On October 15, 1983, a young mother of six was murdered while walking across her village of Huitzilan de Serdán, Mexico, with her infant son and one of her daughters. This woman, Victoria Bonilla, ...was among more than one hundred villagers who perished in violence that broke out soon after the Mexican army chopped down a cornfield that had been planted on an unused cattle pasture by forty Nahuat villagers. In this anthropological account, based on years of fieldwork in Huitzilan, James M. Taggart turns to Victoria’s husband, Nacho Angel Hernández, to try to understand how a community based on respect and cooperation descended into horrific violence and fratricide. When the army chopped down the cornfield at Talcuaco, the war that broke out resulted in the complete breakdown of the social and moral order of the community. At its heart, this is a tragic love story, chronicling Nacho’s feelings for Victoria spanning their courtship, marriage, family life, and her death. Nacho delivered his testimonio to the author in Nahuat, making it one of the few autobiographical love stories told in an Amerindian language, and a very rare account of love among the indigenous people of Mesoamerica. There is almost nothing in the literature on how a man develops and changes his feelings for his wife over his lifetime. This study contributes to the anthropology of emotion by focusing on how the Nahuat attempt to express love through language and ritual.
Introduction
Violence between brothers and / or sisters is one of the most important forms of violence within families. To understand homicides between them, the hypothesis of rivalry has been put ...forward. But how is it really in reality?
Objectives
To construct both the clinical and medicolegal profile of perpetrators of fratricide and sororicide.
Methods
This is a retrospective study of 12 cases of fratricide, which were examined in the context of criminal psychiatric expertise in the psychiatry department of Hedi Chaker University Hospital in Sfax (Tunisia), between January 2002 and December 2018.
Results
The mean age of offenders was 31.9 years; they were all male. Eight fratricide perpetrators were unmarried and had an irregular occupation. They had a psychiatric follow-up prior to homicide in 5 cases. Previous criminal records were noted in one third of the cases. Three perpetrators of fratricide were using psychoactive substances. History of violence against the victim was presented in 7/12 of cases, and the victim was younger than the perpetrator in 5 cases. Aggression was premeditated in 4 cases. The knife was the most used weapon (11/12). Seven offenders suffered from a major mental illness. The most common diagnosis was schizophrenia (6/12). The experts had concluded that 8 cases were in a state of insanity at the time of the offense.
Conclusions
Our data indicates that fratricides are lack preparation and most often preceded by violence. It seems to be important to do other researches to assess psychopathology and assess risk factors for fratricide.
Chimeric antigen receptor T cells (CART) targeting lymphocyte antigens can induce T cell fratricide and require additional engineering to mitigate self-damage. We demonstrate that the expression of a ...chimeric antigen receptor (CAR) targeting CD5, a prominent pan-T cell antigen, induces rapid internalization and complete loss of the CD5 protein on T cells, protecting them from self-targeting. Notably, exposure of healthy and malignant T cells to CD5.CART cells induces similar internalization of CD5 on target cells, transiently shielding them from cytotoxicity. However, this protection is short-lived, as sustained activity of CD5.CART cells in patients with T cell malignancies results in full ablation of CD5+ T cells while sparing healthy T cells naturally lacking CD5. These results indicate that continuous downmodulation of the target antigen in CD5.CART cells produces effective fratricide resistance without undermining their on-target cytotoxicity.
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•CD5 is highly expressed in T cell malignancies and normal T cells•CD5.CAR causes full degradation of CD5 in T cells leading to fratricide resistance•CD5.CAR transiently downmodulates CD5 on target cells in trans•CD5 modulation in trans does not protect target cells from CD5.CART cells long-term
CD5 is a pan-T cell marker highly expressed in T cell cancers. Ma et al. show that expression of CD5.CAR in T cells drives full degradation of CD5 to achieve fratricide resistance. While CD5.CAR also transiently downmodulates CD5 in trans on target T cells, this process does not protect them from elimination long term.
