Asynchronous abundance fluctuations can drive giant genotype frequency fluctuations.

Large stochastic population abundance fluctuations are ubiquitous across the tree of life1-7, impacting the predictability of population dynamics and influencing eco-evolutionary outcomes. It has generally been thought that these large abundance fluctuations do not strongly impact evolution (in contrast to genetic drift), as the relative frequencies of alleles in the population will be unaffected if the abundance of all alleles fluctuate in unison. However, we argue that large abundance fluctuations can lead to significant genotype frequency fluctuations if different genotypes within a population experience these fluctuations asynchronously. By serially diluting mixtures of two closely related E. coli strains, we show that such asynchrony can occur, leading to giant frequency fluctuations that far exceed expectations from models of genetic drift. We develop a flexible, effective model that explains the abundance fluctuations as arising from correlated offspring numbers between individuals, and the large frequency fluctuations result from even slight decoupling in offspring numbers between genotypes. This model accurately describes the observed abundance and frequency fluctuation scaling behaviors. Our findings suggest chaotic dynamics underpin these giant fluctuations, causing initially similar trajectories to diverge exponentially; subtle environmental changes can be magnified, leading to batch correlations in identical growth conditions. Furthermore, we present evidence that such decoupling noise is also present in mixed-genotype S. cerevisiae populations. We demonstrate that such decoupling noise can strongly influence evolutionary outcomes, in a manner distinct from genetic drift. Given the generic nature of asynchronous fluctuations, we anticipate they are widespread in biological populations, significantly affecting evolutionary and ecological dynamics.

Lineage frequency time series reveal elevated levels of genetic drift in SARS-CoV-2 transmission in England.

Genetic drift in infectious disease transmission results from randomness of transmission and host recovery or death. The strength of genetic drift for SARS-CoV-2 transmission is expected to be high due to high levels of superspreading, and this is expected to substantially impact disease epidemiology and evolution. However, we don't yet have an understanding of how genetic drift changes over time or across locations. Furthermore, noise that results from data collection can potentially confound estimates of genetic drift. To address this challenge, we develop and validate a method to jointly infer genetic drift and measurement noise from time-series lineage frequency data. Our method is highly scalable to increasingly large genomic datasets, which overcomes a limitation in commonly used phylogenetic methods. We apply this method to over 490,000 SARS-CoV-2 genomic sequences from England collected between March 2020 and December 2021 by the COVID-19 Genomics UK (COG-UK) consortium and separately infer the strength of genetic drift for pre-B.1.177, B.1.177, Alpha, and Delta. We find that even after correcting for measurement noise, the strength of genetic drift is consistently, throughout time, higher than that expected from the observed number of COVID-19 positive individuals in England by 1 to 3 orders of magnitude, which cannot be explained by literature values of superspreading. Our estimates of genetic drift suggest low and time-varying establishment probabilities for new mutations, inform the parametrization of SARS-CoV-2 evolutionary models, and motivate future studies of the potential mechanisms for increased stochasticity in this system.

Rediversification following ecotype isolation reveals hidden adaptive potential.

Microbial communities play a critical role in ecological processes, and their diversity is key to their functioning. However, little is known about whether communities can regenerate ecological diversity following ecotype removal or extinction and how the rediversified communities would compare to the original ones. Here, we show that simple two-ecotype communities from the E. coli long-term evolution experiment (LTEE) consistently rediversified into two ecotypes following the isolation of one of the ecotypes, coexisting via negative frequency-dependent selection. Communities separated by more than 30,000 generations of evolutionary time rediversify in similar ways. The rediversified ecotype appears to share a number of growth traits with the ecotype it replaces. However, the rediversified community is also different from the original community in ways relevant to the mechanism of ecotype coexistence-for example, in stationary phase response and survival. We found substantial variation in the transcriptional states between the two original ecotypes, whereas the differences within the rediversified community were comparatively smaller, although the rediversified community showed unique patterns of differential expression. Our results suggest that evolution may leave room for alternative diversification processes even in a maximally reduced community of only two strains. We hypothesize that the presence of alternative evolutionary pathways may be even more pronounced in communities of many species where there are even more potential niches, highlighting an important role for perturbations, such as species removal, in evolving ecological communities.

