The delivery of therapeutic molecules to the brain remains an unsolved problem to the researchers due to the existence of the blood–brain barrier (BBB), which halts the entry of unwanted substances to the brain. Central nervous system (CNS) disorders, mainly Parkinson’s disease, Alzheimer’s disease, schizophrenia, brain tumors, and stroke, are highly prevalent globally and are a growing concern for researchers due to restricting the delivery of pharmaceutical drugs to the brain. So effective treatment modalities are essential to combat the growing epidemic of CNS diseases. Recently, the growing attention in the field of nanotechnology has gained the faith of researchers for the delivery of therapeutics to the brain by targeting them to the specific target site. Polymeric nanoparticles (PNPs) emerge out to be an instrumental approach in drug targeting to the brain by overcoming the physiological barrier, biomedical barrier, and BBB. Preclinical discovery has shown the tremendous potential and versatility of PNPs in encapsulating several drugs and their targeting to the deepest regions of the brain, thus improving therapeutic intervention of CNS disorders. The current review will summarize advances in the development of PNPs for targeting therapeutics to the brain and the functional and molecular effects obtained in the preclinical model of most common CNS diseases. The advancement of PNPs in clinical practice and their prospect in brain targeting will also be discussed briefly. The blood–brain barrier (BBB) works as a dynamic regulator in ion hemostasis and nutrient transport and a deterrent to harmful molecules . It is cAlso, the development of new treatment for CNS disorders represents the largest market that was US$75.3 billion in 2010, $102.0 billion in 2015, and $35,497.3 million in 2018 and expected to grow  million till 2026 according to a recent report by Fortune Business Insights .The emergence of nanotechnology has gained much popularity as the drug delivery vehicle to the brain and brought the diversity of new feasibility in clinical practice and biological discovery. Particularly, nano-scaled carriers in drug delivery have revolutionized, allowing selective and targeted delivery of therapeutic carriers to organ, tissue, and cell-specific levels, also reducing the exposure of drugs to healthy tissues . Polymervia the ligand-receptor mechanism. Ligand-mediated PNPs easily pass the BBB via receptor-mediated endocytosis, thus providing targeted delivery of therapeutics to the parenchyma of the brain. Also, PNPs can rapidly diffuse within the brain parenchyma when they are coated with a dense layer of polyethylene glycol (PEG) also termed as brain-penetrating NPs. PEG is a hydrophilic polymer that effectively reduces the adhesion between the particle and the charged components in the parenchyma of the brain (Surface modification of PNPs with ligands like transferrin (Tf), apolipoprotein E, apolipoprotein B, apolipoprotein A, and antibodies have shown promising results in delivering the therapeutic carriers to the specific receptor-targeted site he brain . It was he brain .Specifically, this is an active targeting approach where the ligand is either directly connected to the ligand surface or through a linker. Ligands can be segregated based on their mechanism of transcytosis. For conjugation with a drug, an ideal ligand should abide by a precise functional group as well as should have giant specificity towards the receptor . A briefvia TfR present on the BBB  can result in significant enhancement of drug therapeutic efficacy, thus reducing administered drug dose and dosing frequency. Tf conjugation provides site-specific delivery of the drugs, thus reducing drug-related adverse effects and peripheral drug toxicity  in all nucleated cells and the BBB and overexpression in a variety of tumors . TfR is  the BBB . The tra the BBB . Transpotoxicity . Some sttoxicity . Tf can reported . Tf  Anti-TfR antibody is mainly used in brain targeting in the management of brain glioma and binds to the TfR epitope; thus, it does not compete with the natural binding site of Tf. It is basically an anti-rat TfR monoclonal antibody and does not bind to human TfR; thus, the clinical implication of this technology is impossible . It is tscytosis . OX26 isscytosis . In vitrval time .via receptor-mediated endocytosis. A study conducted by Kang and associates summarized an increased penetration and uptake of docetaxel (DTX) liposomes co-modified with muscone and R17-217 into tumor spheroids. Also, in vivo results reported increased brain targeting and survival rate in tumor-bearing nude mice  a cationic glycoprotein (iron-bounded) that belongs to the Tf family and exhibited higher activity in comparison to OX26 and Tf for transferring active therapeutics across the BBB . Lf exhiapillary . Lf-modishikonin . The repshikonin .via receptor-mediated transcytosis to the brain and specifically acts on insulin receptors . In CNS, these receptors have effective action in neuronal survival, homeostasis, and reproductive endocrinology . Insulineceptors . The traeceptors .via energy-independent or receptor-mediated processed, and without compromising their bioavailability, they efficiently internalize the associated biomolecules to the cells. They have been exploited widely to establish their efficiency in the management of brain-related diseases. Various kinds of CPPs used in the medical domain are penetratin, transactivator of transcription peptide (TAT), and poly-l-arginine (Cell-penetrating peptides (CPPs) are amphipathic or small cationic cargo having the ability to transport molecular molecules like , liposomes, etc.) to the innermost cells. CPPs can cross the cell membrane arginine . Currentarginine . They caarginine . A cell-arginine .via the receptor-mediated endocytosis mechanism to the endothelial low-density lipoprotein (LDL) receptor  ligand showed higher transcytosis across capillary endothelial cells of the brain  is a transmembrane glycoprotein receptor whose extracellular domain acts as a receptor, while the intracellular domain acts as tyrosine kinase with a high affinity towards EGF . In cancGLUT is majorly expressed at the brain capillary luminal surface with choroid plexus and can be