Genomes of Novel Myxococcota Reveal Severely Curtailed Machineries for Predation and Cellular Differentiation.

Cultured Myxococcota are predominantly aerobic soil inhabitants, characterized by their highly coordinated predation and cellular differentiation capacities. Little is currently known regarding yet-uncultured Myxococcota from anaerobic, nonsoil habitats. We analyzed genomes representing one novel order (o__JAFGXQ01) and one novel family (f__JAFGIB01) in the Myxococcota from an anoxic freshwater spring (Zodletone Spring) in Oklahoma, USA. Compared to their soil counterparts, anaerobic Myxococcota possess smaller genomes and a smaller number of genes encoding biosynthetic gene clusters (BGCs), peptidases, one- and two-component signal transduction systems, and transcriptional regulators. Detailed analysis of 13 distinct pathways/processes crucial to predation and cellular differentiation revealed severely curtailed machineries, with the notable absence of homologs for key transcription factors (e.g., FruA and MrpC), outer membrane exchange receptor (TraA), and the majority of sporulation-specific and A-motility-specific genes. Further, machine learning approaches based on a set of 634 genes informative of social lifestyle predicted a nonsocial behavior for Zodletone Myxococcota. Metabolically, Zodletone Myxococcota genomes lacked aerobic respiratory capacities but carried genes suggestive of fermentation, dissimilatory nitrite reduction, and dissimilatory sulfate-reduction (in f_JAFGIB01) for energy acquisition. We propose that predation and cellular differentiation represent a niche adaptation strategy that evolved circa 500 million years ago (Mya) in response to the rise of soil as a distinct habitat on Earth. IMPORTANCE The phylum Myxococcota is a phylogenetically coherent bacterial lineage that exhibits unique social traits. Cultured Myxococcota are predominantly aerobic soil-dwelling microorganisms that are capable of predation and fruiting body formation. However, multiple yet-uncultured lineages within the Myxococcota have been encountered in a wide range of nonsoil, predominantly anaerobic habitats, and the metabolic capabilities, physiological preferences, and capacity of social behavior of such lineages remain unclear. Here, we analyzed genomes recovered from a metagenomic analysis of an anoxic freshwater spring in Oklahoma, USA, that represent novel, yet-uncultured, orders and families in the Myxococcota. The genomes appear to lack the characteristic hallmarks for social behavior encountered in Myxococcota genomes and displayed a significantly smaller genome size and a smaller number of genes encoding biosynthetic gene clusters, peptidases, signal transduction systems, and transcriptional regulators. Such perceived lack of social capacity was confirmed through detailed comparative genomic analysis of 13 pathways associated with Myxococcota social behavior, as well as the implementation of machine learning approaches to predict social behavior based on genome composition. Metabolically, these novel Myxococcota are predicted to be strict anaerobes, utilizing fermentation, nitrate reduction, and dissimilarity sulfate reduction for energy acquisition. Our results highlight the broad patterns of metabolic diversity within the yet-uncultured Myxococcota and suggest that the evolution of predation and fruiting body formation in the Myxococcota has occurred in response to soil formation as a distinct habitat on Earth.

Tracing the pathway of spindle assembly checkpoint signaling.

Most current models of spindle assembly checkpoint signaling involve inhibition of the Cdc20-APC by Mad2 protein. Interestingly, a paper from Hongtao Yu and colleagues in this issue of Developmental Cell suggests that the Cdc20/APC can also be inhibited in a Mad2-independent manner by a complex of proteins that includes BubR1.

Exercise testing in special situations: ER, preoperative and disability evaluation.

In a number of medical centers, exercise testing has proven to be a safe and useful tool in the evaluation of patients presenting chest pain in an emergency room. At these centers, after a period of observation without evidence of acute myocardial infarction, exercise testing is done. If the exercise test result is normal, the patient is discharged from the emergency room, without being admitted to the hospital. Exercise testing is a well-accepted noninvasive method to evaluate at-risk patients being considered for elective noncardiac surgery. Exercise testing is frequently used to determine functional capacity during disability assessment.

The secret of successful defense.

The demise of stimulus-response behaviorism has brought radical changes in the way psychologists conceptualize classical Pavlovian conditioning, as described by Rescorla (1988). The new emphasis on learned expectations sheds light on Freud's 1926 theory of intrapsychic conflict which explains neurotic anxiety by the same principles that account for realistic anxiety. Learned expectations also figure prominently in the recent writings of a number of psychoanalytic theorists. This paper uses these principles to explain "successful defense," which is customarily defined as the activation of defense in the absence of conscious anxiety. These same principles elucidate an important difference between the therapeutic mechanisms of supportive versus expressive psychotherapy. This distinction parallels the difference between conditioned inhibition versus extinction in Pavlovian conditioning.

False-negative endoscopic biopsy of colonic adenocarcinoma in a young man.

