A single amino acid substitution in MdLAZY1A dominantly impairs shoot gravitropism in Malus.

Plant architecture is 1 of the most important factors that determines crop yield potential and productivity. In apple (Malus domestica), genetic improvement of tree architecture has been challenging due to a long juvenile phase and growth as complex trees composed of a distinct scion and a rootstock. To better understand the genetic control of apple tree architecture, the dominant weeping growth phenotype was investigated. We report the identification of MdLAZY1A (MD13G1122400) as the genetic determinant underpinning the Weeping (W) locus that largely controls weeping growth in Malus. MdLAZY1A is 1 of the 4 paralogs in apple that are most closely related to AtLAZY1 involved in gravitropism in Arabidopsis (Arabidopsis thaliana). The weeping allele (MdLAZY1A-W) contains a single nucleotide mutation c.584T>C that leads to a leucine to proline (L195P) substitution within a predicted transmembrane domain that colocalizes with Region III, 1 of the 5 conserved regions in LAZY1-like proteins. Subcellular localization revealed that MdLAZY1A localizes to the plasma membrane and nucleus in plant cells. Overexpressing the weeping allele in apple cultivar Royal Gala (RG) with standard growth habit impaired its gravitropic response and altered the growth to weeping-like. Suppressing the standard allele (MdLAZY1A-S) by RNA interference (RNAi) in RG similarly changed the branch growth direction to downward. Overall, the L195P mutation in MdLAZY1A is genetically causal for weeping growth, underscoring not only the crucial roles of residue L195 and Region III in MdLAZY1A-mediated gravitropic response but also a potential DNA base editing target for tree architecture improvement in Malus and other crops.

Causal inference accounts for heading perception in the presence of object motion.

The brain infers our spatial orientation and properties of the world from ambiguous and noisy sensory cues. Judging self-motion (heading) in the presence of independently moving objects poses a challenging inference problem because the image motion of an object could be attributed to movement of the object, self-motion, or some combination of the two. We test whether perception of heading and object motion follows predictions of a normative causal inference framework. In a dual-report task, subjects indicated whether an object appeared stationary or moving in the virtual world, while simultaneously judging their heading. Consistent with causal inference predictions, the proportion of object stationarity reports, as well as the accuracy and precision of heading judgments, depended on the speed of object motion. Critically, biases in perceived heading declined when the object was perceived to be moving in the world. Our findings suggest that the brain interprets object motion and self-motion using a causal inference framework.

Cortical Balance Between ON and OFF Visual Responses Is Modulated by the Spatial Properties of the Visual Stimulus.

The primary visual cortex of carnivores and primates is dominated by the OFF visual pathway and responds more strongly to dark than light stimuli. Here, we demonstrate that this cortical OFF dominance is modulated by the size and spatial frequency of the stimulus in awake primates and we uncover a main neuronal mechanism underlying this modulation. We show that large grating patterns with low spatial frequencies drive five times more OFF-dominated than ON-dominated neurons, but this pronounced cortical OFF dominance is strongly reduced when the grating size decreases and the spatial frequency increases, as when the stimulus moves away from the observer. We demonstrate that the reduction in cortical OFF dominance is not caused by a selective reduction of visual responses in OFF-dominated neurons but by a change in the ON/OFF response balance of neurons with diverse receptive field properties that can be ON or OFF dominated, simple, or complex. We conclude that cortical OFF dominance is continuously adjusted by a neuronal mechanism that modulates ON/OFF response balance in multiple cortical neurons when the spatial properties of the visual stimulus change with viewing distance and/or optical blur.

Molecular screening of familial hypercholesterolemia in Icelanders.

Familial hypercholesterolemia (FH) is a monogenic disease characterized by a lifelong exposure to high LDL-C levels that can lead to early onset coronary heart disease (CHD). The main causes of FH identified to date include loss-of-function mutations in LDLR or APOB, or gain-of-function mutations in PCSK9. Early diagnosis and genetic testing of FH suspects is critical for improved prognosis of affected individuals as lipid lowering treatments are effective in preventing CHD related morbidity and mortality. In the present study, we carried out a comprehensive screening, using a next-generation sequencing (NGS) panel, for FH culprit mutations in two Icelandic studies representative of either FH families or the general population. We confirmed all previously known mutations in the FH families, and identified two subjects that had been misdiagnosed clinically at young age. We identified six new mutations in the Icelandic FH families and detected three pathogenic mutations in the general population-based study. The application of the NGS panel revealed substantial diagnostic yields in identifying pathogenic mutations, or 68.2% of those with definite clinical diagnosis of FH in the family material and 5.6-fold enrichment in the population-based genetic testing.

