Mapping the Genetic Landscape of Human Cells.

Seminal yeast studies have established the value of comprehensively mapping genetic interactions (GIs) for inferring gene function. Efforts in human cells using focused gene sets underscore the utility of this approach, but the feasibility of generating large-scale, diverse human GI maps remains unresolved. We developed a CRISPR interference platform for large-scale quantitative mapping of human GIs. We systematically perturbed 222,784 gene pairs in two cancer cell lines. The resultant maps cluster functionally related genes, assigning function to poorly characterized genes, including TMEM261, a new electron transport chain component. Individual GIs pinpoint unexpected relationships between pathways, exemplified by a specific cholesterol biosynthesis intermediate whose accumulation induces deoxynucleotide depletion, causing replicative DNA damage and a synthetic-lethal interaction with the ATR/9-1-1 DNA repair pathway. Our map provides a broad resource, establishes GI maps as a high-resolution tool for dissecting gene function, and serves as a blueprint for mapping the genetic landscape of human cells.

Dirac mass induced by optical gain and loss.

Mass is commonly considered an intrinsic property of matter, but modern physics reveals particle masses to have complex origins1, such as the Higgs mechanism in high-energy physics2,3. In crystal lattices such as graphene, relativistic Dirac particles can exist as low-energy quasiparticles4 with masses imparted by lattice symmetry-breaking perturbations5-8. These mass-generating mechanisms all assume Hermiticity, or the conservation of energy in detail. Using a photonic synthetic lattice, we show experimentally that Dirac masses can be generated by means of non-Hermitian perturbations based on optical gain and loss. We then explore how the spacetime engineering of the gain and loss-induced Dirac mass affects the quasiparticles. As we show, the quasiparticles undergo Klein tunnelling at spatial boundaries, but a local breaking of a non-Hermitian symmetry can produce a new flux non-conservation effect at the domain walls. At a temporal boundary that abruptly flips the sign of the Dirac mass, we observe a variant of the time-reflection phenomenon: in the non-relativistic limit, the Dirac quasiparticle reverses its velocity, whereas in the relativistic limit, the original velocity is retained.

Brain charts for the human lifespan.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined genome-wide association studies of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD. APPROACH AND RESULTS: We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1 , TNKS , LYPLAL1 , and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD. CONCLUSIONS: Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.

Genome-Wide Genetic Associations Prioritize Evaluation of Causal Mechanisms of Atherosclerotic Disease Risk.

OBJECTIVE: The goal of this review is to discuss the implementation of genome-wide association studies to identify causal mechanisms of vascular disease risk. APPROACH AND RESULTS: The history of genome-wide association studies is described, the use of imputation and the creation of consortia to conduct meta-analyses with sufficient power to arrive at consistent associated loci for vascular disease. Genomic methods are described that allow the identification of causal variants and causal genes and how they impact the disease process. The power of single-cell analyses to promote genome-wide association studies of causal gene function is described. CONCLUSIONS: Genome-wide association studies represent a paradigm shift in the study of cardiovascular disease, providing identification of genes, cellular phenotypes, and disease pathways that empower the future of targeted drug development.

An integrated approach to identify environmental modulators of genetic risk factors for complex traits.

Complex traits and diseases can be influenced by both genetics and environment. However, given the large number of environmental stimuli and power challenges for gene-by-environment testing, it remains a critical challenge to identify and prioritize specific disease-relevant environmental exposures. We propose a framework for leveraging signals from transcriptional responses to environmental perturbations to identify disease-relevant perturbations that can modulate genetic risk for complex traits and inform the functions of genetic variants associated with complex traits. We perturbed human skeletal-muscle-, fat-, and liver-relevant cell lines with 21 perturbations affecting insulin resistance, glucose homeostasis, and metabolic regulation in humans and identified thousands of environmentally responsive genes. By combining these data with GWASs from 31 distinct polygenic traits, we show that the heritability of multiple traits is enriched in regions surrounding genes responsive to specific perturbations and, further, that environmentally responsive genes are enriched for associations with specific diseases and phenotypes from the GWAS Catalog. Overall, we demonstrate the advantages of large-scale characterization of transcriptional changes in diversely stimulated and pathologically relevant cells to identify disease-relevant perturbations.

