The human brain is comprised of a complex web of functional networks that link anatomically distinct regions. However, the biological mechanisms supporting network organization remain elusive, ...particularly across cortical and subcortical territories with vastly divergent cellular and molecular properties. Here, using human and primate brain transcriptional atlases, we demonstrate that spatial patterns of gene expression show strong correspondence with limbic and somato/motor cortico-striatal functional networks. Network-associated expression is consistent across independent human datasets and evolutionarily conserved in non-human primates. Genes preferentially expressed within the limbic network (encompassing nucleus accumbens, orbital/ventromedial prefrontal cortex, and temporal pole) relate to risk for psychiatric illness, chloride channel complexes, and markers of somatostatin neurons. Somato/motor associated genes are enriched for oligodendrocytes and markers of parvalbumin neurons. These analyses indicate that parallel cortico-striatal processing channels possess dissociable genetic signatures that recapitulate distributed functional networks, and nominate molecular mechanisms supporting cortico-striatal circuitry in health and disease.
The in situ generation of ethanol from glycerol-containing wastewater shows promise to improve the economics of the biodiesel industry. Consequently, we developed a microbial electrolysis cell (MEC) ...driven by the synergistic metabolisms of the exoelectrogen Geobacter sulfurreducens and the bacterium Clostridium cellobioparum, which fermented glycerol into ethanol in high yields (90%) and produced fermentative byproducts that served as electron donors for G. sulfurreducens. Syntrophic cooperation stimulated glycerol consumption, ethanol production, and the conversion of fermentation byproducts into cathodic H2 in the MEC. The platform was further improved by adaptively evolving glycerol-tolerant strains with robust growth at glycerol loadings typical of biodiesel wastewater and by increasing the buffering capacity of the anode medium. This resulted in additional increases in glycerol consumption (up to 50 g/L) and ethanol production (up to 10 g/L) at rates that greatly exceeded the capacity of the anode biofilms to concomitantly remove the fermentation byproducts. As a result, 1,3-propanediol was generated as a metabolic sink for electrons not converted into electricity syntrophically. The results highlight the potential of consortia to process glycerol in MECs and provide insights into genetic engineering and system design approaches that can be implemented to further improve MEC performance to satisfy industrial needs.
Over the past decades, significant strides have been made in understanding the pathobiology, prognosis, and treatment options for mantle cell lymphoma (MCL). The heterogeneity observed in MCL's ...biology, genomics, and clinical manifestations, including indolent and aggressive forms, is intricately linked to factors such as the mutational status of the variable region of the immunoglobulin heavy chain gene, epigenetic profiling, and Sox11 expression. Several intriguing subtypes of MCL, such as Cyclin D1-negative MCL, in situ mantle cell neoplasm, CCND1/IGH FISH-negative MCL, and the impact of karyotypic complexity on prognosis, have been explored. Notably, recent immunochemotherapy regimens have yielded long-lasting remissions in select patients. The therapeutic landscape for MCL is continuously evolving, with a shift towards nonchemotherapeutic agents like ibrutinib, acalabrutinib, and venetoclax. The introduction of BTK inhibitors has brought about a transformative change in MCL treatment. Nevertheless, the challenge of resistance to BTK inhibitors persists, prompting ongoing efforts to discover strategies for overcoming this resistance. These strategies encompass non-covalent BTK inhibitors, immunomodulatory agents, BCL2 inhibitors, and CAR-T cell therapy, either as standalone treatments or in combination regimens. Furthermore, developing novel drugs holds promise for further improving the survival of patients with relapsed or refractory MCL. In this comprehensive review, we methodically encapsulate MCL's clinical and pathological attributes and the factors influencing prognosis. We also undertake an in-depth examination of stratified treatment alternatives. We investigate conceivable resistance mechanisms in MCL from a genetic standpoint and offer precise insights into various therapeutic approaches for relapsed or refractory MCL.
The ability of some metal-reducing bacteria to produce a rough (no O-antigen) lipopolysaccharide (LPS) could facilitate surface interactions with minerals and metal reduction. Consistent with this, ...the laboratory model metal reducer Geobacter sulfurreducens PCA produced two rough LPS isoforms (with or without a terminal methyl-quinovosamine sugar) when growing with the soluble electron acceptor fumarate but expressed only the shorter and more hydrophilic variant when reducing iron oxides. We reconstructed from genomic data conserved pathways for the synthesis of the rough LPS and generated heptosyltransferase mutants with partial (Δ
) or complete (Δ
) truncations in the core oligosaccharide. The stepwise removal of the LPS core sugars reduced the hydrophilicity of the cell and increased outer membrane vesiculation. These changes in surface charge and remodeling did not substantially impact planktonic growth but disrupted the developmental stages and structure of electroactive biofilms. Furthermore, the mutants assembled conductive pili for extracellular mineralization of the toxic uranyl cation but were unable to prevent permeation and mineralization of the radionuclide in the cell envelope. Hence, not only does the rough LPS promote cell-cell and cell-mineral interactions critical to biofilm formation and metal respiration but it also functions as a permeability barrier to toxic metal cations. In doing so, the rough LPS maximizes the extracellular reduction of soluble and insoluble metals and preserves cell envelope functions critical to the environmental survival of
bacteria in metal-rich environments and their performance in bioremediation and bioenergy applications.
