Reinforcement learning of biomimetic navigation: a model problem for sperm chemotaxis.

Motile biological cells can respond to local environmental cues and exhibit various navigation strategies to search for specific targets. These navigation strategies usually involve tuning of key biophysical parameters of the cells, such that the cells can modulate their trajectories to move in response to the detected signals. Here we introduce a reinforcement learning approach to modulate key biophysical parameters and realize navigation strategies reminiscent to those developed by biological cells. We present this approach using sperm chemotaxis toward an egg as a paradigm. By modulating the trajectory curvature of a sperm cell model, the navigation strategies informed by reinforcement learning are capable to resemble sperm chemotaxis observed in experiments. This approach provides an alternative method to capture biologically relevant navigation strategies, which may inform the necessary parameter modulations required for obtaining specific navigation strategies and guide the design of biomimetic micro-robotics.

Ocular adnexal intramuscular hemangioma arising from the eyelid: case report and literature review.

Intramuscular hemangioma (IMH) is rare in the ocular adnexa and is uncommonly found in infants. We describe a 1-month-old female infant with an unremarkable birth history presented with subacute onset of right upper eyelid swelling. Clinical examination revealed a purplish subcutaneous mass over the right upper eyelid causing mechanical ptosis. MRI revealed a well-defined subcutaneous mass, which was hyperintense on the T1 weighted images and showed intense enhancement after administration of intravenous gadolinium. Our working diagnosis was infantile capillary hemangioma, and the patient received two intralesional steroid injections without diminishing the lesion size. The lesion had become static in size and the subsequent MRI 14 years later revealed the same lesion had become hyperintense on the T1 weighted image. An excisional biopsy revealed mixed type IMH. IMH should be considered among young patients with upper eyelid swelling, particularly in those who show a poor response to steroid treatment.

Single or double? A comparison of evisceration techniques.

PURPOSE: We compared the rates of implant exposure and extrusion after evisceration with single and double scleral closure techniques. METHODS: This retrospective cohort study included all patients who underwent evisceration with an implant insertion over the past 18 years at Tung Wah Eastern Hospital and Pamela Youde Nethersole Eastern Hospital. Clinical documents and operation records were reviewed. RESULTS: A total of 81 ethnic Chinese patients (44 male) who underwent evisceration with primary implant insertion were reviewed. 39 (48%) patients underwent the double scleral closure technique with an implant placed posterior to the posterior sclera, and 42 (52%) patients underwent the single scleral closure technique with an implant inserted in the intra-scleral cavity. The follow-up interval was 70 months. The surgical indications were endophthalmitis (35%), painful blind eye (23%), traumatic disfigured globe (22%) and phthisis bulbi (20%). Silicone was the most used implant material (69%). The patients who underwent double scleral closure had a larger size of the implant (19.7 vs 17.9 mm, p < 0.05). Both implant exposure (26% vs 3%, p < 0.05) and implant extrusion (26% vs 0%, p < 0.05) were more common in patients who underwent single scleral. CONCLUSIONS: Double scleral closure technique allows a larger implant, and it is associated with a lower rate of implant exposure and extrusion. The double scleral closure technique is a superior technique of choice in these patients with primary implant placement.

A Review of Tolerance and Safety Profiles of Long-Term Botulinum Neurotoxin Type A in Asian Patients with Hemifacial Spasm and Benign Essential Blepharospasm.

This article reports the tolerance and long-term safety profiles of botulinum neurotoxin type A among Asian patients with benign essential blepharospasm (BEB) and hemifacial spasm (HFS). We performed a retrospective review of clinical documents and procedure records of consecutive BEB and HFS patients receiving onabotulinum toxin A (Botox) treatment in our clinic over the past 20 years. We reviewed the information of 105 patients diagnosed with BEB (n = 31) and HFS (n = 74). All of the patients were Asian. The mean age of disease onset was 59 (range 37-80) years old for BEB and 61 (range 31-83) for HFS. The mean follow up was 84 (range 12-240) months and the mean number of sessions per patient was 19 (range 1-61). The botulinum toxin dose per session increased significantly in both BEB (16.5 versus 21.6 units, p < .05) and HFS (22.6 versus 26.9 units, p < .05) patients after a mean of 18 sessions; however, the onset time, effective duration and subjective treatment outcome were similar over time in both BEB and HFS patients. At least one local complication was reported among 26% and 41% of patients with BEB and HFS respectively, with ptosis (32%) being most frequent.