Massive blood loss from urethrorrhage in a 16-year-old boy: Case report and review of two rare causes.

Urethral varices and hemangiomas are rare, underreported conditions that can be asymptomatic or present with intermittent urethrorrhage that can start or worsen with erection, sexual intercourse and ejaculation. Diagnosis can be made with urethroscopy and there are a wide variety of possible treatments that can suit both conditions. We present a case of a pediatric patient with severe blood loss from urethral varices that was treated with electrofulguration after laser treatment with Holmium failed.

Rediversification Following Ecotype Isolation Reveals Hidden Adaptive Potential.

Microbial communities play a critical role in ecological processes, and their diversity is key to their functioning. However, little is known about if communities can regenerate ecological diversity following species removal or extinction, and how the rediversified communities would compare to the original ones. Here we show that simple two-ecotype communities from the E. coli Long Term Evolution Experiment (LTEE) consistently rediversified into two ecotypes following the isolation of one of the ecotypes, coexisting via negative frequency-dependent selection. Communities separated by more than 30,000 generations of evolutionary time rediversify in similar ways. The rediversified ecotype appears to share a number of growth traits with the ecotype it replaces. However, the rediversified community is also different compared to the original community in ways relevant to the mechanism of ecotype coexistence, for example in stationary phase response and survival. We found substantial variation in the transcriptional states between the two original ecotypes, whereas the differences within the rediversified community were comparatively smaller, but with unique patterns of differential expression. Our results suggest that evolution may leave room for alternative diversification processes even in a maximally reduced community of only two strains. We hypothesize that the presence of alternative evolutionary pathways may be even more pronounced in communities of many species, highlighting an important role for perturbations, such as species removal, in evolving ecological communities.

Quantifying the local adaptive landscape of a nascent bacterial community.

The fitness effects of all possible mutations available to an organism largely shape the dynamics of evolutionary adaptation. Yet, whether and how this adaptive landscape changes over evolutionary times, especially upon ecological diversification and changes in community composition, remains poorly understood. We sought to fill this gap by analyzing a stable community of two closely related ecotypes ("L" and "S") shortly after they emerged within the E. coli Long-Term Evolution Experiment (LTEE). We engineered genome-wide barcoded transposon libraries to measure the invasion fitness effects of all possible gene knockouts in the coexisting strains as well as their ancestor, for many different, ecologically relevant conditions. We find consistent statistical patterns of fitness effect variation across both genetic background and community composition, despite the idiosyncratic behavior of individual knockouts. Additionally, fitness effects are correlated with evolutionary outcomes for a number of conditions, possibly revealing shifting patterns of adaptation. Together, our results reveal how ecological and epistatic effects combine to shape the adaptive landscape in a nascent ecological community.

How to Diagnose and Treat CD5-Positive Lymphomas Involving the Spleen.

Patients with CD5-expressing lymphomas presenting with splenomegaly are frequently diagnosed with chronic lymphocytic leukemia. The most important differential diagnosis is mantle cell lymphoma, both in its classical and leukemic, non-nodal forms, given its prognostic and therapeutic implications. Other small B-cell neoplasms that frequently involve the spleen and occasionally express CD5 include the splenic marginal zone lymphoma, hairy cell leukemia and, rarely, lymphoplasmacytic lymphoma. The frequency of CD5 positivity depends in part on the sensitivity of the detection methods employed. Usually, a combination of morphological, immunophenotypic and molecular findings allows for a precise sub-classification of CD5-positive, low-grade B-cell lymphomas of the spleen. Some of these tumors may display a mixture of small and larger B cells, raising the possibility of more aggressive lymphomas, such as diffuse large B-cell lymphomas (DLBCL). Approximately 5-10% of DLBCL are CD5-positive and some may manifest as primary splenic lesions. When available, the morphology of DLBCL in the splenic tissue is distinctive and a leukemic picture is very rare. In conclusion, the appropriate morphological and clinical context assisted by flow cytometry panels and/or immunohistochemistry allows the differential diagnosis of CD5-positive, non-Hodgkin, B-cell lymphomas involving the spleen.