A 26-year-old man presented with intermittent bright red blood per rectum. His physical examination was unremarkable; however, because microcytic anemia was noted, the patient underwent colonoscopy. A large ascending colonic lesion was noted, a biopsy of which was negative for cancer. Nevertheless, the patient underwent a radical hemicolectomy. Adenocarcinoma of the cecum was found. This case report is an example of a false-negative endoscopic-directed biopsy. A review of recorded video-endoscopy assisted the family physician in appropriate management.

Defence mechanisms versus defence contents.

My formulation of the distinction drawn by Wallerstein between defence mechanisms and defence contents (or other defensive behaviours) emphasizes two differences: (a) Defence mechanisms have an innate basis and originate with the differentiation of the rest of the ego, whereas defence contents are compromise formations produced by a complex process in which the defence mechanisms play an important part. (b) Defence mechanisms and their activity are unable to become conscious under any conditions, whereas defence contents, if not repressed, are capable of becoming conscious. I clarify this distinction by using the concept of a causal chain in which the defence content is the proximal cause of the defence effect, defined by Brenner as the minimization of unpleasurable affect, and the operation of the defence mechanism is a more distal cause through its role in causing the defence content. I compare my views with those of Brenner, Schafer, and Wallerstein regarding this distinction.

The relationship of repression to the unconscious.

I try to formulate the simplest topographic model that embodies current theoretical understanding. The repression mechanism is under the control of a single censorship located on the border of consciousness. I argue that neither the operation of the repression mechanism nor the decision process of the censorship, which controls the repression mechanism and other defence mechanisms, can be considered dynamically unconscious. I discuss the distinction drawn by Wallerstein, Sandler & Joffe between the experiential and the non-experiential, concluding that much of the non-conscious id, ego, and superego is non-experiential rather than dynamically unconscious. Within the experiential realm I present the reasons why the censorship is located on the edge of consciousness and the implications of this location for the distinction between the preconscious and the dynamic unconscious.

Learning theory and intrapsychic conflict.

This paper is one in a series (Gillett, 1990, 1994) attempting to explore the implications of modern ideas about learning for psychoanalytic theories of treatment and pathogenesis. The key concept is that of learned expectations, which establishes links with Freud's 1926 theory of neurotic anxiety as caused by the expectation of danger. The new understanding of classical Pavlovian conditioning entails changes in the basic theory of intrapsychic conflict described in previous papers (1990, 1994). The relationship of learning theory to Freud's 1926 theory of intrapsychic conflict has received insufficient attention in the psychoanalytic literature because of insufficient familiarity with the repudiation of behaviourism by psychologists in favour of a representational theory of the mind.

Psychoanalytic theories of infant differentiation of self and other.

Traditional psychoanalytic theories of infancy were challenged a number of years ago by Peterfreund (1978) and Milton Klein (1980), but published debate on this issue has only recently begun to appear. The main purpose of this paper is to respond to Zuriff's (1992) argument that new data from recent observational research on infants fails to refute earlier theories of infancy. The following quote from Zuriff is a good introduction to the topic: "For many years, a frequent and consistent criticism of psychoanalytic theory is that it is not testable (Nagel, 1959; Popper, 1962). That is, no matter what the evidence, psychoanalytic theories can always be maintained because they are too vague, incomplete, and indeterminate to be falsified. Yet, in the area of contemporary psychoanalytic theory of infancy, we seem to have a counterexample to this criticism. Supporters of the new theories claim that the experimental evidence refutes older psychoanalytic notions of infancy, such as normal autism and symbiosis, and establishes a different model, that of the 'competent infant.'" (p. 19).

Novel NKX2.1 mutation associated with hypothyroidism and lethal respiratory failure in a full-term neonate.

We report a case of lethal neonatal hypoxic respiratory failure and hypothyroidism in an infant with a novel missense mutation in NKX2.1.

Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura: outcome with plasma exchange.

A retrospective analysis was made of 14 consecutive adults with hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) who were treated with plasma exchange (PE). In six patients the disease was primary, whilst in eight HUS/TTP was considered secondary to an associated condition. Thirteen patients had renal involvement, six had central nervous system symptoms or signs, three had fever, and one had myocardial damage. Twelve patients (86%) recovered. Four of these relapsed, but responded to further treatment. Two patients failed to respond and died. Hematological response occurred rapidly in survivors: thrombocytopenia resolved after a median of four exchanges, and hemolysis after a median of six. Four patients had a complete recovery, seven had residual mild end organ damage, and one had severe renal impairment. PE was an effective treatment for both primary and secondary HUS/TTP. The platelet count proved to be the earliest indicator of clinical outcome. Continuing follow-up of survivors is required because of the risk of relapse and the high incidence of end organ damage.

Single institution outcomes of treatment of severe aplastic anaemia.