Activity-induced instability of phonons in 1D microfluidic crystals.

One-dimensional crystals of passively-driven particles in microfluidic channels exhibit collective vibrational modes reminiscent of acoustic 'phonons'. These phonons are induced by the long-range hydrodynamic interactions among the particles and are neutrally stable at the linear level. Here, we analyze the effect of particle activity - self-propulsion - on the emergence and stability of these phonons. We show that the direction of wave propagation in active crystals is sensitive to the intensity of the background flow. We also show that activity couples, at the linear level, transverse waves to the particles' rotational motion, inducing a new mode of instability that persists in the limit of large background flow, or, equivalently, vanishingly small activity. We then report a new phenomenon of phonons switching back and forth between two adjacent crystals in both passively-driven and active systems, similar in nature to the wave switching observed in quantum mechanics, optical communication, and density stratified fluids. These findings could have implications for the design of commercial microfluidic systems and the self-assembly of passive and active micro-particles into one-dimensional structures.

Discovery of a novel coronavirus, China Rattus coronavirus HKU24, from Norway rats supports the murine origin of Betacoronavirus 1 and has implications for the ancestor of Betacoronavirus lineage A.

UNLABELLED: We discovered a novel Betacoronavirus lineage A coronavirus, China Rattus coronavirus (ChRCoV) HKU24, from Norway rats in China. ChRCoV HKU24 occupied a deep branch at the root of members of Betacoronavirus 1, being distinct from murine coronavirus and human coronavirus HKU1. Its unique putative cleavage sites between nonstructural proteins 1 and 2 and in the spike (S) protein and low sequence identities to other lineage A betacoronaviruses (ßCoVs) in conserved replicase domains support ChRCoV HKU24 as a separate species. ChRCoV HKU24 possessed genome features that resemble those of both Betacoronavirus 1 and murine coronavirus, being closer to Betacoronavirus 1 in most predicted proteins but closer to murine coronavirus by G+C content, the presence of a single nonstructural protein (NS4), and an absent transcription regulatory sequence for the envelope (E) protein. Its N-terminal domain (NTD) demonstrated higher sequence identity to the bovine coronavirus (BCoV) NTD than to the mouse hepatitis virus (MHV) NTD, with 3 of 4 critical sugar-binding residues in BCoV and 2 of 14 contact residues at the MHV NTD/murine CEACAM1a interface being conserved. Molecular clock analysis dated the time of the most recent common ancestor of ChRCoV HKU24, Betacoronavirus 1, and rabbit coronavirus HKU14 to about the year 1400. Cross-reactivities between other lineage A and B ßCoVs and ChRCoV HKU24 nucleocapsid but not spike polypeptide were demonstrated. Using the spike polypeptide-based Western blot assay, we showed that only Norway rats and two oriental house rats from Guangzhou, China, were infected by ChRCoV HKU24. Other rats, including Norway rats from Hong Kong, possessed antibodies only against N protein and not against the spike polypeptide, suggesting infection by ßCoVs different from ChRCoV HKU24. ChRCoV HKU24 may represent the murine origin of Betacoronavirus 1, and rodents are likely an important reservoir for ancestors of lineage A ßCoVs. IMPORTANCE: While bats and birds are hosts for ancestors of most coronaviruses (CoVs), lineage A ßCoVs have never been found in these animals and the origin of Betacoronavirus lineage A remains obscure. We discovered a novel lineage A ßCoV, China Rattus coronavirus HKU24 (ChRCoV HKU24), from Norway rats in China with a high seroprevalence. The unique genome features and phylogenetic analysis supported the suggestion that ChRCoV HKU24 represents a novel CoV species, occupying a deep branch at the root of members of Betacoronavirus 1 and being distinct from murine coronavirus. Nevertheless, ChRCoV HKU24 possessed genome characteristics that resemble those of both Betacoronavirus 1 and murine coronavirus. Our data suggest that ChRCoV HKU24 represents the murine origin of Betacoronavirus 1, with interspecies transmission from rodents to other mammals having occurred centuries ago, before the emergence of human coronavirus (HCoV) OC43 in the late 1800s. Rodents are likely an important reservoir for ancestors of lineage A ßCoVs.