Low-Grade Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma.

Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only involvement of spleen and hilar lymph nodes. In contrast, secondary low-grade B-cell lymphomas in the spleen, such as follicular lymphomas (FL), lymphoplasmacytic lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma, particularly as part of advanced stage disease, are more common. Indolent B cell lymphomas expressing CD10 almost always represent FL, which in its primary splenic form is the focus of this review. Primary splenic follicular lymphoma (PSFL) is exceedingly infrequent. This type of lymphoproliferative disorder is understudied and, in most cases, clinically characterized by splenomegaly or cytopenias related to hypersplenism. The diagnosis requires correlation of histopathology of spleen, blood and/or bone marrow with the correct immunophenotype (determined by flow cytometry and/or immunohistochemistry) and if necessary, additional molecular profiling. Management of this incurable disease is evolving, and splenectomy remains the mainstream treatment for stage I PSFL.

Hairy Cell Leukemia and Ground Water Contamination With Industrial Solvents: a Case Report.

The industrial solvents benzene and trichloroethylene (TCE) are known carcinogens, and these solvents contaminated the drinking water at Marine Corps Base Camp Lejeune from the 1950s to 1980s. Benzene and TCE are linked to the hematopoietic cancers acute myelocytic and lymphocytic leukemia and chronic lymphocytic leukemia. We report the case of a veteran stationed at Marine Corps Base Camp Lejeune during this period who developed hairy cell leukemia (HCL), a rare form of lymphocytic leukemia. We review his presentation, medical history, solvent exposure, and literature on the carcinogenicity of benzene and TCE. This patient represents a possible link of TCE or benzene to HCL. The case also informs clinicians of the updated epidemiology with regards to clinical findings for HCL.

Prostate Leiomyosarcoma: A Rare Misleading Tumor.

CASE REPORT: 73 year-old patient present with lower urinary tract symptoms (LUTS) and a low serum prostate specific antigen (PSA) diagnosed with a prostate leiomyosarcoma following a TURP. Afterwards, he was submitted to radical prostatectomy. A multimodal approach with radiotherapy was considered although death occurred less than three months after surgery. DISCUSSION: Prostate leiomyosarcoma is a rare aggressive tumour with misleading clinical features which may delay the diagnosis. The rarity of prostate sarcomas makes it very difficult to have prospective studies and appropriate clinical research. Therefore, it is of the utmost importance to report its occurrence in order to improve our knowledge of its natural history. There are no guidelines concerning an optimal treatment. When feasible, surgery is the mainstay of treatment. Notwithstanding, recently published data favour multimodal therapies for the treatment of prostatic sarcomas, particularly for locally advanced disease.

Non-monotonic Response to Monotonic Stimulus: Regulation of Glyoxylate Shunt Gene-Expression Dynamics in Mycobacterium tuberculosis.

Understanding how dynamical responses of biological networks are constrained by underlying network topology is one of the fundamental goals of systems biology. Here we employ monotone systems theory to formulate a theorem stating necessary conditions for non-monotonic time-response of a biochemical network to a monotonic stimulus. We apply this theorem to analyze the non-monotonic dynamics of the σB-regulated glyoxylate shunt gene expression in Mycobacterium tuberculosis cells exposed to hypoxia. We first demonstrate that the known network structure is inconsistent with observed dynamics. To resolve this inconsistency we employ the formulated theorem, modeling simulations and optimization along with follow-up dynamic experimental measurements. We show a requirement for post-translational modulation of σB activity in order to reconcile the network dynamics with its topology. The results of this analysis make testable experimental predictions and demonstrate wider applicability of the developed methodology to a wide class of biological systems.