Assessing Prognosis of Acute Coronary Syndrome in Recent Clinical Trials: A Systematic Review.

There is no recent comprehensive overview of contemporary clinical trials assessing short and long-term outcomes in patients with acute coronary syndrome (ACS). This paper reviews factors from recent clinical trials that influenced prognosis in patients with ACS. Cochrane and PubMed databases were screened systematically for clinical trials published in the English literature reporting on ACS prognosis. Two authors independently screened titles, abstracts, and full text. Studies meeting inclusion criteria evaluated the impact of modern practice on prognosis. In vitro and animal models studies, conference abstracts, imaging studies, and review articles were excluded. Disagreement in inclusion criteria was resolved by consensus. A large study of 8,859 patients showed no difference in all-cause mortality between 31 days and 2 years in patients with ST segment elevation myocardial infarction (STEMI) compared to those with non-ST segment elevation myocardial infarction (NSTEMI) or stable ischemic heart disease (SIHD). Other studies showed a significant increase in all-cause mortality in patients with STEMI within the first 30 days, with NSTEMI patients exhibiting a higher mortality rate compared to those with SIHD during the 2-year follow-up period. Our review found that women have a poorer short-term prognosis compared to men. Additionally, reports from patients receiving comprehensive and coordinated care showed longer survival rates. In view of the improved prognosis demonstrated for patients suffering from ACS, assessing prognosis in patients represents a formidable task in modern practice. Our review highlights the need for further evidence-based studies evaluating long-term outcomes on diagnostic and treatment strategies.

Highly Efficient Synthesis of a Staphylococcus aureus Targeting Payload to Enable the First Antibody-Antibiotic Conjugate.

A practical synthesis of the complex payload for an anti-Staphylococcus aureus THIOMABTM antibody-antibiotic conjugate (TAC) is described. The route takes advantage of a delicate oxidative condensation, achieved using a semi-continuous flow procedure. It allows for the generation of kilogram quantities of a key intermediate to enable a mild nucleophilic aromatic substitution to the tertiary amine free drug. The linker component is introduced as a benzylic chloride, which allows formation of the quaternary ammonium salt linker-drug. This chemical process surmounts numerous synthetic challenges and navigates deeply colored and unstable compounds to support clinical studies to counter S. aureus bacterial infections.

Comprehensive genetic testing for female and male infertility using next-generation sequencing.

PURPOSE: To develop a comprehensive genetic test for female and male infertility in support of medical decisions during assisted reproductive technology (ART) protocols. METHODS: We developed a next-generation sequencing (NGS) gene panel consisting of 87 genes including promoters, 5' and 3' untranslated regions, exons, and selected introns. In addition, sex chromosome aneuploidies and Y chromosome microdeletions were analyzed concomitantly using the same panel. RESULTS: The NGS panel was analytically validated by retrospective analysis of 118 genomic DNA samples with known variants in loci representative of female and male infertility. Our results showed analytical accuracy of > 99%, with > 98% sensitivity for single-nucleotide variants (SNVs) and > 91% sensitivity for insertions/deletions (indels). Clinical sensitivity was assessed with samples containing variants representative of male and female infertility, and it was 100% for SNVs/indels, CFTR IVS8-5T variants, sex chromosome aneuploidies, and copy number variants (CNVs) and > 93% for Y chromosome microdeletions. Cost analysis shows potential savings when comparing this single NGS assay with the standard approach, which includes multiple assays. CONCLUSIONS: A single, comprehensive, NGS panel can simplify the ordering process for healthcare providers, reduce turnaround time, and lower the overall cost of testing for genetic assessment of infertility in females and males, while maintaining accuracy.

Neuronal nonlinearity explains greater visual spatial resolution for darks than lights.