efficiently used for the delivery of therapeutic biomolecules to the brain. Cholesterol glucosyl derivative was formulated by Quin and associates to enhance the therapeutic efficacy of drugs in the brain .Glutathione (GSH) is an endogenous tripeptide with antioxidant nature and expressed highly on the BBB. Previous literature proved that GSH has a profound ability to enhance brain uptakes when they are conjugated to liposomes . Thus, tThese are precursors of neurotransmitters and acetylcholine; that is why they are tremendously expressed in the brain. Choline does not have the flexibility to be modified, so quaternary ammonium compounds were researched that can bind choline receptors and act as choline transporters .via vascular gaps or any defect credited in process angiogenesis that is characteristic of tumor sites , polylactide-co-glycolide (PLGA), PEG, poly-ε-caprolactone (PCL), and PLA. These polymers are approved by the FDA for pharmaceutical purposes  and poloxamer as a coating agent, which could be coated or linked to PNP surfaces to target the BBB❖Surface modification of PNPs using PEG to provide long-circulating characteristics and BBB-crossing ability to PNPsvia effective movement across the BBB crossing❖Ligand conjugation with specific proteins, antibodies, peptides, etc., on PNP surfaces to enhance brain targeting ❖Utilization of magnetic field for driving NPs to the BBB target siteFurther, to facilitate drug delivery, PNP surfaces can be modified to escape them from the RES. For crossing the BBB and targeting the CNS ed below .❖Surfacevia endocytosis, which is described in For TfRs and glioma cells, which are upregulated transporters and receptors, the substrates or ligands have been conjugated to NP surfaces so that they can specifically bind to the overexpressed targets of diseased cells and trigger them Various PNPs developed for targeting therapeutics to the brain for the treatment of neurological disorders like PD, AD, psychotic disorders, brain tumors, and stroke will be further discussed in this review, and the molecular and functional effects obtained in the preclinical model will be outlined.in vitro demonstrate that NPs with the size range of 10–60 nm have higher cellular uptake in nonphagocytic cells irrespective of their surface charge and composition  stabilizer with constant stirring at 1,000 rpm and room temperature. Similarly, C-6-NPs were prepared by substituting GB for C6 under dark conditions. The study conducted in Madin–Darby canine kidney cells depicted that the prepared NPs were effectively taken by the body via multiple nonspecific mechanisms including clathrin-mediated endocytosis, micropinocytosis, and caveolae/lipid raft-mediated endocytosis. NPs of GB showed the ability to transport across chorion, the BBB, gastrointestinal (GI) barrier, and blood–retinal barrier (BRB) in a zebrafish model. Pharmacokinetics data revealed the enhanced uptakes (11.03-fold) of GB in rats’ brains and plasma after oral administration as compared to free GB. The poor oral bioavailability of ginkgolide B (GB) limits its clinical efficacy in PD treatment despite having good neuroprotective action. PEG-PCL NPs of GB were engineered by antisolvent precipitation and stabilization-based technique. PEG-PCL (20 mg/ml of acetone) and 2 ml of GB were mixed with 10 ml of dHAuthor’s opinion: Thus, the above study demonstrates that PEG-coated PNPs might be potential vehicles for targeting therapeutic active molecules to the brain to treat PD.in vitro drug release in 24 h  polymeric NPs modified with rabies virus glycoprotein (RVG)29 as brain targeting peptide for intracerebral delivery of DFO. RVG29- and DFO-loaded NPs exhibited mean diameter of 168.8 ± 1.9, −27.40 ± 0.71 zeta potential, uniform and smooth morphology represented by transmission electron microscopy (TEM), and about 75% of  in 24 h . The stunt of PD .In vitro drug release data demonstrate sustained miRNA release up to 60 h with approximately 40% of released in 24 h while ∼70% release at 60 h. RVG29-conjugated miRNA-NPs showed higher permeability in vitro BBB model in comparison to nontargeted NPs. MTT assay performed in BV 2 cells showed no toxicity of blank NPs for <100 μg/ml concentrations, indicating the safety of NPs. A marked decrease in cell viability after treatment with 200 μg/ml of placebo NPs was observed. Results reported a significant increment of inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), cytokines (interleukin-6), and mRNA levels after lipopolysaccharide administration. However, the levels of mRNA in the miR-NP treated control group and the abovementioned cytokines were found almost equal, suggesting miR-124 exposure. Also, miR-NPs showed a significant reduction in expression of P-P65 and MEKK3 protein kinase. The studies indicated that miR-124 could target nuclear factor kappa B cell (NF-κb) pathways and MEKK3. mi-RNA-NPs results in the downregulation of MEKK3 expression in animal studies with ca. threefold decrease in cell apoptosis. The research revealed that mi-RNA-NP exhibits the potential to boost neuroprotection by inhibiting pro-inflammatory signaling -124 were designed by Gan and co-workers to improve neuroinflammation in PD. Polymeric NPs were prepared using a double-emulsion technique, and maleimide–thiol interaction was used for RVG29 conjugation onto the NP surface. ignaling .Psychotic disorders are clinically driven by cognitive conditions, i.e., delirium, dementia, hallucination, delusions, and schizophrenia. Conventionally available antipsychotics suffer from poor bioavailability, significant extrapyramidal effects, poor brain delivery due to the BBB, and drug-related peripheral toxicity. PNPs are under clinical trials for the management of psychotic symptoms and emerge out as more efficient and efficacious for delivery of antipsychotics to the brain . A ratioT80-coated chitosan NPs of doxycycline hydrochloride were prepared by Yadav and associates for the treatment of psychosis. Optimized NPs were evaluated for their efficacy in the ketamine-induced psychotic mouse model. The NPs exhibited 237-nm particle and 78.16% drug entrapment efficiency. The NPs easily passed through the BBB and demonstrated significant antipsychotic activity. A marked increase in GSH and GABA