BACKGROUND: In severe aplastic anaemia, the treatment of choice for young patients with a human leucocyte antigen-matched sibling is now established as allogeneic bone marrow transplantation (BMT). In older patients and in those without a matched sibling donor, immunosuppressive therapy is the usual first option. 'Alternative' marrow donors are emerging as an option for those without a matched sibling donor. AIMS: To review 10 years of local experience in treating severe aplastic anaemia with BMT and immunosuppressive therapy with emphasis on long-term outcomes. METHODS: A retrospective analysis was performed of all patients with severe aplastic anaemia presenting to the Royal Brisbane and Royal Children's Hospitals between 1989 and 1999. Data were abstracted regarding patient demographics, pretreatment characteristics and outcome measures, including response rates, overall survival and long-term complications. RESULTS: Twenty-seven consecutive patients were identified, 12 treated with immunosuppression alone and 15 with BMT. In these two groups, transfusion independence was attained in 25% and 100%, respectively, with overall survival being 36% and 100%, respectively. Those treated with immunosuppression were significantly older (median 41.5 versus 22 years, P = 0.008). Long-term survivors of either treatment had extremely low morbidity. Three patients carried pregnancies to term post-transplant. Three patients received alternative donor BMT with correspondingly excellent survival. CONCLUSIONS: Patients treated with allogeneic BMT for severe aplastic anaemia enjoyed extremely good long-term survival and minimal morbidity. Patients treated with immunosuppressive therapy had a poorer outcome reflecting their older age and different usage of therapies over the past decade. Optimal treatment strategies for severe aplastic anaemia remain to be determined.

Abnormal neutrophil phenotype and neutrophil FcRIII deficiency corrected by bone marrow transplantation.

BACKGROUND: Neutrophils from a patient in first remission of acute myeloid leukemia were found to lack NA1 and NA2 alloantigens. This NA null phenotype was converted to the normal phenotype of NA1, NB2 by the transplantation of bone marrow from an HLA-identical sibling. To investigate the inherited or acquired nature of this rare phenotype, a combination of conventional neutrophil serology and recently developed restriction fragment length polymorphism (RFLP) and polymerase chain reaction (PCR) assays was used. STUDY DESIGN AND METHODS: Diagnosis, remission, and posttransplant patient peripheral blood samples were used for neutrophil phenotyping by granulocyte agglutination and immunofluorescence tests. The presence and dose of the gene for neutrophil Fc gamma RIIIb (Fc gamma RIIIB) were tested for with RFLP and Southern analysis and PCR-based RFLP tests. Plasma levels of circulating soluble Fc gamma RIII (sFc gamma RIII) were measured with radioimmunoassay. The sibling bone marrow donor and the patient's parents were also studied. RESULTS: RFLP analysis of DNA obtained from the patient at the time of diagnosis showed that she lacked the Fc gamma RIIIB gene for neutrophil Fc gamma RIII (i.e., Fc gamma RIIIb), but that, in DNA prepared from posttransplant samples, the Fc gamma RIIIB gene was present. Quantitation of plasma levels of soluble FcRIII (sFcRIII) demonstrated a complete absence of sFcRIII in the patient's pretransplant plasma. However, 20 units of sFcRIII were detected in the patient's plasma by 160 days after graft. Hair samples from the patient provided sufficient nonhematopoietic, genomic DNA to confirm that her genotype was NA0NA0. DNA prepared from lymphocytes of both parents and the sibling marrow donor was used to quantitate their Fc gamma RIIIB gene dose. The mother and brother had only one Fc gamma RIIIB gene each, while the father apparently had a normal complement of two Fc gamma RIIIB genes. CONCLUSION: In this case, an inherited absence of Fc gamma RIIIB gene in a patient with acute myeloid leukemia was unintentionally corrected by the transplantation of bone marrow from a sibling donor who himself carried only one Fc gamma RIIIB gene.

p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.

We describe the cloning of p63, a gene at chromosome 3q27-29 that bears strong homology to the tumor suppressor p53 and to the related gene, p73. p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. Unlike p53, the p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis. Importantly, the predominant p63 isotypes in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53. We demonstrate that these truncated p63 variants can act as dominant-negative agents toward transactivation by p53 and p63, and we suggest the possibility of physiological interactions among members of the p53 family.

Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia.

Patterns of failure were studied in two consecutive randomized trials of intensified induction therapy carried out by the Australian Leukaemia Study Group (ALSG) between 1984 and 1991 to determine the impact of dose intensification. Patients received standard dose cytarabine and daunorubicin (7-3), 7-3 plus etoposide (7-3-7) or 7-3 plus high-dose cytarabine (HIDAC-3-7) chemotherapy. Patients with FAB M3 morphology were excluded. Time to failure (TTF) was defined as the time from randomization to induction death or removal from study for non-responders, or to relapse or death in complete response (CR) for complete responders. An estimated 86% of 470 de novo patients with acute myeloid leukaemia failed within 10 years of randomization, as a result of death in induction in 17% of the randomized patients, failure to achieve CR in a further 17%, relapse in 44% and death in CR in 8% of patients. An estimated 66% of patients failed as a result of refractory disease or relapse within that period (disease-related failures). Multifactor analysis identified age and peripheral blast count as the most significant pretreatment factors associated with overall TTF. These factors, together with cytogenetics, were significantly associated with disease-related failures. High-dose cytarabine in induction significantly decreased the disease-related failure rate as did allogeneic transplantation in first CR. The impact of high-dose cytarabine did not depend on the cytogenetic risk group.