Density Shock Waves in Confined Microswimmers.

Motile and driven particles confined in microfluidic channels exhibit interesting emergent behavior, from propagating density bands to density shock waves. A deeper understanding of the physical mechanisms responsible for these emergent structures is relevant to a number of physical and biomedical applications. Here, we study the formation of density shock waves in the context of an idealized model of microswimmers confined in a narrow channel and subject to a uniform external flow. Interestingly, these density shock waves exhibit a transition from "subsonic" with compression at the back to "supersonic" with compression at the front of the population as the intensity of the external flow increases. This behavior is the result of a nontrivial interplay between hydrodynamic interactions and geometric confinement, and it is confirmed by a novel quasilinear wave model that properly captures the dependence of the shock formation on the external flow. These findings can be used to guide the development of novel mechanisms for controlling the emergent density distribution and the average population speed, with potentially profound implications on various processes in industry and biotechnology, such as the transport and sorting of cells in flow channels.

Isolation and Characterization of Dromedary Camel Coronavirus UAE-HKU23 from Dromedaries of the Middle East: Minimal Serological Cross-Reactivity between MERS Coronavirus and Dromedary Camel Coronavirus UAE-HKU23.

Recently, we reported the discovery of a dromedary camel coronavirus UAE-HKU23 (DcCoV UAE-HKU23) from dromedaries in the Middle East. In this study, DcCoV UAE-HKU23 was successfully isolated in two of the 14 dromedary fecal samples using HRT-18G cells, with cytopathic effects observed five days after inoculation. Northern blot analysis revealed at least seven distinct RNA species, corresponding to predicted subgenomic mRNAs and confirming the core sequence of transcription regulatory sequence motifs as 5'-UCUAAAC-3' as we predicted previously. Antibodies against DcCoV UAE-HKU23 were detected in 58 (98.3%) and 59 (100%) of the 59 dromedary sera by immunofluorescence and neutralization antibody tests, respectively. There was significant correlation between the antibody titers determined by immunofluorescence and neutralization assays (Pearson coefficient = 0.525, p < 0.0001). Immunization of mice using recombinant N proteins of DcCoV UAE-HKU23 and Middle East respiratory syndrome coronavirus (MERS-CoV), respectively, and heat-inactivated DcCoV UAE-HKU23 showed minimal cross-antigenicity between DcCoV UAE-HKU23 and MERS-CoV by Western blot and neutralization antibody assays. Codon usage and genetic distance analysis of RdRp, S and N genes showed that the 14 strains of DcCoV UAE-HKU23 formed a distinct cluster, separated from those of other closely related members of Betacoronavirus 1, including alpaca CoV, confirming that DcCoV UAE-HKU23 is a novel member of Betacoronavirus 1.

Acute middle East respiratory syndrome coronavirus infection in livestock Dromedaries, Dubai, 2014.

Camels carry Middle East respiratory syndrome coronavirus, but little is known about infection age or prevalence. We studied >800 dromedaries of all ages and 15 mother-calf pairs. This syndrome constitutes an acute, epidemic, and time-limited infection in camels <4 years of age, particularly calves. Delayed social separation of calves might reduce human infection risk.

A novel astrovirus from dromedaries in the Middle East.