levels was observed after oral administration of T80-coated doxycycline hydrochloride NPs in ketamine-induced psychotic mice. However, a marked decrease in MDA level, TNF-α, and dopamine levels was noticed in the NP-treated group compared to the toxic group. The above results indicated the enhanced penetration of doxycycline hydrochloride through the BBB with T80-coated NPs .Author’s opinion: The study demonstrated the potential of targeted NPs for the management of psychotic disorders and might be potential carriers in the treatment of neurological disorders.GBM is the most destructive and common kind of brain tumor, affecting a large number of populations globally. Chemotherapy for the treatment of brain tumors is a challenging therapy, and the presence of the BBB also hinders the permeation of active drugs to the brain. GBM treatment is the most difficult despite having multimodal treatment facilities like radiation therapy, systemic chemotherapy, and surgical incision . Moreovevia vasculature, thus limiting the extent of treatment in the region of the tumor  in Cltx-consolidated-alisertib/Ag-NPs, the cell viability decreased when compared to control (untreated cells). The cell viability was found to be 98% and 99%, respectively, after 48 and 72 h of exposure to NPs as compared to alisertib alone at each time point. 99mTc showed approximately 0.6% concentration in the tumor after 60 min of injection, indicating the enhanced retention and drug permeability. Also, Cltx consolidated alisertib/Ag NPs reduced the tumor growth size, revealing the synergistic effect as compared to Cltx consolidated Ag NPs and control groups, which did not show a marked effect on the size of the tumor. The above research concluded the potentiality of these novel therapeutics for targeted delivery of therapeutics in the treatment of GBM (Chlorotoxin (Cltx)-consolidated-alisertib/silver-(Ag)-NPs were prepared t of GBM .In vitro results indicated the burst release of DTX initially from NPs for 24 h following the controlled release of DTX (18.49% ± 5.21%) for 10 days. MTT assays in C6 and RG2 cells revealed that GSH-conjugated NPs of DTX reduce the cell viability when compared to untreated cells and PEG-PLGA NPs and DTX suspension. The permeation of the drug was analyzed utilizing in vitro BBB (Transwell™) model. GSH-conjugated PEG-PLGA NPs showed time-dependent release of DTX in the first 16 h followed by constant release over 48 h, suggesting the ability of NPs in permeating the BBB -gold NPs as a targeted drug carrier for GBM therapy (Aptamer (U2)-conjugated gold NPs were prepared for GBM therapy. U2-gold NP complex was synthesized by dissolving 5ʹ thiol-modified aptamer in phosphate buffer and then deprotecting in dark with TCEP. Aptamer and TCEP were separated using the NAP-5 column, and then U2 was purified. Excess of gold NPs was added to purified U2 and underwent 20-min reaction; then 0.1 M of phosphate buffer and sodium chloride was added and kept overnight for a reaction and then centrifuged for 30 min to remove aptamer and free gold. Cell line studies in U87-EGFRvIII depicted that U2 aptamer-conjugated gold NPs cross the BBB and reach the tumor by inhibiting the EGFR pathway and helping in preventing damage DNA repair in cells of GBM.  therapy . Table 1AD is a chronic and growing neurodegenerative disorder that occurs due to the accumulation and accretion of Beta-amyloid (βA) peptides . AD is aIn vitro BBB study was carried out among NPs and T80-NPs-RIN using mouse brain endothelial cell b.End.3, and it was observed that the uptake efficiency of T80-NPs-RIN in b.End.3 was higher when compared to that of uncoated NPs. Moreover, the incorporation of T80 in the formulation resulted in improvement in the neuroprotective outcome. Additionally, the hemolytic data revealed that T80-NPs-RIN did not instigate any hemolysis, displaying virtuous biocompatibility. Hence, the study was later concluded by depicting that the T80-coated NP had more efficiency towards the treatment of AD therapy as compared to NPs and free RIN (Rhynchophylline (RIN) is the main active tetracyclic oxindole alkaloid stem found to be effective in the treatment of AD, but its poor aqueous solubility, penetrability, and bioavailability limit its use in AD. Therefore, to achieve its therapeutic effect, Xu and his associates developed methoxy PEG-PLGA NP loaded with (RIN) attached with T80 (T80-NPs-RIN) using the nanoprecipitation method to enhance its brain targeting efficacy. free RIN .ex vivo parameters, for instance, immunostaining, Western blotting, and Bielschowsky’s silver staining displayed that PLGA-PEG-B6/CUR could inhibit the hippocampal βA development followed by deposition of tau-hyperphosphorylation. Therefore, it was concluded that PLGA-PEG-B6/CUR is a more promising carrier for the management of AD  attached with B6 peptide using the ring-opening method. HT22 cells were used to perform cellular uptake study and cytotoxicity studies among the developed formulations (PLGA-PEG-B6/CUR), free CUR, uncoated formulation (PLGA-PEG/CUR), and PLGA-PEG-B6 NPs. It was observed that all the particles were compatible and exhibited a low toxicity profile as shown in nt of AD .via NPs can be a better approach. Therefore, Sun et al. developed quercetin-loaded PLGA NPs (PLGA at Q) NPs via the double emulsion solvent evaporation technique. The developed formulation showed less cytotoxicity on SH-SY5Y cell lines in addition to inhibition and disruption assay on Aβ42 fibrils depicting that PLGA (at Q) NPs had more potential than any other formulation. It was further observed that there was a dose-dependent effect of the formulation on SH-SY5Y cells. Moreover, it was observed that the developed formulation had the potential to obstruct the neurotoxicity of Zn2+–Aβ42 and further increase the feasibility of neuron cells. The data obtained by performing behavioral studies using APP/PS1 mice depicted that the formulation was able to limit cognition and memory damage. No adverse effects of the formulation were reported in any of the organs after the histopathological study. Thus, the study was then concluded by stating that the prepared nanoformulation was efficient in delivering the drug at the targeted site with increased therapeutic efficacy