A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease

Membrane protein extraction and purification using partially-esterified SMA polymers

Styrene maleic acid (SMA) polymers have proven to be very successful for the extraction of membrane proteins, forming SMA lipid particles (SMALPs), which maintain a lipid bilayer around the membrane protein. SMALP-encapsulated membrane proteins can be used for functional and structural studies. The SMALP approach allows retention of important protein-annular lipid interactions, exerts lateral pressure, and offers greater stability than traditional detergent solubilisation. However, SMA polymer does have some limitations, including a sensitivity to divalent cations and low pH, an absorbance spectrum that overlaps with many proteins, and possible restrictions on protein conformational change. Various modified polymers have been developed to try to overcome these challenges, but no clear solution has been found. A series of partially-esterified variants of SMA (SMA 2625, SMA 1440 and SMA 17352) has previously been shown to be highly effective for solubilisation of plant and cyanobacterial thylakoid membranes. It was hypothesised that the partial esterification of maleic acid groups would increase tolerance to divalent cations. Therefore, these partially-esterified polymers were tested for the solubilisation of lipids and membrane proteins, and their tolerance to magnesium ions. It was found that all partially esterified polymers were capable of solubilising and purifying a range of membrane proteins, but the yield of protein was lower with SMA 1440, and the degree of purity was lower for both SMA1440 and SMA17352. SMA2625 performed comparably to SMA 2000. SMA 1440 also showed an increased sensitivity to divalent cations. Thus, it appears the interactions between SMA and divalent cations are more complex than proposed and require further investigation

The interactive effect of remittances and civil liberties on investment and consumption

Purpose – The purpose of this paper is to investigate the level of influence that civil liberties has on the marginal effect of remittances on gross domestic investment and consumption separately and measures it across all levels of civil liberties. Design/methodology/approach – The authors employ a two-stage system generalized method of moments procedure and the civil liberties subset of the Freedom in the World Index as a proxy for civil liberty. Findings – The findings indicate a substitution effect from investment to consumption as civil liberties deteriorate for developing south economies, though not for emerging economies. In addition, the marginal effect of remittances on investment diminishes less quickly as economies become less free than it increases for consumption indicating that the substitution is not quite one-for-one. Practical implications – Economies with low levels of civil liberties could benefit by improving them in ways that would encourage recipients to channel remittances into investment rather than consumption. Originality/value – This paper differs from previous research in that the authors evaluate investment and consumption separately rather than embedding these component parts within growth. In addition, when interactions are employed in existing literature, the inference drawn is static with regard to the varying degrees of institutional development. Third, none of the prior studies directly explores civil liberties proper; they usually aggregate civil liberties with other aspects of political or economic freedom.Civil and political rights, Consumption, Developing countries, Investments

Bioinformatic Characterization of Mosquito Viromes within the Eastern United States and Puerto Rico: Discovery of Novel Viruses

Mosquitoes are efficient, militarily relevant vectors of infectious disease pathogens, including many RNA viruses. The vast majority of all viruses are thought to be undiscovered. Accordingly, recent studies have shown that viruses discovered in insects are very divergent from known pathogens and that many of them lack appropriate reference sequences in the public databases. Given that the majority of viruses are likely still undiscovered, environmental sampling stands to provide much needed reference samples as well as genetic sequences for comparison. In this study, we sought to determine whether samples of mosquitoes collected from different sites (the Caribbean and locations on the US East Coast) could be differentiated using metagenomic analysis of the RNA viral fraction. We report here distinct virome profiles, even from samples collected short distances apart. In addition to profiling the previously known viruses from these samples, we detected a number of viruses that have been previously undiscovered

Single-Stage Externalized Locked Plating for Treatment of Unstable Meta-Diaphyseal Tibial Fractures