The recent emergence of Middle East respiratory syndrome coronavirus from the Middle East and its discovery from dromedary camels has boosted interest in the search for novel viruses in dromedaries. The existence of astroviruses (AstVs) in dromedaries was previously unknown. We describe the discovery of a novel dromedary camel AstV (DcAstV) from dromedaries in Dubai. Among 215 dromedaries, DcAstV was detected in faecal samples of four [three (1.5 %) adult dromedaries and one (8.3 %) dromedary calf] by reverse transcription-PCR. Sequencing of the four DcAstV genomes and phylogenetic analysis showed that the DcAstVs formed a distinct cluster. Although DcAstV was most closely related to a recently characterized porcine AstV 2, their capsid proteins only shared 60-66 % amino acid identity, with a mean amino acid genetic distance of 0.372. Notably, the N-terminal halves of the capsid proteins of DcAstV shared ≤ 85 % amino acid identity, but the C-terminal halves only shared ≤ 49 % amino acid identity compared with the corresponding proteins in other AstVs. A high variation of the genome sequences of DcAstV was also observed, with a mean amino acid genetic distance of 0.214 for ORF2 of the four strains. Recombination analysis revealed a possible recombination event in ORF2 of strain DcAstV-274. The low Ka/Ks ratios (number of non-synonymous substitutions per non-synonymous site to number of synonymous substitutions per synonymous site) of the four ORFs in the DcAstV genomes supported the suggestion that dromedaries are the natural reservoir where AstV is stably evolving. These results suggest that AstV is a novel species of the genus Mamastrovirus in the family Astroviridae. Further studies are important to understand the pathogenic potential of DcAstV.

Development and Evaluation of Novel Real-Time Reverse Transcription-PCR Assays with Locked Nucleic Acid Probes Targeting Leader Sequences of Human-Pathogenic Coronaviruses.

Based on findings in small RNA-sequencing (Seq) data analysis, we developed highly sensitive and specific real-time reverse transcription (RT)-PCR assays with locked nucleic acid probes targeting the abundantly expressed leader sequences of Middle East respiratory syndrome coronavirus (MERS-CoV) and other human coronaviruses. Analytical and clinical evaluations showed their noninferiority to a commercial multiplex PCR test for the detection of these coronaviruses.

Discovery of a novel bottlenose dolphin coronavirus reveals a distinct species of marine mammal coronavirus in Gammacoronavirus.

While gammacoronaviruses mainly comprise infectious bronchitis virus (IBV) and its closely related bird coronaviruses (CoVs), the only mammalian gammacoronavirus was discovered from a white beluga whale (beluga whale CoV [BWCoV] SW1) in 2008. In this study, we discovered a novel gammacoronavirus from fecal samples from three Indo-Pacific bottlenose dolphins (Tursiops aduncus), which we named bottlenose dolphin CoV (BdCoV) HKU22. All the three BdCoV HKU22-positive samples were collected on the same date, suggesting a cluster of infection, with viral loads of 1 × 10(3) to 1 × 10(5) copies per ml. Clearance of virus was associated with a specific antibody response against the nucleocapsid of BdCoV HKU22. Complete genome sequencing and comparative genome analysis showed that BdCoV HKU22 and BWCoV SW1 have similar genome characteristics and structures. Their genome size is about 32,000 nucleotides, the largest among all CoVs, as a result of multiple unique open reading frames (NS5a, NS5b, NS5c, NS6, NS7, NS8, NS9, and NS10) between their membrane (M) and nucleocapsid (N) protein genes. Although comparative genome analysis showed that BdCoV HKU22 and BWCoV SW1 should belong to the same species, a major difference was observed in the proteins encoded by their spike (S) genes, which showed only 74.3 to 74.7% amino acid identities. The high ratios of the number of synonymous substitutions per synonymous site (Ks) to the number of nonsynonymous substitutions per nonsynonymous site (Ka) in multiple regions of the genome, especially the S gene (Ka/Ks ratio, 2.5), indicated that BdCoV HKU22 may be evolving rapidly, supporting a recent transmission event to the bottlenose dolphins. We propose a distinct species, Cetacean coronavirus, in Gammacoronavirus, to include BdCoV HKU22 and BWCoV SW1, whereas IBV and its closely related bird CoVs represent another species, Avian coronavirus, in Gammacoronavirus.

Recombinant influenza A virus hemagglutinin HA2 subunit protects mice against influenza A(H7N9) virus infection.