and decreased side effects  in the ischemic neuron causing the injury or death of the neurons. So Lv and associates formulated a ROS-sensitive nanocarrier to deliver the neuroprotective agent, i.e., NR2B9C at the stroke site in contrast to ischemic brain damage. The nanocarrier is comprised of a dextran polymer core altered with the boronic ester (ROS-sensitive) along with a red blood cell (RBC) membrane shell followed by insertion of the homing peptide (SHp). The developed NP (SHp-RBC-NP) showed controlled release of NR2B9C at ischemic brain tissues. Additionally, the study further revealed that the formulation possessed marked cytotoxic activity against glutamate-induced cytotoxicity in PC-12 cells. Moreover, the data obtained by performing n damage .Han and associates designed chlorotoxin (CTX)-modified PLGA NPs of Lexiscan (Lx) to improve the BBB permeability of Lx and autocatalytically augmenting stroke-targeting delivery of NPs to the ischemic microenvironment into the brain. The CTX-modified Lx NPs specifically accumulated to the ischemic brain microenvironment compared to unmodified NPs, and an increment in targeting efficiency was observed. The above findings reveal that CTX can be a promising ligand for targeted delivery of therapeutics to the ischemic brain region. The targeted delivery of NPs using CTX as a ligand could be a new approach for better management of stroke .In vivo results indicated significant promotion in new blood vessel formation by RGD-DMAPA-Amyp/HIF-1α-AA. The results indicated that RGD-modified NPs are the safe and promising therapeutic strategy for delivering non-viral gene vectors to the brain for ischemic stroke therapy , which has an angiogenic effect, was encapsulated to hyperbranched cationic amylopectin derivative (DMAPA-Amyp) NPs and modified with RGD peptide for directly delivering it to the endothelial cells of the brain peri-infarct site. Findings suggested higher cell uptake and good biocompatibility of RGD-DMAPA-Amyp, indicating the endocytosis of this nonviral gene vector by human cells and its safety. Studies conducted in ischemic stroke rat models demonstrated higher aggregation of RGD-DMAPA-Amyp NPs to the brain pre-infarct region and vascular endothelial cells with significant enhancement in neurological function recovery.  therapy .In vitro and animal models have been used to detect the potential toxicity of NPs, which demonstrate neurotoxic effects of NPs, e.g., neuroinflammation and neurodegeneration in the CNS. NPs tend to accumulate in the specific brain regions after crossing the BBB and have access to neurons, astrocytes, and microglia (via trans-synaptic transport mechanism or by disrupting the BBB results in CNS toxicity. Polysorbate 80-coated NPs of poly-n-butylcyano-acrylate NPs have been shown to increase interleukin-8 (IL-8) levels to disrupt the integrity of the BBB. An increase in surface area to size ratio of many NPs can result in the interaction with cellular macromolecules and result in oxidative stress (There is a lack of research and a lack of complete understanding of the mechanisms of NPs mediating toxicity on exposures to humans. icroglia . Previouicroglia . NPs have stress . Many mee stress . Howeverin situ brain models, drug-resistant brain cancer models, and brain stem cell models should be established and applied to future in vivo studies. Further research should be conducted to ascertain the localization of PNPs to the specifically targeted cells by utilizing neuroimaging techniques, but the areas need more evaluation. The benefit–risk ratio of PNPs for clinical development should be determined. Moreover, ligand-based PNPs formulated for clinical use should be industrially scalable with remarkable therapeutic effectiveness, lower toxicity, and side effects.Rapid development has been witnessed in the formulation and development of ligand-directed based polymeric NPs in the past years for neurological disorders. It is anticipated that in the coming 10 years, a large number of ligand-based targeted PNPs will enter the phases of the clinical trials globally for the treatments of brain-related disorders, which cannot be treated properly now. The concept of PNP drug delivery vehicles concept is proposed 2 decades ago; however, there is a scarcity of translational and systemic preclinical research for drug targeting to the brain. The data obtained from different studies reviewed above indicate that PNPs could be promising vehicles for drugs targeting the brain in neurological disorders and brain tumors, as they can easily bypass the BBB and the body’s defensive mechanism, bringing sudden removal of PNPs from the circulation. Ligand-conjugated PNPs provide site-specific drug delivery, thus reducing drug-related peripheral toxicity and adverse events, reducing drug dose and dosing frequency, and improving drug therapeutic efficacy. Extensive research based on cellular and molecular levels should be done to analyze the efficacy and safety of PNPs as a whole entity. Moreover, in the future, extensive work is required to inspect the potentiality of targeted PNPs at the clinical and commercial levels. In the future, more polymers should be approved by the FDA for ascertaining their safety in brain disease, as presently very few polymers are available that are approved by the FDA. The research warrants the evaluation of the biological activity and concentration of the targeted PNPs at the target-specific site. Ligand-based NPs need to be examined carefully for their toxicity and safety in the brain. Additionally, for accurate examination of the therapeutic activity of ligand-based PNPs, In vitro and pharmacokinetics models manifest higher therapeutic efficacy of ligand-based PNPs compared to their conventional formulation and PNPs without ligand, with lower toxicity and side effects. However, unmet clinical trials and further research are warranted to explore the safety and efficacy of ligand-mediated PNPs.The current review outlines the role of ligand-conjugated PNPs for targeting the therapeutic active molecules to brain cells for the safe and effective management of neurological disorders and brain cancer. A lot of research was carried out to explore the potential of ligand-mediated PNPs for the cure of CNS disorders.


