Rational design of a SOCS1-edited tumor-infiltrating lymphocyte therapy using CRISPR/Cas9 screens.

Cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of responses nevertheless sought. To identify targets capable of enhancing the antitumor activity of T cell therapies, large-scale in vitro and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens were performed, with the SOCS1 gene identified as a top T cell-enhancing target. In murine CD8+ T cell-therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of central memory T cells in lymphoid organs as well as intermediate (Texint) and effector (Texeff) exhausted T cell subsets derived from progenitor exhausted T cells (Texprog) in tumors.

Detecting Anosognosia from the Prodromal Stage of Alzheimer's Disease.

Background: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer's disease (AD).

Objectives: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could add additional support for detecting anosognosia.

Methods: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants.

Inoperative Love and Social Well-Being in the Face of Oppression: A Psychoanalytic-Agambenian Developmental Perspective and Its Implications for Psychoanalytic Therapy.

The author depicts, relying on several of Giorgio Agamben's philosophical concepts as well as a psychoanalytic developmental perspective, the origins and features of inoperative love and spaces, especially as they pertain to oppressive situations wherein social, political, and economic apparatuses undermine the psychosocial well-being of individuals, families, and communities. In addition, the author conceptualizes psychoanalytic therapy as an inoperative space wherein patients actualize their capacity for impotentiality and experience singularity and rapport.

Novel and Engineered Type II CRISPR Systems from Uncultivated Microbes with Broad Genome Editing Capability.

Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nucleases have been extensively used in biotechnology and therapeutics. However, many applications are not possible owing to the size, targetability, and potential off-target effects associated with currently known systems. In this study, we identified thousands of CRISPR type II effectors by mining an extensive, genome-resolved metagenomics database encompassing hundreds of thousands of microbial genomes.

Designing a Dyad-Based Digital Health Intervention to Reduce Sedentary Time in Black Breast Cancer Survivors and Their First-degree Relatives: Human-Centered Design Study.

Background: Breast cancer, the most commonly diagnosed cancer and second leading cause of cancer-related death in women in the United States, disproportionately affects women from minoritized or low socioeconomic backgrounds. The average woman has an approximately 12% lifetime risk of developing breast cancer. Lifetime risk nearly doubles if a woman has a first-degree relative with breast cancer, and the risk increases as multiple family members are affected.

Novel CRISPR-Associated Gene-Editing Systems Discovered in Metagenomic Samples Enable Efficient and Specific Genome Engineering.

Development of medicines using gene editing has been hampered by enzymological and immunological impediments. We described previously the discovery and characterization of improved, novel gene-editing systems from metagenomic data. In this study, we substantially advance this work with three such gene-editing systems, demonstrating their utility for cell therapy development.

Compact Cas9d and HEARO enzymes for genome editing discovered from uncultivated microbes.

Programmable, RNA-guided nucleases are diverse enzymes that have been repurposed for biotechnological applications. However, to further expand the therapeutic application of these tools there is a need for targetable systems that are small enough to be delivered efficiently. Here, we mined an extensive genome-resolved metagenomics database and identified families of uncharacterized RNA-guided, compact nucleases (between 450 and 1,050 aa).

Psychoanalysis, Trauma, and Giorgio Agamben.

The author uses the work of Italian philosopher Giorgio Agamben to reimagine the meaning and dynamics of trauma, as well as psychoanalysis as a process that remedies, in part, traumatic experiences. More particularly, trauma is conceptualized in terms of Agamben's notions of potentiality, singularity/suchness, and inoperativity, although these are inflected from psychosocial developmental and political perspectives. This provides a way to bridge the idea of individual trauma with the larger political milieu's apparatuses that can be systemically traumatizing, as seen in the social death of racism.

The Future of an Illusion: The Problem of Sovereignty.

The author explores the idea of sovereignty as an illusion that is and will continue to have deleterious effects on cooperative efforts to slow or stop climate change and the extinction of millions of species. To make this case, the notion of sovereignty is defined and its attributes described. This lays the foundation for arguing, from a psychoanalytic perspective, that sovereignty is a tightly held illusion (and practice).

Psychoanalysis and the Ungovernable Self: Further Explorations.

The author explores the idea that psychoanalysis is a process that facilitates, for some patients, the emergence of an ungovernable self. To make this case, Agamben's notion of the ungovernable self and its relation to potentiality-actuality, excess, and inoperativity are explained in light of psychosocial development. It is argued that the seeds of the ungovernable self lie within the parent-infant space of speaking and acting together, wherein good-enough parents' personalizing attunements to infants' assertions facilitate children's sense of singularity that is not contingent on social-political apparatuses.

Cohesin residency determines chromatin loop patterns.

The organization of chromatin into higher order structures is essential for chromosome segregation, the repair of DNA-damage, and the regulation of gene expression. Using Micro-C XL to detect chromosomal interactions, we observed the pervasive presence of cohesin-dependent loops with defined positions throughout the genome of budding yeast, as seen in mammalian cells. In early S phase, cohesin stably binds to cohesin associated regions (CARs) genome-wide.

An Indecent Society, Sick Souls, and the Weak Messianic Force of God: A Reflection on Religious Health in the Anthropocene Era.

This article posits that the dire realities associated with the Anthropocene Era will increase the presence of indecent societies that humiliate Others while securing the well-being of privileged groups. Within the society, humiliation, which is carried out by various political, social, and economic apparatuses, leads to civic carelessness and perfidy that accompanies both the foreclosure of the space of appearances, wherein people speak and act together, and the diminution of Others' self-esteem, self-confidence, and self-respect. It is argued that indecent societies depend on sick souls who seek to retain social, political, and economic privileges that depend on the illusions of their superiority and the inferiority of humiliated Others.