Some metal-reducing bacteria produce an LPS without the repeating sugars (O-antigen) that decorate the surface of most Gram-negative bacteria, but the biological significance of this adaptive feature was not previously investigated. Using the model representative Geobacter sulfurreducens strain PCA and mutants carrying stepwise truncations in the LPS core sugars, we demonstrate the importance of the rough LPS in the control of cell surface chemistry during the respiration of iron minerals and the formation of electroactive biofilms. Importantly, we describe hitherto overlooked roles for the rough LPS in metal sequestration and outer membrane vesiculation that are critical for the extracellular reduction and detoxification of toxic metals and radionuclides. These results are of interest for the optimization of bioremediation schemes and electricity-harvesting platforms using these bacteria.
Background
Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra‐articular ...(IA) administration.
Hypothesis/Objectives
Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens.
Animals
Eight healthy neonatal foals.
Methods
Foals received 3 amikacin treatment protocols: (1) IV‐only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA‐only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 μg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility.
Results
Foal age was a significant variable. The IV‐only protocol met or exceeded the 30‐minute plasma concentrations considered therapeutic (mean μg/mL 95% confidence interval, CI) in 7‐ to 9‐day‐old (54.0 52.2‐56.9), 14‐ to 16‐day‐old (58.1 55.2‐61.0), and 21‐ to 23‐day‐old (66.6 63.7‐69.6) foals. Concurrent IV and IA protocol did not reach the 30‐minute concentration considered therapeutic in 7‐ to 9‐day‐old foals (46.5 43.6‐49.4) but did in 14‐ to 16‐day‐old (62.9 60.0‐65.8) and 21‐to 23‐day‐old (62.6 59.7‐65.6) foals.
Conclusions and Clinical Importance
Concurrent IV and IA administration of amikacin produces 30‐minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin.
Imidazolium ionic liquids (IILs) have a range of biotechnological applications, including as pretreatment solvents that extract cellulose from plant biomass for microbial fermentation into ...sustainable bioenergy. However, residual levels of IILs, such as 1-ethyl-3-methylimidazolium chloride (C
C
imCl), are toxic to biofuel-producing microbes, including the yeast
strains isolated from diverse ecological niches differ in genomic sequence and in phenotypes potentially beneficial for industrial applications, including tolerance to inhibitory compounds present in hydrolyzed plant feedstocks. We evaluated >100 genome-sequenced
strains for tolerance to C
C
imCl and identified one strain with exceptional tolerance. By screening a library of genomic DNA fragments from the C
C
imCl-tolerant strain for improved IIL tolerance, we identified
, which encodes a plasma membrane multidrug efflux pump, and a previously uncharacterized gene that we named
(
), which encodes a predicted membrane protein. Analyses of
sequences from our panel of
strains together with growth phenotypes implicated two single nucleotide polymorphisms (SNPs) that associated with IIL tolerance and sensitivity. We confirmed these phenotypic effects by transferring the
SNPs into a C
C
imCl-sensitive yeast strain using CRISPR/Cas9 genome editing. Further studies indicated that these SNPs affect Sge1 protein stability and cell surface localization, influencing the amount of toxic IILs that cells can pump out of the cytoplasm. Our results highlight the general potential for discovering useful biotechnological functions from untapped natural sequence variation and provide functional insight into emergent
alleles with reduced capacities to protect against IIL toxicity.
Four-factor prothrombin complex concentrate (4F-PCC) may be an option for patients with bleeding unrelated to therapeutic anticoagulation to help with bleeding cessation and reduce blood component ...requirements.
Retrospective, observational study of adult patients who received 4F-PCC for bleeding not associated with therapeutic anticoagulation between June 2019 and July 2021. Primary outcome was to describe off-label 4F-PCC use in patients not on therapeutic anticoagulation for bleeding management in surgical and non-surgical patients. Additional outcomes evaluated were blood product use, chest tube and drainage output, and coagulation studies before and after 4F-PCC administration as well as other hemostatic agent use and thromboembolic events.