Dynamical processes induced by the external time-dependent fields can provide valuable insight into the characteristic energy scales of a given physical system. We investigate them here in a nanoscopic heterostructure, consisting of the double quantum dot coupled in series to the superconducting and the metallic reservoirs, analyzing its response to (i) abrupt bias voltage applied across the junction, (ii) sudden change of the energy levels, and imposed by (iii) their periodic driving. We explore subgap properties of this setup which are strictly related to the in-gap quasiparticles and discuss their signatures manifested in the time-dependent charge currents. The characteristic multi-mode oscillations, their beating patters and photon-assisted harmonics reveal a rich spectrum of dynamical features that might be important for designing the superconducting qubits. Specifically, the superconducting qubits3 have been considered as promising candidates, making use of the bound states formed inside the pairing gap4. Their implementations could protect the parity of Cooper pairs on proximitized superconducting nonoscopic islands5. Further perspectives for the proximitized double quantum dots appeared with the topological superconductors6, where the zero energy in-gap modes are protected by symmetry reasons. These Majorana-type quasiparticles could be used for constructing the charge qubit in a transmission line resonator (transmon)7 and may be incorporated in the gate tunable superconducting qubits (gatemons)8. Readout by means of a switching-event measurement using the attached superconducting quantum interference devices has revealed quantum-state oscillations with sufficiently high fidelity9, that seems appealing for realization of quantum computing.The double quantum dots embedded on interfaces between various external leads have been proposed for possible spin11 and recently also for nanoscopic length atomic chains, semiconducting nanowires, and magnetic islands proximitized to bulk superconductors12. Their particular realizations in the double quantum dots (DQDs) have been experimentally probed by the tunneling spectroscopy, using InAs18, InSb19, Ge/Si20 and carbon nanotubes22 and by the scanning tunneling microscopy applied to various di-molecules deposited on superconducting substrates27. Rich properties of such in-gap bound states of the DQDs have been analyzed theoretically by a number groups43. Major features of two quantum dots coupled in series to the superconducting lead(s) originate from the ground state configuration which can vary its even-odd parity, depending on: the energy levels, hybridization with the external reservoirs, the inter-dot coupling, and the Coulomb potential38. Such parity changes are corroborated by crossings of the in-gap bound states and can be empirically detected by discontinuities of the Josephson current in S-DQD-S junctions16 or the subgap Andreev current in N-DQD-S junctions19. The resulting zero-bias conductance as a function the quantum dot levels (tunable by the plunger gates) resembles a honeycomb structure16 instead of a diamond shape, typical for the single quantum dot junctions. Influence of the coupling to external reservoirs is also meaningful. For instance in a regime of the strong coupling to superconducting lead(s) the spin of quantum dots would be screened14. In general, various arrangements of two quantum dots enable realization of the on-dot and inter-dot electron pairing, affecting the measurable charge transport properties36. In particular, for the singly occupied quantum dots (what can be assured by appropriate gating) the superconducting proximity effect could be blocked. Such triplet blockade effect has been recently reported in S-DQD-S17 and N-DQD-S18 nanostructures. As regards the Coulomb potential, its influence is indirectly manifested through the singlet-doublet transitions (related to variations between the even-odd occupancies of the quantum dots18) and, under specific conditions, can lead to the subgap Kondo effect44.So far the static properties of in-gap bound states have been throughly investigated for the single and multiple quantum dots45 or buildup46 of the electron pairing. For specific discussion we consider (i) abrupt detuning of the chemical potentials by the source-drain voltage, (ii) quench of the quantum dot energy levels, and (iii) their periodic driving. The latter effect has been recently achieved experimentally in the microwave-assisted tunneling via the single quantum dot in the Josephson-type junctions49, but similar measurements should be feasible using N-DQD-S heterostructures as well. Our calculations of the time-dependent electron occupancy and charge currents reveal the damped quantum oscillations whose frequencies coincide with the energies of in-gap bound sates. We inspect their nature and determine the characteristic time/energy scales, focusing on the limit of large superconductor gap, 51 and for the double quantum dot heterostructures52 that dc or ac external potentials.To our knowledge, however, the dynamical signatures of proximitized DQDs have not been investigated yet. Such dynamics could be important for designing future operations on the superconducting qubits, thefore we analyze here various time-dependent observables of the setup, comprising two quantum dots arranged in series between the superconducting and normal metallic electrodes Fig. . We inspWe start by discussing the microscopic model of our setup Fig.  and nexti-th quantum dot, Our heterostructure, consisting of the quantum dots QD53N and S electrodes, (ii) sudden change of the energy levels 54We restrict our considerations to the wide-band limit, assuming the constant (energy-independent) auxiliary couplings ons see “” sectionΓS2 see “” section30. Here we shall address the post-quench dynamics, treating the electron–electron interactions within the Hartree–Fock–Bogoliubov decoupling scheme55. We use of this decoupling  panel refers to the uncorrelated case, A does not exceed the energies of subgap quasiparticles. Such behavior can be contrasted with the larger amplitude driving  display the characteristic features originating from the photon-assisted tunneling. We notice that besides the main quasiparticle