A single-cell CRISPRi platform for characterizing candidate genes relevant to metabolic disorders in human adipocytes.

CROP-Seq combines gene silencing using CRISPR interference with single-cell RNA sequencing. Here, we applied CROP-Seq to study adipogenesis and adipocyte biology. Human preadipocyte SGBS cell line expressing KRAB-dCas9 was transduced with a sgRNA library. Following selection, individual cells were captured using microfluidics at different timepoints during adipogenesis. Bioinformatic analysis of transcriptomic data was used to determine the knockdown effects, the dysregulated pathways, and to predict cellular phenotypes. Single-cell transcriptomes recapitulated adipogenesis states. For all targets, over 400 differentially expressed genes were identified at least at one timepoint. As a validation of our approach, the knockdown of PPARG and CEBPB (which encode key proadipogenic transcription factors) resulted in the inhibition of adipogenesis. Gene set enrichment analysis generated hypotheses regarding the molecular function of novel genes. MAFF knockdown led to downregulation of transcriptional response to proinflammatory cytokine TNF-α in preadipocytes and to decreased CXCL-16 and IL-6 secretion. TIPARP knockdown resulted in increased expression of adipogenesis markers. In summary, this powerful, hypothesis-free tool can identify novel regulators of adipogenesis, preadipocyte, and adipocyte function associated with metabolic disease.NEW & NOTEWORTHY Genomics efforts led to the identification of many genomic loci that are associated with metabolic traits, many of which are tied to adipose tissue function. However, determination of the causal genes, and their mechanism of action in metabolism, is a time-consuming process. Here, we use an approach to determine the transcriptional outcome of candidate gene knockdown for multiple genes at the same time in a human cell model of adipogenesis.

Continuum of Bound States in a Non-Hermitian Model.

In a Hermitian system, bound states must have quantized energies, whereas free states can form a continuum. We demonstrate how this principle fails for non-Hermitian systems, by analyzing non-Hermitian continuous Hamiltonians with an imaginary momentum and Landau-type vector potential. The eigenstates, which we call "continuum Landau modes" (CLMs), have Gaussian spatial envelopes and form a continuum filling the complex energy plane. We present experimentally realizable 1D and 2D lattice models that host CLMs; the lattice eigenstates are localized and have other features matching the continuous model. One of these lattices can serve as a rainbow trap, whereby the response to an excitation is concentrated at a position proportional to the frequency. Another lattice can act a wave funnel, concentrating an input excitation onto a boundary over a wide frequency bandwidth. Unlike recent funneling schemes based on the non-Hermitian skin effect, this requires a simple lattice design with reciprocal couplings.

Anomalous Single-Mode Lasing Induced by Nonlinearity and the Non-Hermitian Skin Effect.

Single-mode operation is a desirable but elusive property for lasers operating at high pump powers. Typically, single-mode lasing is attainable close to threshold, but increasing the pump power gives rise to multiple lasing peaks due to inter-modal gain competition. We propose a laser with the opposite behavior: multimode lasing occurs at low output powers, but pumping beyond a certain value produces a single lasing mode, with all other candidate modes experiencing negative effective gain. This phenomenon arises in a lattice of coupled optical resonators with non-fine-tuned asymmetric couplings, and is caused by an interaction between nonlinear gain saturation and the non-Hermitian skin effect. The single-mode lasing is observed in both frequency domain and time domain simulations. It is robust against on-site disorder, and scales up to large lattice sizes. This finding might be useful for implementing high-power laser arrays.

[The ineffective or short-term recurrence of trigeminal neuralgia after microballoon compression:different causes and management strategies].