On Being at Home in the World: A Psychoanalytic-Political Perspective on Dwelling in the Anthropocene Era.

In this article, the notion of dwelling is considered from a psychoanalytic developmental perspective, as well as in terms of the political dimension of life. The author contends that a psychoanalytic portrayal of dwelling should not lose sight of the political-economic realities implicated in experiences of being unhoused, especially when we consider the possibility that climate change, which human beings have caused, is likely to unhouse millions of species, including human beings. Given this, the author briefly indicates what this means for psychoanalytic therapy in the Anthropocene Era.

The spatial regulation of condensin activity in chromosome condensation.

Condensin mediates chromosome condensation, which is essential for proper chromosome segregation during mitosis. Prior to anaphase of budding yeast, the ribosomal DNA (RDN) condenses to a thin loop that is distinct from the rest of the chromosomes. We provide evidence that the establishment and maintenance of this RDN condensation requires the regulation of condensin by Cdc5p (polo) kinase.

Tolerogenic Nanoparticles Induce Antigen-Specific Regulatory T Cells and Provide Therapeutic Efficacy and Transferrable Tolerance against Experimental Autoimmune Encephalomyelitis.

T cells reacting to self-components can promote tissue damage when escaping tolerogenic control mechanisms which may result in autoimmune disease. The current treatments for these disorders are not antigen (Ag) specific and can compromise host immunity through chronic suppression. We have previously demonstrated that co-administration of encapsulated or free Ag with tolerogenic nanoparticles (tNPs) comprised of biodegradable polymers that encapsulate rapamycin are capable of inhibiting Ag-specific transgenic T cell proliferation and inducing Ag-specific regulatory T cells (Tregs).

Giving Counsel: Donald Capps' Contributions to Pastoral Counseling.

This article explores some of Donald Capps' contributions to the ministry of pastoral counseling. In particular, several key attributes of pastoral counseling as a ministry of the church are identified and discussed. This is followed by identifying six features necessary for good enough pastoral counseling.

Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability.

Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent.

Improving the efficacy and safety of biologic drugs with tolerogenic nanoparticles.

The development of antidrug antibodies (ADAs) is a common cause for the failure of biotherapeutic treatments and adverse hypersensitivity reactions. Here we demonstrate that poly(lactic-co-glycolic acid) (PLGA) nanoparticles carrying rapamycin, but not free rapamycin, are capable of inducing durable immunological tolerance to co-administered proteins that is characterized by the induction of tolerogenic dendritic cells, an increase in regulatory T cells, a reduction in B cell activation and germinal centre formation, and the inhibition of antigen-specific hypersensitivity reactions. Intravenous co-administration of tolerogenic nanoparticles with pegylated uricase inhibited the formation of ADAs in mice and non-human primates and normalized serum uric acid levels in uricase-deficient mice.

The Willie Lomans of a Market Society: Addressing Political-Economic Sources of Suffering in Pastoral Counseling.

This article focuses on the culture of state-corporate capitalism as a source of psychological suffering for some people who seek the aid of pastoral counselors. An underlying premise of this article and, more particularly, the work of pastoral counseling comes from Frantz Fanon's view that the aims of psychotherapy are (a) 'to 'consciousnessize' [the patient's] unconscious, to no longer be tempted by a hallucinatory lactification', and (b) 'to enable [the patient] to choose an action with respect to the real source of the conflict, i.e.

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance.

Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists.

An Arabidopsis gene regulatory network for secondary cell wall synthesis.

The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function.

Winnicott and helplessness: developmental theory, religion, and personal life.

The author examines Winnicott's theory of development from the perspective of existential helplessness, arguing that (a) his views illuminate healthy (and unhealthy) aspects of religion, and (b) express his stance toward the helplessness of dying and death. The author contends that Winnicott understood the infant's psychic growth in relation to the reality of existential helplessness and absolute dependency. Four interrelated, dynamic paradoxes embedded in Winnicott's developmental perspective are discussed, and these paradoxes are seen as frameworks to depict his notions of ego, transitional objects, and true/false selves.

Pastoral counseling in the 21st century: the centrality of community.

In this article, I argue that the notion of ecclesia or faith community is a central, existential anthropological premise that can shape how we understand facets of pastoral counseling such as diagnosis, process, and aims. Implicit here is the idea that the distinctiveness of pastoral counseling lies not simply in accountability and authority vis-à-vis community, but in its use of a communitarian anthropology to understand the importance of community for psychosocial development, resiliency, and healing. I argue further that in the 21st century the centrality of the notion of community is, and will continue to be, critical, because of political and economic forces that undermine community, giving rise to psychosocial alienation, depression, etc.

Winnicott and Arendt: bridging potential and political spaces.

In this article, the author seeks to bridge analytic theory, which is used as an interpretive framework to understand patients' psychic lives, and political philosophy, which accounts for individuals living a life in common as citizens. Specifically, I address how we can understand the relation between the psychosocial space of a parent(s) and child interaction, which becomes part of the child's psychic life, and the political space between and within citizens. The underlying claim is that there is a correlation between political space and the space between parent and child.

Generation of a universal CD4 memory T cell recall peptide effective in humans, mice and non-human primates.

CD4T cells play a key role in humoral immunity by providing help to B cells, enabling effective antibody class switching and affinity maturation. Some vaccines may generate a poor response due to a lack of effective MHC class II epitopes, resulting in ineffective helper T cell activation and recall and consequently poor humoral immunity. It may be beneficial to provide a CD4T cell helper peptide with a vaccine particularly in the case of a poorly immunogenic antigen.