Methodology for the inference of gene function from phenotype data.

BACKGROUND: Biomedical ontologies are increasingly instrumental in the advancement of biological research primarily through their use to efficiently consolidate large amounts of data into structured, accessible sets. However, ontology development and usage can be hampered by the segregation of knowledge by domain that occurs due to independent development and use of the ontologies. The ability to infer data associated with one ontology to data associated with another ontology would prove useful in expanding information content and scope. We here focus on relating two ontologies: the Gene Ontology (GO), which encodes canonical gene function, and the Mammalian Phenotype Ontology (MP), which describes non-canonical phenotypes, using statistical methods to suggest GO functional annotations from existing MP phenotype annotations. This work is in contrast to previous studies that have focused on inferring gene function from phenotype primarily through lexical or semantic similarity measures. RESULTS: We have designed and tested a set of algorithms that represents a novel methodology to define rules for predicting gene function by examining the emergent structure and relationships between the gene functions and phenotypes rather than inspecting the terms semantically. The algorithms inspect relationships among multiple phenotype terms to deduce if there are cases where they all arise from a single gene function. We apply this methodology to data about genes in the laboratory mouse that are formally represented in the Mouse Genome Informatics (MGI) resource. From the data, 7444 rule instances were generated from five generalized rules, resulting in 4818 unique GO functional predictions for 1796 genes. CONCLUSIONS: We show that our method is capable of inferring high-quality functional annotations from curated phenotype data. As well as creating inferred annotations, our method has the potential to allow for the elucidation of unforeseen, biologically significant associations between gene function and phenotypes that would be overlooked by a semantics-based approach. Future work will include the implementation of the described algorithms for a variety of other model organism databases, taking full advantage of the abundance of available high quality curated data.

Multiple bony amyloidomas as an initial presentation of myeloma.

Amyloidosis complicating multiple myeloma is an uncommon but well-recognized phenomenon. Multiple bone amyloidomas are rare as the initial presenting feature of myeloma. Solitary bone amyloidomas share common features with those of patients who have solitary plasmacytomas and progression to disseminated myeloma is common. We report a case of an elderly man who presented with extensive amyloid deposition in multiple plasmacytoma sites as well as evidence of amyloid in a fat pad aspirate but with none of the usual organ damage associated with systemic amyloidosis. This presentation is similar to a subset of patients said to have macrofocal myeloma. These patients are typically aged < 40 years, have no bone marrow involvement, and have a good prognosis. This report may represent the first description of macrofocal myeloma associated with amyloid deposition in an older individual.

Gene and microRNA analysis of neutrophils from patients with polycythemia vera and essential thrombocytosis: down-regulation of micro RNA-1 and -133a.

BACKGROUND: Since the V617F mutation in JAK2 may not be the initiating event in myeloprofilerative disorders (MPDs) we compared molecular changes in neutrophils from patients with polycythemia vera (PV) and essential thrombocythosis (ET), to neutrophils stimulated by G-CSF administration and to normal unstimulated neutrophils METHODS: A gene expression oligonucleotide microarray with more than 35,000 probes and a microRNA (miR) expression array with 827 probes were used to assess neutrophils from 6 MPD patients; 4 with PV and 2 with ET, 5 healthy subjects and 6 healthy subjects given G-CSF. In addition, neutrophil antigen expression was analyzed by flow cytometry and 64 serum protein levels were analyzed by ELISA. RESULTS: Gene expression profiles of neutrophils from the MPD patients were similar but distinct from those of healthy subjects, either unstimulated or G-CSF-mobilized. The differentially expressed genes in MPD neutrophils were more likely to be in pathways involved with inflammation while those of G-CSF-mobilized neutrophils were more likely to belong to metabolic pathways. In MPD neutrophils the expression of CCR1 was increased and that of several NF-kappaB pathway genes were decreased. MicroRNA miR-133a and miR-1 in MPD neutrophils were down-regulated the most. Levels of 11 serum proteins were increased in MPD patients including MMP-10, MMP-13, VCAM, P-selectin, PDGF-BB and a CCR1 ligand, MIP-1alpha. CONCLUSION: These studies showed differential expression of genes particularly involved in inflammatory pathways including the NF-kappaB pathway and down-regulation of miR-133a and miR-1. These two microRNAs have been previous associated with certain cancers as well as the regulation of hyperthrophy of cardiac and skeletal muscle cells. These changes may contribute to the clinical manifestations of the MPDs.

