Cerebellar Integrity in the Amyotrophic Lateral Sclerosis - Frontotemporal Dementia Continuum

Amyotrophic lateral sclerosis (ALS) and behavioural variant frontotemporal dementia (bvFTD) are multisystem neurodegenerative disorders that manifest overlapping cognitive, neuropsychiatric and motor features. The cerebellum has long been known to be crucial for intact motor function although emerging evidence over the past decade has attributed cognitive and neuropsychiatric processes to this structure. The current study set out i) to establish the integrity of cerebellar subregions in the amyotrophic lateral sclerosis-behavioural variant frontotemporal dementia spectrum (ALS-bvFTD) and ii) determine whether specific cerebellar atrophy regions are associated with cognitive, neuropsychiatric and motor symptoms in the patients. Seventy-eight patients diagnosed with ALS, ALS-bvFTD, behavioural variant frontotemporal dementia (bvFTD), most without C9ORF72 gene abnormalities, and healthy controls were investigated. Participants underwent cognitive, neuropsychiatric and functional evaluation as well as structural imaging using voxel-based morphometry (VBM) to examine the grey matter subregions of the cerebellar lobules, vermis and crus. VBM analyses revealed: i) significant grey matter atrophy in the cerebellum across the whole ALS-bvFTD continuum; ii) atrophy predominantly of the superior cerebellum and crus in bvFTD patients, atrophy of the inferior cerebellum and vermis in ALS patients, while ALS-bvFTD patients had both patterns of atrophy. Post-hoc covariance analyses revealed that cognitive and neuropsychiatric symptoms were particularly associated with atrophy of the crus and superior lobule, while motor symptoms were more associated with atrophy of the inferior lobules. Taken together, these findings indicate an important role of the cerebellum in the ALS-bvFTD disease spectrum, with all three clinical phenotypes demonstrating specific patterns of subregional atrophy that associated with different symptomology.     

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5 mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgG-scFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures.     

Sequencing of multiple clostridial genomes related to biomass conversion and biofuel production

Modern methods to develop microbe-based biomass conversion processes require a system-level understanding of the microbes involved. Clostridium species have long been recognized as ideal candidates for processes involving biomass conversion and production of various biofuels and other industrial products. To expand the knowledge base for clostridial species relevant to current biofuel production efforts, we have sequenced the genomes of 20 species spanning multiple genera. The majority of species sequenced fall within the class III cellulosome-encoding Clostridium and the class V saccharolytic Thermoanaerobacteraceae. Species were chosen based on representation in the experimental literature as model organisms, ability to degrade cellulosic biomass either by free enzymes or by cellulosomes, ability to rapidly ferment hexose and pentose sugars to ethanol, and ability to ferment synthesis gas to ethanol. The sequenced strains significantly increase the number of noncommensal/nonpathogenic clostridial species and provide a key foundation for future studies of biomass conversion, cellulosome composition, and clostridial systems biology.     

A mark-recapture population estimate for invasive silver carp (<Emphasis Type="Italic">Hypophthalmichthys molitrix</Emphasis>) in the La Grange Reach,Illinois River

Invasive silver carp (Hypophthalmichthys molitrix) populations have expanded greatly in the Upper Mississippi River System (UMRS) since their introduction in the early 1970s. We conducted a Chapman-modified, continuous Schnabel mark-recapture population and biomass estimate for silver carp (106–901 mm) in the La Grange reach, Illinois River during 2007–2008. We estimated a total of 328,192 (95% CI 231,226–484,474) silver carp (2,544 per river km 1,792–3,756) comprising 705 (95% CI; 496–1,040) metric tons of biomass (5.5 metric tons per river km 3.8–8.1). Long Term Resource Monitoring Program (LTRMP) data from the La Grange reach showed an exponential increase in silver carp catches since 1998, with an intrinsic rate of increase approaching 84%. In 2008, silver carp comprised about 51% of the total LTRMP annual fish collection. To our knowledge, this large river reach may contain the greatest ambient densities of wild silver carp in the world. Our findings provide a target for reduction efforts and also emphasize the importance of the La Grange reach as a source population for potential expansion of the species to the Laurentian Great Lakes.     

Microbial degradation of petroleum hydrocarbons in a polluted tropical stream

Summary Crude oil degradation was observed in water samples from three sites along the course of a polluted stream in Lagos, Nigeria. Consistent increase and decrease in the total viable counts (TVCs) of indigenous organisms occurred in the test and control experiments, respectively. Enrichments of the water samples with crude oil resulted in the isolation of nine bacteria belonging to seven genera. A mixed culture was developed from the assemblage of the nine species. The defined microbial consortium utilized a wide range of pure HCs including cycloalkane and aromatic HCs. Utilization of crude oil and petroleum cuts, i.e., kerosene and diesel resulted in an increase in TVC (till day 10) concomitant with decreases in pH and residual oil concentration. Crude oil, diesel and kerosene were degraded by 88, 85 and 78%, respectively, in 14 days. Substrate uptake studies with axenic cultures showed that growth was not sustainable on either cyclohexane or aromatics while degradation of the petroleum fractions fell below 67% in spite of extended incubation period (20 day). From the GC analysis of recovered oil, while reductions in peaks of n-alkane fractions and in biomarkers namely n-C₁₇/pristane and n-C₁₈/phytane ratios were observed in culture fluids of pure strains, complete removal of all the HC components of kerosene, diesel and crude oil including the isoprenoids was obtained with the consortium within 14 days.     

Naive and memory T lymphocytes migrate in comparable numbers through normal rat liver: activated T cells accumulate in the periportal field.

Although the liver is known to contain a significant number of lymphocytes, migration of these through the compartments of the liver, parenchyma and periportal field, has not been studied. The periportal field, in particular, is affected in several immunological disorders of the liver. Populations of labeled naive, activated, and memory T cells were injected into congenic rats. The recipient livers and draining lymph nodes were removed at various time points, and cryostat sections were analyzed for the presence of donor cells using quantitative immunohistology. Donor cell proliferation and apoptosis were examined in vivo by BrdU (5 microM 5-bromo-2-deoxyuridine) incorporation and the TUNEL technique, respectively. Early after injection (0.5-1 h), naive, activated, and memory T cells were localized to the parenchyma and periportal field in comparable numbers. With time, all T cell subsets left the parenchyma but remained or, in the case of activated T cells, significantly accumulated in the periportal field. Furthermore, 12% of activated donor T cells proliferated in vivo within the periportal field, and 0.5% showed evidence of apoptosis. Taken together, not only activated and memory, but also naive T cells continuously migrate through the liver, showing a preference for the periportal field, and activated T cells mainly proliferate there. This may explain why many immunological liver diseases predominantly affect the periportal field.