Objectives: To explore the causes of ineffective or short-term recurrence (within 3 months)of trigeminal neuralgia treated by percutaneous microballoon compression(PBC), and to examine the reoperative strategies and clincal outcomes of modified PBC. Methods: The clinical data of 21 patients with ineffective or short-term recurrence after PBC treatment (5.7% of 369 patient received PBC) admitted to the Department of Neurosurgery,Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University from June 2018 to June 2020 were retrospectively analyzed.There were 8 males and 13 females, mean aged 66.6 years (range:51 to 79 years).Among them,2 patients was ineffective after PBC and 19 patients relapsed within 3 months.The distribution of pain was along V2 branches in 2 cases,V3 branches in 3 cases,V1+V2 branches in 1 case,and V2+V3 branches in 15 cases.The mean time of recurrence was 46.8 days (range:23 to 76 days) among the 19 patients with short-term recurrence.The patients were divided into 4 types based on the causes of postoperative ineffectiveness or short-term recurrence.TypeⅠ:extracapsular false pear (1 case);Type Ⅱ:invalid true pear(2 cases);Type Ⅲ:capsular rupture (6 cases);Type Ⅳ:compression blind area (12 cases).The individualized modified PBC operation plans were used according to the types of the patients and the clinical effect and complications of the patients were observed. Results: The pain symptoms of the patients disappeared after the second operation with immediate effective rate of 100%. All patients had mild facial numbness after surgery.Five patients(23.8%,5/21) had masseter muscle weakness, 3 (14.3%,3/21) had peristomatous herpes, 1(4.8%, 1/21) had diplopia.No bleeding or other complications occurred.All patients were followed up for at least 12 months (range:13 to 28 months). One patient (4.8%,1/21) (compression blind area type) had pain recurrence 9 months after surgery, and cured by receiving the original modified PBC surgery again with no recurrence after another 13 months' follow-up. None of the other patients relapsed during the follow-up period.Up to the last follow-up,19 cases(90.5%,19/21) were cured,and 2 cases (9.5%,2/21) were relieved. Conclusions: The main reason for ineffective or short-term recurrence of PBC in trigeminal neuralgia patients is the ineffectively compressed of trigeminal ganglion.According to the different types of patients,the use of individualized modified surgical scheme can improve the efficacy of PBC surgery.

Giant Enhancement of Unconventional Photon Blockade in a Dimer Chain.

Unconventional photon blockade refers to the suppression of multiphoton states in weakly nonlinear optical resonators via the destructive interference of different excitation pathways. It has been studied in a pair of coupled nonlinear resonators and other few-mode systems. Here, we show that unconventional photon blockade can be greatly enhanced in a chain of coupled resonators. The strength of the nonlinearity in each resonator needed to achieve unconventional photon blockade is suppressed exponentially with lattice size. The analytic derivation, based on a weak drive approximation, is validated by wave function Monte Carlo simulations. These findings show that customized lattices of coupled resonators can be powerful tools for controlling multiphoton quantum states.

Observation of Dislocation-Induced Topological Modes in a Three-Dimensional Acoustic Topological Insulator.

The interplay between real-space topological lattice defects and the reciprocal-space topology of energy bands can give rise to novel phenomena, such as one-dimensional topological modes bound to screw dislocations in three-dimensional topological insulators. We obtain direct experimental observations of dislocation-induced helical modes in an acoustic analog of a weak three-dimensional topological insulator. The spatial distribution of the helical modes is found through spin-resolved field mapping, and verified numerically by tight-binding and finite-element calculations. These one-dimensional helical channels can serve as robust waveguides in three-dimensional media. Our experiment paves the way to studying novel physical modes and functionalities enabled by topological lattice defects in three-dimensional classical topological materials.

Interocular optical biometry differences as predictors of postoperative cataract surgery refractive outcomes: A retrospective cohort study.