Astronomers and physicists noticed centuries ago that visual spatial resolution is higher for dark than light stimuli, but the neuronal mechanisms for this perceptual asymmetry remain unknown. Here we demonstrate that the asymmetry is caused by a neuronal nonlinearity in the early visual pathway. We show that neurons driven by darks (OFF neurons) increase their responses roughly linearly with luminance decrements, independent of the background luminance. However, neurons driven by lights (ON neurons) saturate their responses with small increases in luminance and need bright backgrounds to approach the linearity of OFF neurons. We show that, as a consequence of this difference in linearity, receptive fields are larger in ON than OFF thalamic neurons, and cortical neurons are more strongly driven by darks than lights at low spatial frequencies. This ON/OFF asymmetry in linearity could be demonstrated in the visual cortex of cats, monkeys, and humans and in the cat visual thalamus. Furthermore, in the cat visual thalamus, we show that the neuronal nonlinearity is present at the ON receptive field center of ON-center neurons and ON receptive field surround of OFF-center neurons, suggesting an origin at the level of the photoreceptor. These results demonstrate a fundamental difference in visual processing between ON and OFF channels and reveal a competitive advantage for OFF neurons over ON neurons at low spatial frequencies, which could be important during cortical development when retinal images are blurred by immature optics in infant eyes.

Separate collection of plastic waste, better than technical sorting from municipal solid waste?

The politically preferred solution to fulfil legal recycling demands is often implementing separate collection systems. However, experience shows their limitations, particularly in urban centres with a high population density. In response to the European Union landfill directive, mechanical biological waste treatment plants have been installed all over Europe. This technology makes it possible to retrieve plastic waste from municipal solid waste. Operators of mechanical biological waste treatment plants, both in Germany and the Netherlands, have started to change their mechanical separation processes to additionally produce plastic pre-concentrates. Results from mechanical biological waste treatment and separate collection of post-consumer packaging waste will be presented and compared. They prove that both the yield and the quality of plastic waste provided as feedstock for the production of secondary plastic raw material are largely comparable. An economic assessment shows which conditions for a technical sorting plant are economically attractive in comparison to separate collection systems. It is, however, unlikely that plastic recycling will ever reach cost neutrality.

Chromatic and Achromatic Spatial Resolution of Local Field Potentials in Awake Cortex.

Local field potentials (LFPs) have become an important measure of neuronal population activity in the brain and could provide robust signals to guide the implant of visual cortical prosthesis in the future. However, it remains unclear whether LFPs can detect weak cortical responses (e.g., cortical responses to equiluminant color) and whether they have enough visual spatial resolution to distinguish different chromatic and achromatic stimulus patterns. By recording from awake behaving macaques in primary visual cortex, here we demonstrate that LFPs respond robustly to pure chromatic stimuli and exhibit ∼2.5 times lower spatial resolution for chromatic than achromatic stimulus patterns, a value that resembles the ratio of achromatic/chromatic resolution measured with psychophysical experiments in humans. We also show that, although the spatial resolution of LFP decays with visual eccentricity as is also the case for single neurons, LFPs have higher spatial resolution and show weaker response suppression to low spatial frequencies than spiking multiunit activity. These results indicate that LFP recordings are an excellent approach to measure spatial resolution from local populations of neurons in visual cortex including those responsive to color.

Segregating animals in naturalistic surroundings: interaction of color distributions and mechanisms.

Humans have been shown to rapidly detect animals in naturalistic scenes, but the role of color in this task is unclear. We first analyze the color information contained in a large number of images of salient and camouflaged animals in generic backgrounds. We found that color distributions of most animals and of their immediate backgrounds were oriented along other than the cardinal directions of color space. In addition, the maximum distances between animals and background distributions also tended to be along noncardinal directions, suggesting a role for higher-order cortical color mechanisms whose preferred axes are distributed widely in color space. We measured temporal thresholds for segmenting animal color distributions from background distributions in the absence of spatial cues. Combined over all observers and all images in our sample, thresholds for segmenting isoluminant projections of these distributions were lower than for segmenting the original distributions and considerably lower than for segmenting achromatic projections. Color information is thus likely to be useful in segregating animals in generic views, i.e., views not purposely chosen by the photographer to enhance the visibility of the animal. However, a comparison of thresholds with distances between distributions failed to reveal any advantage conferred by higher-order color mechanisms.

The quantitative trait gene latexin influences the size of the hematopoietic stem cell population in mice.