Differences amid bone marrow and cord blood hematopoietic stem/progenitor cell division kinetics.

Human hematopoietic stem/progenitor cells (HSC) isolated based upon specific patterns of CD34 and CD38 expression, despite phenotypically identical, were found to be functionally heterogeneous, raising the possibility that reversible expression of these antigens may occur during cellular activation and/or proliferation. In these studies, we combined PKH67 tracking with CD34/CD38 immunostaining to compare cell division kinetics between human bone marrow (BM) and cord blood (CB)-derived HSC expanded in a serum-free/stromal-based system for 14 days (d), and correlated CD34 and CD38 expression with the cell divisional history. CB cells began dividing 24 h earlier than BM cells, and significantly higher numbers underwent mitosis during the time in culture. By d10, over 55% of the CB-cells reached the ninth generation, whereas BM-cells were mostly distributed between the fifth and seventh generation. By d14, all CB cells had undergone multiple cell divisions, while 0.7-3.8% of BM CD34(+) cells remained quiescent. Furthermore, the percentage of BM cells expressing CD34 decreased from 60.8 +/- 6.3% to 30.6 +/- 6.7% prior to initiating division, suggesting that downmodulation of this antigen occurred before commencement of proliferation. Moreover, with BM, all primitive CD34(+)CD38(-) cells present at the end of culture arose from proliferating CD34(+)CD38(+) cells that downregulated CD38 expression, while in CB, a CD34(+)CD38(-) population was maintained throughout culture. These studies show that BM and CB cells differ significantly in cell division kinetics and expression of CD34 and CD38, and that the inherent modulation of these antigens during ex vivo expansion may lead to erroneous quantification of the stem cell content of the expanded graft.

Familial myeloma and monoclonal gammopathy: a report of eight African American families.

Previous descriptions of familial myeloma have been mainly of Caucasian families. We report here eight African American families with familial multiple myeloma and monoclonal gammopathy identified over a 30 year period. Six patients with multiple myeloma (MM) and two with monoclonal gammopathy of unknown significance (MGUS) reported a family history of MM or had family members with MGUS found on screening. A pedigree compiled for each family included a history of other cancers. In the eight families, 21 of 58 first degree relatives had a plasma cell dyscrasia including 12 MM, eight MGUS, and one amyloidosis patient(s). The age of the MM patients ranged from 50 to 78 years (median 61 years). Four families had two members with MM, including one mother-son and three sibling pairs. Two MM families each had two additional first degree relatives with MGUS, with three generations involved in one family. Anticipation was suggested in two families with parent-child pairs with monoclonal gammopathy. The eight pedigrees had 66 members, 21 of whom had a diagnosis of cancer, including non-Hodgkin lymphoma and Hodgkin disease, or a clonal myeloproliferative disorder other than MM. Although the mode of genetic transmission and anticipation cannot be confirmed due to the small sample size, the increased number of MM and MGUS family members suggests underlying genetic susceptibility factors for plasma cell dyscrasias and possibly for other cancers in these families.