Antibiotics are classically perceived as biological weapons that bacteria produce to hold their ground against competing species in their natural habitat. But in the context of multicellular ...differentiation processes, antimicrobial compounds sometimes also play a role in intraspecies competition, resulting in the death of a sub-population of genetically identical siblings for the benefit of the population. Such a strategy is based on the diversification and hence phenotypic heterogeneity of an isogenic bacterial population. This review article will address three such phenomena. In Bacillus subtilis, cannibalism is a differentiation strategy that enhances biofilm formation, prolongs or potentially even prevents full commitment to endospore formation under starvation conditions, and protects cells within the biofilm against competing species. The nutrients released by lysed cells can be used by the toxin producers, thereby delaying the full activation of the master regulator of sporulation. A related strategy is associated with the initiation of competence development under nutrient excess in Streptococcus pneumoniae. This process, termed fratricide, causes allolysis in a sub-population and is thought to enhance genetic diversity within the species. In Myxococcus xanthus, a large fraction of the population undergoes programmed cell death during the formation of fruiting bodies. This sacrifice ensures the survival of the sporulating sub-population by providing nutrients and hence energy to complete this differentiation process. The biological relevance and underlying regulatory mechanisms of these three processes will be discussed in order to extract common features of such strategies. Moreover, open questions and future challenges will be addressed.
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•Multicellular bacterial differentiation processes usually require diversification of an isogenic population into phenotypically different sub-populations.•Coordinated cell death is an extreme form of phenotypic heterogeneity, with one sub-population being eliminated for the benefit of the remaining population.•Cannibalism is a differentiation strategy of Bacillus subtilis that enhances biofilm formation and allows the producing sub-population to delay starvation-induced endospore formation by toxin-induced lysis of another sub-population.•Fratricide leads to allolysis of a sub-population of genetically competent Streptococcus pneumoniae, thereby increasing the genetic diversity of the population after transformation and providing a fitness advantage in biofilms and within the host.•A majority of Myxococcus xanthus cells undergo programmed cell death during fruiting body formation to provide the sporulating sub-population with nutrients to complete the sporulation process.
The human pathogens
and
have both evolved complex quorum sensing (QS) systems that regulate the production of bacteriocins and the entry into the competent state, a requirement for natural ...transformation. Natural transformation provides bacteria with a mechanism to repair damaged genes or as a source of new advantageous traits. In
, the competence pathway is controlled by the two-component signal transduction pathway ComCDE, which directly regulates SigX, the alternative sigma factor required for the initiation into competence. Over the past two decades, effectors of cellular killing (i.e., fratricides) have been recognized as important targets of the pneumococcal competence QS pathway. Recently, direct interactions between the ComCDE and the paralogous BlpRH pathway, regulating bacteriocin production, were identified, further strengthening the interconnections between these two QS systems. Interestingly, a similar theme is being revealed in
, the primary etiological agent of dental caries. This review compares the relationship between the bacteriocin and the competence QS pathways in both
and
, and hopes to provide clues to regulatory pathways across the genus
as a potential tool to efficiently investigate putative competence pathways in nontransformable streptococci.
Acute myeloid leukemia (AML) remains a significant health problem, with poor outcomes despite chemotherapy and bone marrow transplants. Although one form of AML, acute promyelocytic leukemia (APL), ...is successfully treated with all-trans retinoic acid (ATRA), this drug is seemingly ineffective against all other forms of AML. Here, we show that ATRA up-regulates CD38 expression on AML blasts to sufficient levels that promote antibody-mediated fratricide following the addition of anti-CD38 daratumumab (DARA). The combination of ATRA plus DARA induced Fc-dependent conjugate formation and cytotoxicity among AML blasts in vitro. Combination treatment also led to reduction in tumor volume and resulted in increased overall survival in murine engraftment models of AML. These results suggest that, although ATRA does not induce differentiation of non-APL, it may be effective as a therapy in conjunction with DARA.
Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive ...differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases. Supplementation with ibrutinib and dasatinib rescued the ex vivo expansion of unedited CD7 CAR T cells and allowed regaining full CAR-mediated cytotoxicity in vitro and in vivo on withdrawal of the inhibitors. The unedited CD7 CAR T cells persisted long term and mediated sustained anti-leukemic activity in two mouse xenograft models of human T cell acute lymphoblastic leukemia (T-ALL) by self-selecting for CD7−, fratricide-resistant CD7 CAR T cells that were transcriptionally similar to control CD7-edited CD7 CAR T cells. Finally, we showed feasibility of cGMP manufacturing of unedited autologous CD7 CAR T cells for patients with CD7+ malignancies and initiated a phase I clinical trial (ClinicalTrials.gov: NCT03690011) using this approach. These results indicate pharmacologic inhibition of CAR signaling enables generating functional CD7 CAR T cells without additional engineering.