We mapped quantitative trait loci that accounted for the variation in hematopoietic stem cell (HSC) numbers between young adult C57BL/6 (B6) and DBA/2 (D2) mice. In reciprocal chromosome 3 congenic mice, introgressed D2 alleles increased HSC numbers owing to enhanced proliferation and self-renewal and reduced apoptosis, whereas B6 alleles had the opposite effects. Using oligonucleotide arrays, real-time PCR and protein blots, we identified latexin (Lxn), a gene whose differential transcription and expression was associated with the allelic differences. Expression was inversely correlated with the number of HSCs; therefore, ectopic expression of Lxn using a retroviral vector decreased stem cell population size. We identified clusters of SNPs upstream of the Lxn transcriptional start site, at least two of which are associated with potential binding sites for transcription factors regulating stem cells. Thus, promoter polymorphisms between the B6 and D2 alleles may affect Lxn gene expression and consequently influence the population size of hematopoietic stem cells.

Salience of unique hues and implications for color theory.

The unique hues--blue, green, yellow, red--form the fundamental dimensions of opponent-color theories, are considered universal across languages, and provide useful mental representations for structuring color percepts. However, there is no neural evidence for them from neurophysiology or low-level psychophysics. Tapping a higher prelinguistic perceptual level, we tested whether unique hues are particularly salient in search tasks. We found no advantage for unique hues over their nonunique complementary colors. However, yellowish targets were detected faster, more accurately, and with fewer saccades than their complementary bluish targets (including unique blue), while reddish-greenish pairs were not significantly different in salience. Similarly, local field potentials in primate V1 exhibited larger amplitudes and shorter latencies for yellowish versus bluish stimuli, whereas this effect was weaker for reddish versus greenish stimuli. Consequently, color salience is affected more by early neural response asymmetries than by any possible mental or neural representation of unique hues.

Central sorting and recovery of MSW recyclable materials: A review of technological state-of-the-art, cases, practice and implications for materials recycling.

Today's waste regulation in the EU comprises stringent material recovery targets and calls for comprehensive programs in order to achieve them. A similar movement is seen in the US where more and more states and communities commit to high diversion rates from landfills. The present paper reviews scientific literature, case studies and results from pilot projects, on the topic of central sorting of recyclable materials commonly found in waste from households. The study contributes, inter alia, with background understanding on the development of materials recovery, both in a historical and geographical perspective. Physical processing and sorting technology has reached a high level of maturity, and many quality issues linked to cross-contamination by commingling have been successfully addressed to date. New sorting plants tend to benefit from economies of scale, and innovations in automation and process control, which are targeted at curtailing process inefficiencies shown by operational practice. Technology developed for the sorting of commingled recyclables from separate collection is also being successfully used to upgrade residual MSW processing plants. The strongest motivation for central sorting of residual MSW is found for areas where source separation and separate collection is difficult, such as urban agglomerations, and can in such areas contribute to increasing recycling rates, either complementary to- or as a substitute for source separation of certain materials, such as plastics and metals.

Medical service use among individuals receiving HIV prevention services in Los Angeles County.

Timely provision of medical services among communities at increased risk of HIV infection is crucial to detect the infection and to further prevent the spread of HIV. In the US, about one third of HIV cases were identified in the later stage of infection. The current study utilized the Gelberg-Andersen behavioral model for predicting medical service use among people who were at risk of HIV infection. The candidate variables included: social support, attitudinal, and behavioral variables. The data were collected from clients of HIV prevention agencies in Los Angeles County in 2004 who participated in the Countywide Risk Assessment Survey (CRAS). Using a logistic regression model, the study suggested that factors that were positively associated with use of medical services included living in a treatment center/halfway house or mission/shelter, experience of physical/sexual abuse, and ever receiving HIV testing/counseling. Factors inversely associated with medical service use were male gender, education, and consumption of alcohol. Analysis was conducted using SAS 9.3. Most of the findings are consistent with the Gelberg-Andersen model. The exception was that victims of physical or sexual abuse were more likely to use services instead of less likely as predicted by the model.

Malpractice Cases Arising From Telephone Based Telemedicine Triage in Ophthalmology.