Conjugated equine estrogens and colorectal cancer incidence and survival: the Women's Health Initiative randomized clinical trial.

BACKGROUND: In separate Women's Health Initiative randomized trials, combined hormone therapy with estrogen plus progestin reduced colorectal cancer incidence but estrogen alone in women with hysterectomy did not. We now analyze features of the colorectal cancers that developed and examine the survival of women following colorectal cancer diagnosis in the latter trial. PARTICIPANTS AND METHODS: 10,739 postmenopausal women who were 50 to 79 years of age and had undergone hysterectomy were randomized to conjugated equine estrogens (0.625 mg/d) or matching placebo. Colorectal cancer incidence was a component of the monitoring global index of the study but was not a primary study endpoint. Colorectal cancers were verified by central medical record and pathology report review. Bowel exam frequency was not protocol defined, but information on their use was collected. RESULTS: After a median 7.1 years, there were 58 invasive colorectal cancers in the hormone group and 53 in the placebo group [hazard ratio, 1.12; 95% confidence interval (95% CI), 0.77-1.63]. Tumor size, stage, and grade were comparable in the two randomization groups. Bowel exam frequency was also comparable in the two groups. The cumulative mortality following colorectal cancer diagnosis among women in the conjugated equine estrogen group was 34% compared with 30% in the placebo group (hazard ratio, 1.34; 95% CI, 0.58-3.19). CONCLUSIONS: In contrast to the preponderance of observational studies, conjugated equine estrogens in a randomized clinical trial did not reduce colorectal cancer incidence nor improve survival after diagnosis.

Mobilization strategies for the collection of peripheral blood progenitor cells: Results from a pilot study of delayed addition G-CSF following chemotherapy and review of the literature.

OBJECTIVE: Given the potential to limit cost, we conducted a pilot study evaluating delayed, low-dose granulocyte colony-stimulating factor (G-CSF) following chemotherapy for the procurement of peripheral blood progenitor cells (PBPCs) for autologous transplantation and reviewed the relevant literature. PATIENTS AND METHODS: Twenty-eight patients with various malignancies received cyclophosphamide 4 gm/m(2) and paclitaxel 170 mg/m2 followed by G-CSF 300 microg/d or 480 microg/d starting day +5 until two to four daily large volume leukapheresis yielded > or =5.0 x 10(6) CD34+ cells. We searched MEDLINE, Pubmed, and EMBASE databases from 1990 to the present to identify papers on PBPC procurement using delayed G-CSF (starting day +4 or later) following chemotherapy. RESULTS: G-CSF was administered for a median of 9 days at an average cost of 1260 USD per 70-kg patient. Collection was initiated at a median of 12 days after chemotherapy. A median 2.5 (range 2-4) apheresis were performed yielding an average daily CD34+ collection of 6.9 x 10(6)/kg (range 0.35-56.7). After one apheresis, 82% and 57% of patients collected > or =2.5 x 10(6)/kg and > or =5.0 x 10(6)/kg, respectively. Ultimately, 89% collected > or =5.0 x 10(6)/kg. Febrile neutropenia and catheter-related infection developed in five and two patients, respectively. All patients proceeded to transplantation and engrafted successfully with a median of 14.9 x 10(6)/kg (range 1.05-113) cells infused. Eleven published reports were identified involving 590 patients of whom 498 received G-CSF at a dose range of 250 microg/d to 10 microg/kg/d starting day +4 to 15 for a period of 4 to 9 days for PBPC procurement. Among these reports, 62 to 100% and 33 to 96% of patients collected > or =2 to 2.5 x 10(6) and > or =5.0 x 10(6) CD34+ cells, respectively. CONCLUSION: The use of delayed, low-dose G-CSF plus chemotherapy for stem cell mobilization was feasible and provides further evidence supporting this potentially cost-effective strategy. A review of the literature supports our findings and emphasizes the need for larger studies to address this issue.