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Mamonkin and colleagues demonstrate CAR-mediated fratricide in T cells can be effectively minimized ex vivo by reversible pharmacologic inhibition of CAR signaling kinases. Removal of the inhibitors restores T cell cytotoxicity and enables selection for a fratricide-resistant CAR T cell population with potent anti-tumor activity in vivo.
Résumé Cet ouvrage prend un texte littéraire de l'écrivain cap-verdien Germano Almeida comme les anthropologues prennent les faits de la culture. J'examine la complexe intrigue développée dans le ...roman Os Dois Irmãos, centrée sur un cas de fratricide survenu sur l'île de Santiago, pour comprendre comment la tradition est localement vécue. En analysant les actions tragiques des personnages principaux de ce roman, je cherche à révéler certaines des tensions puissantes qui imprègnent les pratiques des paysans cap-verdiens ainsi que les valeurs primordiales qu’ils éprouvent comme une sorte de destin œdipien.
Abstract This work takes a literary text from Cape Verdean writer Germano Almeida as anthropologists analyze cultural facts. I examine the complex plot developed in the novel Os Dois Irmãos, centered around a case of fratricide occurred on the island of Santiago, seeking to understand how the idea of tradition is locally experienced. Analyzing the tragic actions of the main characters of this novel, I seek to unveil some of the powerful tensions that permeate the practices of the Cape Verdean peasants as well as the primordial values that they experience as a kind of Oedipal fate.
Resumo Esse trabalho toma um romance do escritor caboverdiano Germano Almeida como os antropólogos analisam os fatos culturais. Examino a trama do romance Os Dois Irmãos, centrada num caso de fratricídio ocorrido na ilha de Santiago, buscando compreender como a ideia de tradição é localmente vivida. Ao analisar as ações trágicas dos principais personagens do romance, eu procuro desvelar algumas das poderosas tensões que permeiam as práticas dos camponeses caboverdianos e os valores primordiais que eles vivenciam como uma espécie de destino edipiano.
Acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid blasts and a suppressed immune state. Interferons have been previously shown to aid in the clearance of AML ...cells. Type I interferons are produced primarily by plasmacytoid dendritic cells (pDCs). However, these cells exist in a quiescent state in AML. Because pDCs express TLR 7-9, we hypothesized that the TLR7/8 agonist R848 would be able to reprogram them toward a more active, IFN-producing phenotype. Consistent with this notion, we found that R848-treated pDCs from patients produced significantly elevated levels of IFNβ. In addition, they showed increased expression of the immune-stimulatory receptor CD40. We next tested whether IFNβ would influence antibody-mediated fratricide among AML cells, as our recent work showed that AML cells could undergo cell-to cell killing in the presence of the CD38 antibody daratumumab. We found that IFNβ treatment led to a significant, IRF9-dependent increase in CD38 expression and a subsequent increase in daratumumab-mediated cytotoxicity and decreased colony formation. These findings suggest that the tolerogenic phenotype of pDCs in AML can be reversed, and also demonstrate a possible means of enhancing endogenous Type I IFN production that would promote daratumumab-mediated clearance of AML cells.
Successful translation of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors has proved to be troublesome, mainly due to the complex tumor microenvironment promoting T ...cell dysfunction and antigen heterogeneity. Mesothelin (MSLN) has emerged as an attractive target for CAR T cell therapy of several solid malignancies, including ovarian cancer. To improve clinical response rates with MSLN-CAR T cells, a better understanding of the mechanisms impacting CAR T cell functionality in vitro is crucial. Here, we demonstrated superior cytolytic capacity of CD28-costimulated MSLN-CAR T cells (M28z) relative to 4-1BB-costimulated MSLN-CAR T cells (MBBz). Furthermore, CD28-costimulated MSLN CAR T cells displayed enhanced cytolytic capacity against tumor spheroids with heterogeneous MSLN expression compared to MBBz CAR T cells. In this study, we identified CAR-mediated trogocytosis as a potential impeding factor for successful MSLN-CAR T cell therapy due to fratricide killing and contributing to tumor antigen heterogeneity. Moreover, we link antigen-dependent upregulation of LAG-3 with reduced CAR T cell functionality. Taken together, our study highlights the therapeutic potential and bottlenecks of MSLN-CAR T cells, providing a rationale for combinatorial treatment strategies.
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