Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+ CD25- LAP+ T cells

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+ CD25- LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-beta-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.     

Yeast kinesin-8 depolymerizes microtubules in a length-dependent manner

The microtubule cytoskeleton and the mitotic spindle are highly dynamic structures, yet their sizes are remarkably constant, thus indicating that the growth and shrinkage of their constituent microtubules are finely balanced. This balance is achieved, in part, through kinesin-8 proteins (such as Kip3p in budding yeast and KLP67A in Drosophila) that destabilize microtubules. Here, we directly demonstrate that Kip3p destabilizes microtubules by depolymerizing them--accounting for the effects of kinesin-8 perturbations on microtubule and spindle length observed in fungi and metazoan cells. Furthermore, using single-molecule microscopy assays, we show that Kip3p has several properties that distinguish it from other depolymerizing kinesins, such as the kinesin-13 MCAK. First, Kip3p disassembles microtubules exclusively at the plus end and second, remarkably, Kip3p depolymerizes longer microtubules faster than shorter ones. These properties are consequences of Kip3p being a highly processive, plus-end-directed motor, both in vitro and in vivo. Length-dependent depolymerization provides a new mechanism for controlling the lengths of subcellular structures.     

Contrasting management paradigms for pronghorn in the arid Southwest and their northern range: a review

Pronghorn (Antilocapra americana), a symbol of western North America, experienced diverging population trajectories since the mid-twentieth century, with northern populations showing signs of recovery while those in the arid Southwest have struggled to persist. We conducted a systematic literature review of papers published through August 2023 to understand 3 questions. What are the habitat conditions needed for pronghorn to persist? What management actions can be taken to foster higher quality habitat? Do these actions differ for populations in the arid Southwest compared to their northern counterparts? Although the fundamental habitat requirements for pronghorn persistence have remained constant since the early 2000s, it has become clear that precipitation is a key factor influencing pronghorn populations in the arid Southwest. The precise mechanisms by which precipitation influences pronghorn population dynamics are not yet clear, whether through the availability of free water, by affecting forage quality, or indirectly via predator-prey dynamics. Although range-wide forage enhancement may be impractical, providing additional free water sources could facilitate greater movement, enabling pronghorn to access more and higher quality forage and areas with lower predation risk. To clarify how pronghorn persisted for thousands of years in this harsh environment, we must gain a better understanding of their historical metapopulation and migratory behaviors in the arid Southwest.     

Macrophage intracellular signaling induced by Listeria monocytogenes

Macrophages are critical for control of Listeria monocytogenes infections; accordingly, the interactions of L. monocytogenes with these cells have been intensively studied. It has become apparent that this facultative intracellular pathogen interacts with macrophages both prior to entry and during the intracellular phase. This review covers recent work on signaling induced in macrophages by L. monocytogenes, especially intracellular signals induced by secreted proteins including listeriolysin O and two distinct phospholipases C.     

Design, synthesis, and biological activity of novel factor Xa inhibitors: 4-aryloxy substituents of 2,6-diphenoxypyridines

A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.     

Maternal and neonatal separation and mortality associated with concurrent admissions to intensive care units

Background:

Concurrent admission of a mother and her newborn to separate intensive care units (herein referred to as co-ICU admission), possibly in different centres, can magnify family discord and stress. We examined the prevalence and predictors of mother–infant separation and mortality associated with co-ICU admissions.

Methods:

We completed a population-based study of all 1 023 978 singleton live births in Ontario between Apr. 1, 2002, and Mar. 31, 2010. We included data for maternal–infant pairs that had co-ICU admission (n = 1216), maternal ICU admission only (n = 897), neonatal ICU (NICU) admission only (n = 123 236) or no ICU admission (n = 898 629). The primary outcome measure was mother–infant separation because of interfacility transfer.