(1) Background: Unstable meta-diaphyseal tibial fractures represent a heterogeneous group of injuries. Recently, good clinical results have been reported when applying a technique of externalized locked plating in appropriate cases, highlighting its advantage in terms of less additional tissue injury compared with conventional methods of fracture fixation. The aims of this prospective clinical cohort study were, firstly, to investigate the biomechanical and clinical feasibility and, secondly, to evaluate the clinical and functional outcomes of single-stage externalized locked plating for treatment of unstable, proximal (intra- and extra-articular) and distal (extra-articular), meta-diaphyseal tibial fractures. (2) Methods: Patients, who matched the inclusion criteria of sustaining a high-energy unstable meta-diaphyseal tibial fracture, were identified prospectively for single-stage externalized locked plating at a single trauma hospital in the period from April 2013 to December 2022. (3) Results: Eighteen patients were included in the study. Average follow-up was 21.4 ± 12.3 months, with 94% of the fractures healing without complications. The healing time was 21.1 ± 4.6 weeks, being significantly shorter for patients with proximal extra- versus intra-articular meta-diaphyseal tibial fractures, p = 0.04. Good and excellent functional outcomes in terms of HSS and AOFAS scores, and knee and ankle joints range of motion were observed among all patients, with no registered implant breakage, deep infection, and non-union. (4) Conclusions: Single-stage externalized locked plating of unstable meta-diaphyseal tibial fractures provides adequate stability of fixation with promising clinical results and represents an attractive alternative to the conventional methods of external fixation when inclusion criteria and rehabilitation protocol are strictly followed. Further experimental studies and randomized multicentric clinical trials with larger series of patients are necessary to pave the way of its use in clinical practice

Single-Stage Externalized Locked Plating for Treatment of Unstable Meta-Diaphyseal Tibial Fractures

(1) Background: Unstable meta-diaphyseal tibial fractures represent a heterogeneous group of injuries. Recently, good clinical results have been reported when applying a technique of externalized locked plating in appropriate cases, highlighting its advantage in terms of less additional tissue injury compared with conventional methods of fracture fixation. The aims of this prospective clinical cohort study were, firstly, to investigate the biomechanical and clinical feasibility and, secondly, to evaluate the clinical and functional outcomes of single-stage externalized locked plating for treatment of unstable, proximal (intra- and extra-articular) and distal (extra-articular), meta-diaphyseal tibial fractures. (2) Methods: Patients, who matched the inclusion criteria of sustaining a high-energy unstable meta-diaphyseal tibial fracture, were identified prospectively for single-stage externalized locked plating at a single trauma hospital in the period from April 2013 to December 2022. (3) Results: Eighteen patients were included in the study. Average follow-up was 21.4 ± 12.3 months, with 94% of the fractures healing without complications. The healing time was 21.1 ± 4.6 weeks, being significantly shorter for patients with proximal extra- versus intra-articular meta-diaphyseal tibial fractures, p = 0.04. Good and excellent functional outcomes in terms of HSS and AOFAS scores, and knee and ankle joints range of motion were observed among all patients, with no registered implant breakage, deep infection, and non-union. (4) Conclusions: Single-stage externalized locked plating of unstable meta-diaphyseal tibial fractures provides adequate stability of fixation with promising clinical results and represents an attractive alternative to the conventional methods of external fixation when inclusion criteria and rehabilitation protocol are strictly followed. Further experimental studies and randomized multicentric clinical trials with larger series of patients are necessary to pave the way of its use in clinical practice

The Role of Osteopontin in the Development of Albuminuria

Several gene array studies have suggested that osteopontin (Opn) expression strongly correlates with albuminuria and glomerular disease. Urinary Opn concentration and kidney Opn immunoreactivity were found to be increased in patients with steroid-sensitive nephrotic syndrome. In addition, renal Opn mRNA was increased in the Ins2(Akita) mouse model of type 1 diabetic nephropathy, in the LPS-induced albuminuria model, and in glomeruli of puromycin aminonucleotide–induced nephrotic rats. Opn knockout mice did not develop albuminuria in response to LPS injection, and Opn knockout mice were protected from diabetes-induced albuminuria and mesangial expansion. In the glomerulus, Opn immunostaining was increased specifically in podocytes. Treatment of podocytes with recombinant Opn activated the NF-κB pathway, increased expression of urokinase plasminogen activator and matrix metalloproteinases 2 and 9, and increased podocyte motility. Taken together, these results indicate that Opn plays an important role in the development of albuminuria, possibly by modulating podocyte signaling and motility