A novel avian influenza A(H7N9) virus has emerged to infect humans in eastern China since 2013. An effective vaccine is needed because of the high mortality despite antiviral treatment and intensive care. We sought to develop an effective vaccine for A(H7N9) virus. The HA2 subunit was chosen as the vaccine antigen because it is highly conserved among the human A(H7N9) virus strains. Moreover, in silico analysis predicted two immunogenic regions within the HA2 subunit that may contain potential human B-cell epitopes. The HA2 fragment was readily expressed in Escherichia coli. In BALB/c mice, intraperitoneal immunization with two doses of HA2 with imiquimod (2-dose-imiquimod) elicited the highest geometric mean titer (GMT) of anti-HA2 IgG (12699), which was greater than that of two doses of HA2 without imiquimod (2-dose-no-adjuvant) (6350), one dose of HA2 with imiquimod (1-dose-imiquimod) (2000) and one dose of HA2 without imiquimod (1-dose-no-adjuvant) (794). The titer of anti-HA2 IgG was significantly higher in the 1-dose-imiquimod group than the 1-dose-no-adjuvant group. Although both hemagglutination inhibition titers and microneutralization titers were below 10, serum from immunized mice showed neutralizing activity in a fluorescent focus microneutralization assay. In a viral challenge experiment, the 2-dose-imiquimod group had the best survival rate (100 %), followed by the 2-dose-no-adjuvant group (90 %), the 1-dose-imiquimod group (70 %) and the 1-dose-no-adjuvant group (40 %). The 2-dose-imiquimod group also had significantly lower mean pulmonary viral loads than the 1-dose-imiquimod, 1-dose-no-adjuvant and non-immunized groups. This recombinant A(H7N9)-HA2 vaccine should be investigated as a complement to egg- or cell-based live attenuated or subunit influenza vaccines.

Metabolomics Analysis Reveals Specific Novel Tetrapeptide and Potential Anti-Inflammatory Metabolites in Pathogenic Aspergillus species.

Infections related to Aspergillus species have emerged to become an important focus in infectious diseases, as a result of the increasing use of immunosuppressive agents and high fatality associated with invasive aspergillosis. However, laboratory diagnosis of Aspergillus infections remains difficult. In this study, by comparing the metabolomic profiles of the culture supernatants of 30 strains of six pathogenic Aspergillus species (A. fumigatus, A. flavus, A. niger, A. terreus, A. nomius and A. tamarii) and 31 strains of 10 non-Aspergillus fungi, eight compounds present in all strains of the six Aspergillus species but not in any strain of the non-Aspergillus fungi were observed. One of the eight compounds, Leu-Glu-Leu-Glu, is a novel tetrapeptide and represents the first linear tetrapeptide observed in Aspergillus species, which we propose to be named aspergitide. Two other closely related Aspergillus-specific compounds, hydroxy-(sulfooxy)benzoic acid and (sulfooxy)benzoic acid, may possess anti-inflammatory properties, as 2-(sulfooxy)benzoic acid possesses a structure similar to those of aspirin [2-(acetoxy)benzoic acid] and salicylic acid (2-hydroxybenzoic acid). Further studies to examine the potentials of these Aspergillus-specific compounds for laboratory diagnosis of aspergillosis are warranted and further experiments will reveal whether Leu-Glu-Leu-Glu, hydroxy-(sulfooxy)benzoic acid and (sulfooxy)benzoic acid are virulent factors of the pathogenic Aspergillus species.

New hepatitis E virus genotype in camels, the Middle East.

In a molecular epidemiology study of hepatitis E virus (HEV) in dromedaries in Dubai, United Arab Emirates, HEV was detected in fecal samples from 3 camels. Complete genome sequencing of 2 strains showed >20% overall nucleotide difference to known HEVs. Comparative genomic and phylogenetic analyses revealed a previously unrecognized HEV genotype.

Novel betacoronavirus in dromedaries of the Middle East, 2013.