Results:

The prevalence of co-ICU admissions was 1.2 per 1000 live births and was higher than maternal ICU admissions (0.9 per 1000). Maternal–newborn separation due to interfacility transfer was 30.8 (95% confidence interval [CI] 26.9–35.3) times more common in the co-ICU group than in the no-ICU group and exceeded the prevalence in the maternal ICU group and NICU group. Short-term infant mortality (< 28 days after birth) was higher in the co-ICU group (18.1 per 1000 live births; maternal age–adjusted hazard ratio [HR] 27.8, 95% CI 18.2–42.6) than in the NICU group (7.6 per 1000; age-adjusted HR 11.5, 95% CI 10.4–12.7), relative to 0.7 per 1000 in the no-ICU group. Short-term maternal mortality (< 42 days after delivery) was also higher in the co-ICU group (15.6 per 1000; age-adjusted HR 328.7, 95% CI 191.2–565.2) than in the maternal ICU group (6.7 per 1000; age-adjusted HR 140.0, 95% CI 59.5–329.2) or the NICU group (0.2 per 1000; age-adjusted HR 4.6, 95% CI 2.8–7.4).

Interpretation:

Mother–infant pairs in the co-ICU group had the highest prevalence of separation due to interfacility transfer and the highest mortality compared with those in the maternal ICU and NICU groups.Admission of a newborn to a neonatal intensive care unit (NICU) produces a great deal of stress for the parents.¹ A new mother who also falls ill may be unable to care for, or bond with, her newborn during the time of her illness.² Although the father will experience a sense of loss of control when his infant is admitted to the NICU,^3,4 this feeling is conceivably worsened when the mother too requires intensive care. In this situation of concurrent ICU admission (herein referred to as “co-ICU”), the mother and newborn may be in different areas of the same hospital or in different facilities. This separation would magnify the degree of mother–infant and family discord and stress and could create competing priorities for family members in terms of decision-making and support. Moreover, the situation would be made more devastating if the mother or newborn died in hospital and the other remained critically ill, or after discharge of one, the other required continuing hospital care or died.Because of the serious, potentially negative consequences of co-ICU admissions, we examined the prevalence and predictors of mother–infant separation and mortality associated with co-ICU admissions.     

Minimal similarity in songs suggests limited exchange between humpback whales (Megaptera novaeangliae) in the southern Indian Ocean

Comparing humpback whale song from different breeding assemblages can reveal similarities in song due to acoustically interacting males, and therefore indirectly test whether males from different breeding sites are mixing. Northern Hemisphere song comparisons illustrated that whales within ocean basins share similar songs and are subpopulations within a larger population, whereas whales in different ocean basins are isolated populations and therefore do not share songs. During the 2006 breeding season, recordings were collected in Madagascar and Western Australia, and were compared visually plus aurally. Both regions shared one theme, whereas each region had four and six private themes, respectively. This study had a substantially low number of shared themes. The co‐occurrence of one theme was interpreted as an indication of limited exchange between these breeding assemblages, and we speculate that limited song similarity is due to inter‐oceanic interactions. Male(s) from an Indian Ocean breeding group could be exposed to novel song when they geographically overlap, and acoustically interact, with males from a different ocean basin. Novel song could induce rapid temporal changes as new song content is incorporated, thereby minimizing song similarities between that breeding group and other Indian Ocean breeding groups that were not exposed to the novel song.     

High frequency of glucose-utilizing mutants in Shewanella oneidensis MR-1

Shewanella oneidensis MR-1 has conventionally been considered unable to use glucose as a carbon substrate for growth. The genome sequence of S. oneidensis MR-1 however suggests the ability to use glucose. Here, we demonstrate that during initial glucose exposure, S. oneidensis MR-1 quickly and frequently gains the ability to utilize glucose as a sole carbon source, in contrast to wild-type S. oneidensis, which cannot immediately use glucose as a sole carbon substrate. High-performance liquid chromatography and (14)C glucose tracer studies confirm the disappearance in cultures and assimilation and respiration, respectively, of glucose. The relatively short time frame with which S. oneidensis MR-1 gained the ability to use glucose raises interesting ecological implications.