Seventy-six patients were included; median age 64 years (IQR 50-69), 66% of bleeding events were associated with surgery, and the majority of 4F-PCC doses ordered by cardiac surgery (68.4%). A total of 110 4F-PCC doses were administered; median 1 dose/patient (IQR 1-2), median total dose 1000 units (IQR 500-1484). Other hemostatic agents commonly administered were protamine (59%), desmopressin (43%), and tranexamic acid (42%). Packed red blood cells, fresh frozen plasma, platelet, and cell saver blood administration and prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (aPTT) were significantly reduced following 4F-PCC administration. Eight patients (11%) experienced thromboembolic complications.
Relatively low doses of 4F-PCC (median total dose 1000 units) were associated with decreased blood component requirements and improved PT, INR, and aPTT values in patients with bleeding unrelated to therapeutic anticoagulation. Other hemostatic agent use was common and thromboembolic complications occurred.
To describe outcomes of horses with temporohyoid osteoarthropathy (THO) treated with partial ceratohyoidectomy.
10 client-owned horses.
Medical records from 2 institutions were examined for records ...of horses with THO treated with partial ceratohyoidectomy between 2010 and 2021. History, signalment, clinical signs, diagnostics, medications, and surgery-related details were recorded. Horses with a minimum of 6 months follow-up were recruited for neurologic and imaging examinations in the hospital or field where radiography of the basihyoid-ceratohyoid articulation were performed along with CT, when available.
10 horses with THO were included (9 unilateral; 1 bilateral). Nine planned partial ceratohyoidectomies were performed in 8 horses, whereas 2 horses had preoperatively planned complete ceratohyoidectomies transitioned to partial ceratohyoidectomies during surgery due to intraoperative complications. Postoperative complications occurred mostly in transitioned surgeries (obstructed airway, tongue mobility issues, and incisional hemorrhage), whereas only 1 horse with a planned ceratohyoidectomy had postoperative complication of rhabdomyolysis. All complications resolved before hospital discharge. Neurologic signs improved in all 10 horses, with 2 showing complete resolution. Nine horses were available for radiographic follow-up, 6 of which also had head CT scans. A space between the ceratohyoid and basihyoid bones was measurable on radiography in all 9 horses, and was confirmed on CT. Three horses demonstrated proliferation of either ceratohyoid or basihyoid bones. The 9 horses with unilateral disease returned to previous work, and the horse with bilateral disease was retired.
Partial ceratohyoidectomy is a surgical option for treatment of THO that provides similar clinical outcomes to published reports on ceratohyoidectomy.
Navicular syndrome is a common cause of forelimb lameness in horses. Beyond changes to the navicular bone itself, horses with a clinical diagnosis of navicular syndrome often have pathology ...associated with other components of the navicular apparatus, including the navicular bursa, deep digital flexor (DDF) tendon, collateral sesamoidean ligaments, and impar ligament. Palmar digital neurectomy (PDN) is often used as a salvage procedure for horses diagnosed with navicular syndrome that become unresponsive to medical management. There are many potential complications associated with PDN, some of which are debilitating.
This report describes two cases of navicular bone fracture with severe DDF tendinopathy and distal interphalangeal joint subluxation/hyperextension that occurred 12 and 19 weeks after bilateral forelimb PDN.
These two cases highlight the importance of proper patient selection before PDN due to the high incidence of undiagnosed soft tissue pathology in conjunction with radiographic evidence of navicular syndrome. Advanced imaging of the digit is recommended to identify and characterize any soft tissue pathology associated with the navicular apparatus before pursuing PDN to avoid disease progression and catastrophic injury.
Summary
The microbial degradation of cellulose contributes greatly to the cycling of carbon in terrestrial environments and feedbacks to the atmosphere, a process that is highly responsive to ...nitrogen inputs. Yet how key groups of cellulolytic microorganisms adaptively respond to the global conditions of nitrogen limitation and/or anthropogenic or climate nitrogen inputs is poorly understood. The actinobacterial genus Cellulomonas is of special interest because it incorporates the only species known to degrade cellulose aerobically and anaerobically. Furthermore, despite their inability to fix nitrogen, they are active decomposers in nitrogen‐limited environments. Here we show that nitrogen limitation induced biofilm formation in Cellulomonas spp., a process that was coupled to carbon sequestration and storage in a curdlan‐type biofilm matrix. The response was reversible and the curdlan matrix was solubilized and used as a carbon and energy source for biofilm dispersal once nitrogen sources became available. The biofilms attached strongly to cellulosic surfaces and, despite the growth limitation, produced cellulases and degraded cellulose more efficiently. The results show that biofilm formation is a competitive strategy for carbon and nitrogen acquisition and provide valuable insights linking nitrogen inputs to carbon sequestration and remobilization in terrestrial environments.
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