peaks  the main quasiparticle peaks loose some part their intensities  at expense of their new higher-order replicas. By varying the amplitude A such replicas appear in the averaged conductance at A the spectral weight of individual harmonics vanishes and then reappears.Let us now consider variation of the averaged Andreev conductance 61. For the larger amplitude, n-fold fine structure driven in the harmonics, whenever the specific constraint To check influence of the inter-dot coupling U the main quasiparticle peaks only slightly change their positions. Major influence of the correlation effects is manifested through noticeable redistribution of the spectral weights, both between the harmonics and between their fine sub-structure. More detailed analysis of the photon-stimulated Andreev transport of the strongly correlated N-DQD-S system would require some sophisticated (nonperturbative) techniques, and such study is beyond the scope of the present work.Finally, in Fig. In addition to the numerical computations of the averaged current directly from the equations of motion, we have also developed the auxiliary procedure based on machine learning algorithm which reliably yields the Andreev conductance for an arbitrary set of the model parameters  with a damping caused by the relaxation processes on a continuum spectrum of the normal lead.We have studied the double quantum dot coupled between the superconducting and normal leads, addressing its dynamical response to (i) abrupt application of the bias voltage, (ii) sudden change of the energy levels, and (iii) their periodic driving. These effects can be routinely triggered either by 62.Inspecting the time-dependent profiles of various physical observables we have found the signatures of such frequency components which coincide with the subgap quasiparticle energies. For the quantum quench imposed by the source-drain voltage and by the gate potential the dynamics of proximitized double quantum dot reveals superposition of the fast and slow oscillatory modes, giving rise to the beating patters. These features are well observable over quite long time interval, A of the periodically varying levels. We have illustrated these phenomena in absence . Using the exact formulaHere, we explicitly present the set of differential equations needed for determination of the time-dependent occupancy We have solved numerically these coupled differential equations –19 subjeResults presented in the main part of this paper have been obtained by solving the differential equations derived for N-DQD-S heterostructure. The computational procedure has been rather straightforward (see the preceding section), but required quite a lot of time and resources. For instance to produce the conduction maps Figs. , 9, 10 wTo train our neural network we have used the collected set of data of 76 different conductance maps (with different resolutions), giving us 971760 conductance data points. Subsequently, we have linearly interpolated every single map to doubly increase a number of the data points, finally giving us 3887040 data points. For this purpose we have used the open-source software for machine learning—Tensorflow with application programming interface—Keras.A) describing noninteracting N-DQD-S setup and 1 single neuron on the output, specifying the averaged Andreev conductance https://www.dropbox.com/sh/0hzs9im3d3bf0jr/AADRr3kltw2mOdCCh8tedoIWa?dl=0www.dropbox.com/sh/0hzs9im3d3bf0jr/AADRr3kltw2mOdCCh8tedoIWa?dl=0 webpage.This neural network has a character of the densely connected type, with 4 input parameters (mentclasspt{minima


Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-related protein family. SUMO modulates protein function through covalent conjugation to lysine residues in a large number of proteins. Once covalently conjugated to a protein, SUMO often regulates that protein’s function by recruiting other cellular proteins. Recruitment frequently involves a non-covalent interaction between SUMO and a SUMO-interacting motif (SIM) in the interacting protein. SIMs generally consist of a four-residue-long hydrophobic stretch of amino acids with aliphatic non-polar side chains flanked on one side by negatively charged amino acid residues. The SIM assumes an extended β-strand-like conformation and binds to a conserved hydrophobic groove in SUMO. In addition to hydrophobic interactions between the SIM non-polar core and hydrophobic residues in the groove, the negatively charged residues in the SIM make favorable electrostatic contacts with positively charged residues in and around the groove. The SIM/SUMO interaction can be regulated by the phosphorylation of residues adjacent to the SIM hydrophobic core, which provide additional negative charges for favorable electrostatic interaction with SUMO. The SUMO interactome consists of hundreds or perhaps thousands of SIM-containing proteins, but we do not fully understand how each SUMOylated protein selects the set of SIM-containing proteins appropriate to its function. SIM/SUMO interactions have critical functions in a large number of essential cellular processes including the formation of membraneless organelles by liquid–liquid phase separation, epigenetic regulation of transcription through histone modification, DNA repair, and a variety of host–pathogen interactions. Small ubiquitin-related modifier (SUMO) is a member of the ubiquitin-like protein family and, like ubiquitin, SUMO can be covalently attached to lysine side chains in a variety of target proteins. Unlike ubiquitylation, however, SUMOylation does not have a direct role in targeting proteins for degradation by the proteasome, and much research has been directed toward elucidating the consequences of this post-translational modification ,2. The SSUMO modification regulates a variety of biological processes ,2,6,7. MIt is likely that a large fraction, perhaps the majority, of SUMO functions require SIMs. Although this review will focus on processes in which the SIMs have been identified, it seems likely that many additional SUMO-mediated processes for which SIMs are a key player have yet to be identified. However, there may also be SIM-independent SUMO functions. For example, it is possible that, in some cases, covalent conjugation of SUMO