INTRODUCTION: Few studies have reported the impact of preoperative interocular discrepancy in optical biometry (axial length, corneal power, white-to-white, central corneal thickness) on postoperative refractive outcomes. This study aims to investigate any predictive value of preoperative optical biometry differences between eyes on postoperative refractive outcomes. MATERIALS AND METHODS: A retrospective cohort study of patients who have undergone optical biometry measurement before unilateral phacoemulsification in the Queen Elizabeth Hospital, Sabah, Malaysia from 2018 to 2020. Biometry data of interest includes axial length (AL), keratometry(K), white-to-white (WTW) and central corneal thickness (CCT). The postoperative outcomes of interest were the patient's preoperative refractive target, postoperative best-corrected visual acuity (BCVA), postoperative refractive outcomes, and optical biometry prediction error. RESULTS: The interocular biometry discrepancies which were associated with higher odds of prediction error >0.5D from the refractive target were Interocular Corneal Power Difference (IKD)-average≥0.8 D (Odds Ratio, OR=1.97; 95% Confidence Intervals, 95%CI: 1.06, 3.67) and Interocular WTW Difference ≥1.5 mm (OR=2.77; 95%CI: 1.11, 6.92). In cases with prediction error >1.0D, the measurements were Interocular AL Difference ≥0.4 mm (OR=2.99; 95%CI: 1.11, 8.06), IKD flat≥0.4D (OR=2.76; 95%CI: 1.31, 5.82) and Interocular CCT Difference ≥15µm (OR=3.53; 95%CI: 1.29, 9.64). CONCLUSION: Interocular axial length difference ≥0.4mm and interocular central corneal thickness difference ≥15µm are associated with refractive error >1.0D from the pre-operative target. Interocular average corneal power difference ≥0.8D and interocular white-to-white difference ≥1.5mm have higher odds of refractive drift >0.5D from the refractive aim. The above cutoff values help clinicians to identify which patients have a higher risk of refractive shift post-cataract surgery and counsel the patient before cataract operation.

Observation of Protected Photonic Edge States Induced by Real-Space Topological Lattice Defects.

Topological defects (TDs) in crystal lattices are elementary lattice imperfections that cannot be removed by local perturbations, due to their real-space topology. In the emerging field of topological photonics, photonic topological edge states arise from the nontrivial topology of the band structure defined in momentum space and are generally protected against defects. Here we show that adding TDs into a valley photonic crystal generates a lattice disclination that acts like a domain wall and hosts photonic topological edge states. Unlike previous topological waveguides, the disclination forms an open arc and functions as a free-form waveguide connecting a pair of TDs of opposite topological charge. This interplay between the real-space topology of lattice defects and momentum-space band topology provides a novel scheme to implement large-scale photonic structures with complex arrangements of robust topological waveguides and resonators.

Non-Hermitian Dirac Cones.

Non-Hermitian systems containing gain or loss commonly host exceptional point degeneracies, not the diabolic points that, in Hermitian systems, play a key role in topological transitions and related phenomena. Non-Hermitian Hamiltonians with parity-time symmetry can have real spectra but generally nonorthogonal eigenstates, impeding the emergence of diabolic points. We introduce a pair of symmetries that induce not only real eigenvalues but also pairwise eigenstate orthogonality. This allows non-Hermitian systems to host Dirac points and other diabolic points. We construct non-Hermitian models exhibiting three exemplary phenomena previously limited to the Hermitian regime: Haldane-type topological phase transition, Landau levels without magnetic fields, and Weyl points. This establishes a new connection between non-Hermitian physics and the rich phenomenology of diabolic points.