PURPOSE: To determine the allegation, precipitating medical issue, and outcome of telephone triage focused malpractice litigation among ophthalmologists. METHODS: The WestLaw Edge database was reviewed using terms pertaining to ophthalmology and telemedicine. The search ranged from 4/7/30 to 1/25/22. RESULTS: Of the 510 lawsuits, 3.5% (18/510) met inclusion criteria. 94.5% (17/18) alleged delays in evaluation and/or treatment. 61.1% (11/18) alleged incorrect diagnoses, 38.9% (7/18) claimed improper discussion of risks or informed consent, and 5.6% (1/18) alleged delayed referrals. The precipitating medical issues included retinal detachment in 33.3% (6/18) of cases, post-procedure and post-trauma endophthalmitis in 33.3% (6/18) of cases, ocular trauma without endophthalmitis in 22.2% (4/18) of cases, and bilateral acute retinal necrosis and allergic reactions each accounting for 5.6% (1/18) of cases. CONCLUSION: Telephone triage creates potential malpractice litigation. Delay in in-person clinical evaluation and alleged failure to inform patients of possible irreversible vision loss may lead to potential malpractice litigation. We suggest offering the option of same day in person evaluation and informing the patient how delay may lead to irreversible vision loss.

Pituitary hyperplasia resulting in visual deficit.

Background: Pituitary hyperplasia is an infrequent cause of visual disturbance and few such cases have been reported in the literature. Case Description: We describe the case of a 16-year-old female who presented with a short history of progressive headache and visual blurring. Examination revealed markedly constricted visual fields. Imaging revealed an enlarged pituitary gland. Hormonal panel was normal. Following endoscopic endonasal transsphenoidal biopsy and decompression of the optic apparatus, an immediate improvement in vision was noted. Final histopathological examination revealed pituitary hyperplasia. Conclusion: In patients with pituitary hyperplasia, visual deficit, and no identifiable reversible causes, surgical decompression can be considered to preserve vision.

Amniotic Membrane Patching to Assist Closure of Recalcitrant Macular Holes.

BACKGROUND AND OBJECTIVE: This study reports a case series of patients with persistent macular holes (MHs) who underwent human amniotic membrane subretinal placement to achieve successful anatomic MH closure. PATIENTS AND METHODS: This was a retrospective case series of patients with persistently open full-thickness MHs who underwent human amniotic membrane placement. Patients were observed up to 6 months postoperatively. RESULTS: Ten patients were included. The mean preoperative best-corrected visual acuity was 1.6 logMAR (20/800). Postoperatively, mean best-corrected visual acuity improved to 1.3 logMAR (20/400) at 1 month and 1.1 logMAR (20/250) by the 3- and 6-month visits. In all cases, the MH appeared closed at the 1-week visit and remained closed at their last follow-up. Optical coherence tomography showed closure in all cases. No adverse events were reported. CONCLUSIONS: Human amniotic membrane sub-retinal placement may serve as a useful surgical technique to assist in the closure of recalcitrant macular holes. [Ophthalmic Surg Lasers Imaging Retina 2023;54:218-222.].

Case report: BRAF-inhibitor therapy in BRAF-mutated primary CNS tumours including one case of BRAF-mutated Rosai-Dorfman disease.

BRAF V600E oncogene mutations have been reported in multiple central nervous system (CNS) tumor types, and emerging evidence supports the use of targeted therapy in BRAF-mutated gliomas. BRAF oncogene mutations have been recently identified in Rosai-Dorfman disease (RDD)-a rare non-Langerhans cell histiocytosis. This series describes three patients from two neurosurgical centers in Ireland with BRAF V600E-mutated CNS tumors. The study participants include a 19-year-old male patient with ganglioglioma with anaplastic features, a 21-year-old male patient with CNS involvement of RDD, and a 28-year-old female patient with ganglioglioma with anaplastic features. Two patients received radiation with concurrent temozolomide before BRAF-targeted therapy. This case series describes clinical and radiological responses to BRAF-targeted therapy in BRAF V600E-mutated gliomas across multiple tumor grades and is only the second published report of response to targeted therapy in BRAF-mutated RDD. The durability of disease control with BRAF-targeted therapy was generally superior to that achieved with chemoradiation; one patient has experienced ongoing disease control for 5 years. The reported case of treatment response in BRAF-mutated RDD supports the strategy of genotyping and utilization of targeted therapy in this rare disease. The optimal sequencing of BRAF-targeted therapy in BRAF-mutated gliomas/glioneuronal tumors remains unclear, and further prospective studies are required to guide the use of genome-matched therapy in this patient population.