to a protein alters its function by disrupting a protein-protein interaction or by directing changes in protein conformation . This review is not meant to be exhaustive. There are many more examples of characterized SIMs than will be mentioned here. After reviewing what we know about SIM structure and function, we will describe a few of the many known processes in which SIMs play a critical role, including the formation of phase-separated membraneless organelles, histone function, DNA repair, and host–pathogen interactions. The initial discovery of SIMs resulted from a yeast two-hybrid screen for human proteins that interact with p73, which is a relative of the p53 tumor suppressor . This scIt is worth nothing, however, that not all SIMs match the consensus described above. For example, Ssa1, the yeast orthologue of Hsp70, contains a SIM with the sequence TVEEVD, thus lacking a hydrophobic core with at least three non-polar aliphatic amino acids. However, this may not represent a truly distinct type of SIM, since it appears to bind to the same SUMO surface (to be discussed below) in much of the same manner as SIMs that follow the motif’s consensus more closely . SUMO and other ubiquitin-family proteins assume what has been termed a “β-grasp” fold, in which a four or five-stranded β sheet wraps around (grasps) an α helix . The solThe solution structure of the complex between SUMO and the PIASX SIM confirms many of the features of the 3 Å-resolution X-ray crystal structure of the complex between SUMOylated RanGAP and the SIM in RanBP2, another SUMO ligase . Both thhhXh, whereas the RanBP2 SIM is of the type hhhh. It has been suggested [hhxh SIM core and SUMO. This conclusion is challenged, however, by a molecular dynamics simulation of binding between the SIM in PIAS1 (a close relative of PIASX) and SUMO-3 [It is possible that differences in the hydrophobic core are sufficient to determine whether binding occurs in the antiparallel or parallel orientation. For example, the PIASX SIM is of the type uggested  that thed SUMO-3 . This siOther studies highlight the importance of the distribution of the flanking charged residues in determining the binding orientation. SIMs that bind to SUMO in the parallel orientation frequently contain a C-terminal negatively charged patch, while SIMs that bind in the antiparallel orientation frequently contain an N-terminal negatively charged patch ,22,23. IThe physiological significance of the SIM binding groove in SUMO is demonstrated by a study looking at the possible role of SUMO in the inhibition of transcriptional activation . Many trThe functional importance of the SIM binding interface in SUMO is also demonstrated by a high-throughput mutagenic screen for mutations in the gene encoding the sole SUMO family protein in yeast . This stIn conclusion, it is clear that SIMs typically contain an essential hydrophobic core of four amino acids that binds to a conserved hydrophobic pocket in SUMO and that a negatively charged stretch of amino acids often flanks this hydrophobic core. While we do not yet understand all the factors that influence binding orientation, it seems clear that electrostatic interactions involving the negatively charged residues play important roles in determining both affinity and orientation of the SUMO/SIM complex. SUMO/SIM complex formation is frequently regulated by post-translational modification. For example, phosphorylation of serine residues adjacent to the SIM hydrophobic core has been shown to stimulate binding to SUMO by introducing negative charges into the SIM that engage in favorable electrostatic interactions with positive charges in SUMO. The role of phosphorylation is particularly well-characterized in the case of the human Daxx protein . Daxx isBoth serine residues in the Daxx SIM are targets for phosphorylation by casein kinase II, and this phosphorylation appears to contribute to the pro-apoptotic function of Daxx. As shown by isothermal titration calorimetry, phosphorylation of one or both serine residues increases the affinity of the Daxx for SUMO-1 by up to 30-fold . DetermiPost-translational modification of SUMO may also function to modulate the affinity of the SIM/SUMO complex. Several of the lysine residues in the SIM binding groove of SUMO are targets for acetylation, which could modulate SIM affinity. This is demonstrated by studies of PIAS family SUMO ligases . PIAS1, The consequences of lysine acetylation and how lysine acetylation interacts with serine phosphorylation have been further illuminated through studies of the effect of SUMO acetylation upon the binding of the phosphorylated forms of the SIMs in Daxx and PML . BindingCells contain a wealth of proteins that interact non-covalently with SUMO. A systematic effort to identify the non-covalent SUMO interactome has been carried out. This study involved the use of SUMO-1, SUMO-2, and a SUMO-2 trimer as affinity reagents to purify interacting proteins from HeLa cell lysates . In thisGiven the large number of SUMO-interacting proteins, it is essential to determine the basis for specificity in SIM/SUMO interactions, an issue that remains largely unaddressed. SUMOylation has been implicated in a broad range of biological activities including pre-mRNA splicing, transcription, mitosis, protein stabilization, and DNA repair ,2. LogicOne possible explanation for selectivity in SUMO/SIM interactions is that SUMOylated proteins do not solely contact the SIM in the target protein, but also interact with other surfaces in the target protein. These additional binding surfaces could function as determinants of specificity by mediating the formation of a cooperative complex that requires the SUMO/SIM interaction and one or more additional protein-protein interactions. An example of such a complex is provided by the ternary complex of SUMO-conjugated RanGAP1 with Ubc9 (the SUMO-conjugating enzyme) and RanBP2 (a SIM-containing SUMO ligase). In this complex, RanBP2 contacts SUMO via its SIM and simultaneously makes multiple stabilizing contacts with Ubc9 . A seconIn other cases, a degree of specificity may be achieved through poly-SUMOylation, in which a target lysine is attached to a chain of SUMO proteins. Poly-SUMOylation can occur because some SUMO isoforms