Disease activity and damage in hospitalized lupus patients: a Sabah perspective.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune disease with variable levels of activity that may wax and wane within the same patient over the years. In view of the scarcity of data about lupus in the East Malaysian population, we aimed to study the disease activity and damage index in patients with SLE hospitalized in a tertiary center in Sabah, East Malaysia. METHODS: We retrospectively studied all patients with SLE admitted from 1 January 2013 to 31 December 2015. Demographic data, clinical features, treatment received, SLEDAI and SLICC/ACR (Systemic Lupus International Collaborating Clinics/American College of Rheumatology) criteria and outcomes were collected. RESULTS: There were 108 patients studied whereby 88.9% were females. They had a mean age of 31.4 ± 11.02 years at admission and were multiethnic in origin. The mean number of ACR criteria for SLE was 5.03 ± 1.5 at the time of diagnosis. There were 158 hospitalizations during the 3 years. The main causes of hospitalization were flare of SLE (66.5%), infection (57.6%), renal biopsy (15.5%) and others (11.4%). Active nephritis (65%), cutaneous (44.4%) and hematological involvement (40.2%) were the three commonest manifestations. There was concurrent flare of SLE and infection in 41.1% of the admissions. The mean SLEDAI score at admission was 10.8 ± 7.20, with a mean SLEDAI of 9.3 ± 6.9 in those without damage and 11.9 ± 7.21 in those with damage (p-value = 0.026). The median SLICC score was 1 with a mean of 0.93 ± 1.07. There were nine deaths (5.6%) during the study period and all patients were females. Compared with those who survived, they had a significantly higher SLEDAI score of 15.80 ± 8.2 (p-value = 0.0207) and a SLICC score of 2.70 ± 1.6 (p-value <0.001). CONCLUSION: SLE is more common among the indigenous population of Sabah, the Kadazan-Dusun, which has not been shown before this study. Disease characteristics were, however, similar to reports from the Asia-Pacific region. Acute flare of SLE and infection remained the main causes of admission and readmissions and was present in 44.4% of the mortalities in our cohort.

Mechanistic convergence and shared therapeutic targets in Niemann-Pick disease.

Niemann-Pick disease type C (NPC) and Tangier disease are genetically and clinically distinct rare inborn errors of metabolism. NPC is caused by defects in either NPC1 or NPC2; whereas Tangier disease is caused by a defect in ABCA1. Tangier disease is currently without therapy, whereas NPC can be treated with miglustat, a small molecule inhibitor of glycosphingolipid biosynthesis that slows the neurological course of the disease. When a Tangier disease patient was misdiagnosed with NPC and treated with miglustat, her symptoms improved. This prompted us to consider whether there is mechanistic convergence between these two apparently unrelated rare inherited metabolic diseases. In this study, we found that when ABCA1 is defective (Tangier disease) there is secondary inhibition of the NPC disease pathway, linking these two diseases at the level of cellular pathophysiology. In addition, this study further supports the hypothesis that miglustat, as well as other substrate reduction therapies, may be potential therapeutic agents for treating Tangier disease as fibroblasts from multiple Tangier patients were corrected by miglustat treatment.

Fermi-Arc-Induced Vortex Structure in Weyl Beam Shifts.

In periodic media, despite the close relationship between geometrical effects in the bulk and topological surface states, the two are typically probed separately. We show that when beams in a Weyl medium reflect off an interface with a gapped medium, the trajectory is influenced by both bulk geometrical effects and the Fermi arc surface states. The reflected beam experiences a displacement, analogous to the Goos-Hänchen or Imbert-Fedorov shifts, that forms a half-vortex in the two-dimensional surface momentum space. The half-vortex is centered where the Fermi arc of the reflecting surface touches the Weyl cone, with the magnitude of the shift scaling as an inverse square root away from the touching point, and diverging at the touching point. This striking feature provides a way to use bulk transport to probe the topological characteristics of a Weyl medium.

Photonic Anomalous Quantum Hall Effect.

We experimentally realize a photonic analogue of the anomalous quantum Hall insulator using a two-dimensional (2D) array of coupled ring resonators. Similar to the Haldane model, our 2D array is translation invariant, has a zero net gauge flux threading the lattice, and exploits next-nearest neighbor couplings to achieve a topologically nontrivial band gap. Using direct imaging and on-chip transmission measurements, we show that the band gap hosts topologically robust edge states. We demonstrate a topological phase transition to a conventional insulator by frequency detuning the ring resonators and thereby breaking the inversion symmetry of the lattice. Furthermore, the clockwise or the counterclockwise circulation of photons in the ring resonators constitutes a pseudospin degree of freedom. The two pseudospins acquire opposite hopping phases, and their respective edge states propagate in opposite directions. These results are promising for the development of robust reconfigurable integrated nanophotonic devices for applications in classical and quantum information processing.