In 2013, a novel betacoronavirus was identified in fecal samples from dromedaries in Dubai, United Arab Emirates. Antibodies against the recombinant nucleocapsid protein of the virus, which we named dromedary camel coronavirus (DcCoV) UAE-HKU23, were detected in 52% of 59 dromedary serum samples tested. In an analysis of 3 complete DcCoV UAE-HKU23 genomes, we identified the virus as a betacoronavirus in lineage A1. The DcCoV UAE-HKU23 genome has G+C contents; a general preference for G/C in the third position of codons; a cleavage site for spike protein; and a membrane protein of similar length to that of other betacoronavirus A1 members, to which DcCoV UAE-HKU23 is phylogenetically closely related. Along with this coronavirus, viruses of at least 8 other families have been found to infect camels. Because camels have a close association with humans, continuous surveillance should be conducted to understand the potential for virus emergence in camels and for virus transmission to humans.

Genetic characterization of Betacoronavirus lineage C viruses in bats reveals marked sequence divergence in the spike protein of pipistrellus bat coronavirus HKU5 in Japanese pipistrelle: implications for the origin of the novel Middle East respiratory syndrome coronavirus.

While the novel Middle East respiratory syndrome coronavirus (MERS-CoV) is closely related to Tylonycteris bat CoV HKU4 (Ty-BatCoV HKU4) and Pipistrellus bat CoV HKU5 (Pi-BatCoV HKU5) in bats from Hong Kong, and other potential lineage C betacoronaviruses in bats from Africa, Europe, and America, its animal origin remains obscure. To better understand the role of bats in its origin, we examined the molecular epidemiology and evolution of lineage C betacoronaviruses among bats. Ty-BatCoV HKU4 and Pi-BatCoV HKU5 were detected in 29% and 25% of alimentary samples from lesser bamboo bat (Tylonycteris pachypus) and Japanese pipistrelle (Pipistrellus abramus), respectively. Sequencing of their RNA polymerase (RdRp), spike (S), and nucleocapsid (N) genes revealed that MERS-CoV is more closely related to Pi-BatCoV HKU5 in RdRp (92.1% to 92.3% amino acid [aa] identity) but is more closely related to Ty-BatCoV HKU4 in S (66.8% to 67.4% aa identity) and N (71.9% to 72.3% aa identity). Although both viruses were under purifying selection, the S of Pi-BatCoV HKU5 displayed marked sequence polymorphisms and more positively selected sites than that of Ty-BatCoV HKU4, suggesting that Pi-BatCoV HKU5 may generate variants to occupy new ecological niches along with its host in diverse habitats. Molecular clock analysis showed that they diverged from a common ancestor with MERS-CoV at least several centuries ago. Although MERS-CoV may have diverged from potential lineage C betacoronaviruses in European bats more recently, these bat viruses were unlikely to be the direct ancestor of MERS-CoV. Intensive surveillance for lineage C betaCoVs in Pipistrellus and related bats with diverse habitats and other animals in the Middle East may fill the evolutionary gap.

Reconfigurability-Encoded Hierarchical Rectifiers for Versatile 3D Liquid Manipulation.

Manipulating small-volume liquids is crucial in natural processes and industrial applications. However, most liquid manipulation technologies involve complex energy inputs or non-adjustable wetting gradient surfaces. Here, a simple and adjustable 3D liquid manipulation paradigm is reported to control liquid behaviors by coupling liquid-air-solid interfacial energy with programmable magnetic fields. This paradigm centers around a hierarchical rectifier with magnetized microratchets, using Laplace pressure asymmetry to enable multimodal directional steering of various surface tension liquids (23-72 mN m-1). The scale-dependent effect in microratchet design shows its superiority in handling small-volume liquids across three orders of magnitude (100-103 µL). Under programmed magnetic fields, the rectifier can reconfigure its morphology to harness interfacial energy to exhibit richer liquid behaviors without dynamic real-time control. Reconfigured rectifiers show improved rectification performance in the inertia-dominant fluid regime, i.e., a remarkable 2000-fold increase in the critical Weber number for pure ethanol. Moreover, the rectifier's switchable reconfigurations offer flexible control over liquid transport directions and spatiotemporally controllable 3D liquid manipulation reminiscent of inchworm motions. This scalable liquid manipulation paradigm promotes versatile engineering and biochemistry applications, e.g., portable liquid purity testing (screening resolution <1 mN m-1), logical open-channel microfluidics, and automated chemical reaction platforms.