication events during ape evolution. Although RGPD homoplasy and maintenance during evolution suggest they might confer an advantage to their hosts, their functions are still unknown and understudied. In this review, we discuss the appearance and importance of RANBP2 in metazoans and its function-related pathologies, caused by an alteration of its expression levels (through promotor activity, post-transcriptional, or post-translational modifications), its localization, or genetic mutations.

Exome sequencing link mutation in RGPD4 with systemic sclerosis-associated interstitial lung disease and the low level of testosterone-an exploration study.

Background: Interstitial lung disease (ILD) is the most common and potentially most devastating manifestation of SSc in pulmonary involvement. However, the mechanism for systemic sclerosis-associated ILD (SSc-ILD) is unclear. This work aims to explore the potential candidates for SSc-ILD upon whole exome sequencing (WES) and attempts to analyze the possible pathogenesis of SSc-ILD from the perspective of the genetic level. Materials: Variants were confirmed by whole exome sequencing (WES), and SKAT analysis was employed to explore the most differential variants. Targeted variants were performed in biological functions, associated with clinical manifestations, and the probable change of downstream. Results: By WES and SKAT analysis of SSc with and without ILD, only the variants of RGPD4 achieved statistical power (P < 2.51 × 10-6, P-FDR = 0.025, OR = 15.95). A total of 20 rare functional variants (missense, truncating, splicing) were tested for the RGPD4 gene, and five truncating and damaging missense variants were identified. Carriers showed the older inclusion age (P = 0.02) and the higher frequency use of prednisone (P=0.02) compared to the non-carriers. Further analysis illustrated that carriers showed lower levels of TES in comparison to non-carriers but did not reach statistical difference (P = 0.08). In bivariate correlation analysis, we analyzed the relationship between the mutant status of RGPD4 and the levels of sex hormones after adjusting for age confounders. Only the level of TES showed a negative correlation with the mutant status (B = -0.509, P = 0.037). Conclusion: The variants of RGPD4 might contribute to the ILD development of SSc and might also be a causative factor of lower TES among SSc-ILD, which provided insight to a better understanding of pathobiology of SSc-ILD, and androgen hormone supplement might be a therapeutic target in this debilitating disease.

[POCT-management during the first wave of Covid-19 in France. Results of a national survey leaded by the SFBC-POCT Working Group]. / Gestion de la biologie délocalisée lors de la première vague de Covid-19 en France. Résultats de l'enquête nationale menée par le groupe de travail des EBMD de la SFBC.

During the first wave of Covid-19 in France, in spring 2020, healthcare institution's laboratory had to adapt itself quickly to the growing demand for emergency biology, in particular by reorganizing their POCT analyzers: redeployment of analyzers and/or new installations. In order to analyze this management, a subgroup of 15 hospital biologists from the SFBC Working Group "Biochemical markers of Covid-19" sent, in fall 2020, an on-line survey to French hospital laboratories using POCT. Answers analysis (n = 86) shows a territorial disparity related to the severity of the first wave: increased activity essentially in red zones, management of unexpected situations, training of additional nursing staff for 40 % of the laboratories... The survey also showed simplification of aspects related to accreditation those periods of health crisis. An additional survey, carried out in the spring of 2021, showed good overall satisfaction of the healthcare services (n = 139) concerning the services provided by biology in the POCT sector. Because of their great adaptation capacity, the laboratories and their POCT-teams have played a key role in the management of the first wave of Covid-19 in France. However, the success of these organizations requires an essential collaboration between laboratories and healthcare services. The results of this survey are fundamental in the context of the prolongation of the pandemia throughout the world with a POCT sector appearing to be growing.

TV-circRGPD6 Nanoparticle Suppresses Breast Cancer Stem Cell-Mediated Metastasis via the miR-26b/YAF2 Axis.

Metastatic tumor is a major contributor to death caused by breast cancer. However, effective and targeted therapy for metastatic breast cancer remains to be developed. Initially, we exploited a feasible biological rationale of the association between metastatic status and tumor-initiating properties in metastatic breast cancer stem cells (BCSCs). Further, we explored that circular RNA RANBP2-like and GRIP domain-containing protein 6 (circRGPD6) regulates the maintenance of stem cell-like characteristics of BCSCs. Targeted expression of circRGPD6 via human telomerase reverse transcriptase (hTERT) promoter-driven VP16-GAL4-woodchuck hepatitis virus post-transcriptional regulatory element (WPRE)-integrated systemic amplifier delivery composite vector (TV-circRGPD6) significantly inhibited expression of stem-cell marker CD44 and increased expression of the DNA damage marker p-H2AX. Furthermore, we determined TV-circRGPD6, alone or synergized with docetaxel, displays significant therapeutic responses on metastatic BCSCs. Mechanistic analyses exploited that TV-circRGPD6 suppresses BCSC-mediated metastasis via the microRNA (miR)-26b/YAF2 axis. Clinically, for the first time, we observed that expressions of circRGPD6 and YAF2 predict a favorable prognosis in patients with breast cancer, whereas expression of miR-26b is an unfavorable prognostic factor. Overall, we have developed a TV-circRGPD6 nanoparticle that selectively expresses circRGPD6 in metastatic BCSCs to eradicate breast cancer metastasis, therefore providing a novel avenue to treat breast cancers.

[Ethics and confidentiality of a patient in a medical biology laboratory]. / L'éthique et la confidentialité du patient au laboratoire de biologie médicale.

Confidentiality is based on principles of deontology and ethics, which are included in French regulations and supported by the professional orders. It contributes to the respect and dignity of the patient. If this consideration of the human person is old, it has been updated to build the framework imposed by the accreditation of medical biology laboratories. Confidentiality is thus reflected in a charter of ethics, a model of which we propose here. It reflects the commitments of healthcare professionals in the processing of biological samples from patients. Confidentiality is thus applied, in a practical way, at each phase of the laboratory's activity. In the pre-analytical phase, it organizes the reception of the patient and the taking of samples, taking into account the particular case of minors. In the analytical phase, confidentiality imposes limited access to the technical premises and the organization of the flow of personnel from outside the laboratory. Finally, in the post-analytical phase, the reporting of results is regulated, depending on the type of analyses performed and the person to whom the results are to be reported (patient or prescriber). The particular case of spermiology illustrates all these points. Finally, during these phases of sample processing, document management is also a matter of confidentiality and data protection. Confidentiality is essential to the functioning of a health care structure, but it is restrictive in its day-to-day implementation. Nevertheless, it must be combined with an awareness of all staff to address the ethical issue of human dignity.

[Adaptation of the General Data Protection Regulation (GDPR) to a smartphone app for rhinitis and asthma (MASK-air®)]. / Règlement général sur la protection des données pour MASK-air® (application mobile rhinite et asthme).

The General Data Protection Regulation (GDPR) regulates the processing of personal data in the European Union. The legal context is adapted to follow the evolution of technologies and of society. This new European regulation became mandatory, especially for connected devices, on May 25, 2018. An app originally known as "The Allergy Diary" is available for Android phones and iPhones. Its name was recently changed to MASK-air. The downloading and use of this app are free of charge and there are no adverts. It enables users to record their symptoms and their medications to better track the progress of their allergic rhinitis and/or asthma. It has been developed by public (Foundation FMC VIA-LR, University of Montpellier) and private (KYomed INNOV) organizations based in France and therefore falls under French jurisdiction. This article summarizes the five main principles of personal data protection to be respected during the development of the app: purpose, proportionality and relevance, limited retention period, security and confidentiality, as well as the rights of the people who are involved in the management of the personal data (including withdrawal and modification).