contain internal SUMO acceptor lysine residues that allow the attachment of one SUMO to another, which makes the formation of a poly-SUMO chain possible . Some SIYet, another mechanism for achieving specificity in SUMO/SIM interactions could be SUMO isoform-specific SIMs. As mentioned above, a proteomic study has revealed 379 SUMO interacting proteins, many of which have differential affinity for SUMO-1 and SUMO-2 . Gene onThe finding that SIMs can be SUMO isoform-specific is not surprising given that human SUMO-1 and human SUMO-2 share only 44% sequence identity. The possibility of SUMO isoform-specific SIMs has also been confirmed by a study in which a phage display screen was used to identify sequences with differential affinity for SUMO-1 and SUMO-2 . StructuSUMO/SIM interactions may play a central role in the formation of phase-separated membraneless organelles. These organelles are protein aggregates that form spherical droplets within the cytoplasm or nucleoplasm in a phenomenon known as liquid–liquid phase separation (LLPS) . It is pOne of the oldest discoveries pertaining to SUMO is the observation that it is enriched in a membraneless nuclear organelle known as the PML nuclear body (PML-NB), which is found in many types of mammalian cells ,38,39. TPML-NBs contain the promyelocytic leukemia (PML) protein, which is highly SUMOylated and contains a SIM . InteracOne role of SUMO/SIM interactions in the function of PML nuclear bodies has been demonstrated in studies of cancer cell proliferation. The unchecked growth of cancer cells requires a mechanism to avoid the excessive shortening of telomeres that occurs in normal cells at every mitotic cycle, which would normally limit the number of cell cycles before permanent arrest of the cell cycle (replicative senescence) or apoptosis . TelomerIn an effort to determine if APBs are functionally required for ALT, artificial Poly-SIM/Poly-SUMO aggregates were targeted to the nuclei of human embryonic kidney 293 cells by the addition of a nuclear localization signal to Poly-SIM . Poly-SIA second, and perhaps even more remarkable example of how SIM/SUMO interactions in PML-NBs bring about a complex biological response, involves ICP0, a STUbL encoded in the Herpes Simplex Virus 1 (HSV-1) genome. This protein has a central role in the interplay between the host cell’s antiviral response and the attempt of the virus to circumvent such a response to further its own proliferation . It willThe role of SUMO/SIM interactions in PML-NB formation may be but one example of a broader role of these interactions in the formation of phase-separated membraneless organelles. For example, these interactions could drive or regulate the formation and/or dynamics of nuclear speckles, which are phase-separated ribonucleoprotein aggregates with essential roles in RNA processing . In addiMore generally, it appears that SUMO modification of multiple members of large protein groups, such as those involved in the formation of phase-separated bodies and inDNA repair, may serve as a strategy for the synergistic assembly of protein complexes ,47. ThisMost core histones, linker histones, and histone variants are targets of SUMOylation . SUMOylaSUMOylation of histone H2B in yeast is stimulated by the dimethylation of histone H3 lysine 4, a histone mark associated with the 5′ ends of actively transcribed genes. SUMOylated histone H2B, in turn, recruits the Set3 histone deacetylase complex (HDAC) leading to deacetylation of histone H3  Figure A. In supRecruitment of the Set3 complex by SUMOylated histone H2B is mediated by a SIM in Cpr1 (core sequence IVVA), which is a subunit of the Set3 complex . MutatioSince both SUMO and histone deacetylation are generally associated with transcriptional repression, it seems paradoxical that histone H2B SUMOylation is enriched at transcriptionally active genes . The resFurther evidence for SIM-mediated crosstalk between SUMOylated histones and components of the histone modification machinery is provided by a biochemical study examining nucleosomes in a cell-free system . Lysine The discovery of a SIM in CoREST prompted an investigation into the possibility that histone demethylation might be regulated by histone SUMOylation . This stIt is worth noting that some of the effects of SUMO on chromatin structure and function may be independent of SIMs. For example, studies with semi-synthetic nucleosomal arrays suggest that SUMOylation of histone H4 on lysine 12 could alter chromatin compaction by disrupting long-range internucleosomal interactions .SUMO/SIM interactions play a prominent role in DNA repair, including the repair of double stranded DNA breaks as well as nucleotide excision repair. Proliferating cell nuclear antigen (PCNA) is a SUMOylated protein that is central to the repair of double stranded DNA breaks. This protein forms a trimeric “sliding clamp” around the DNA and associates with DNA polymerases to greatly increase their processivity. PCNA also serves as an interaction scaffold for DNA replication and repair factors . In yeasLoading and unloading of PCNA on DNA requires a protein complex known as Replications Factor C (RFC) . Elg1 isInterestingly, Elg1 also contains a PCNA interacting protein (PIP) motif that binds directly to PCNA . This suDeletion of Elg1′s SIM and PIP motif-containing region results in the accumulation of SUMOylated-PCNA on chromatin, which suggests that the Elg1-containing RFC-like complex normally functions to unload SUMOylated-PCNA from chromatin B. The faNucleotide excision repair (NER) is a DNA repair pathway responsible for repairing DNA distorting lesions such as UV-induced pyrimidine dimers and other pyrimidine photo adducts . Many ofPoly-SUMOylation of XPC increases upon exposure to UV radiation . Poly-SUSUMO/SIM interactions are a key feature of the interplay between many pathogens and their hosts. The pathogens that manipulate SUMO are diverse, and examples are found among fungi, bacteria, and viruses. On one hand, SUMO and SIM can be used by the host cell to enhance cellular defenses against infection. On the other hand, the pathogens can hijack the SUMO pathway to aid in their proliferation or to overcome host cell defenses. Therefore, SUMOylation and non-covalent SUMO interactions mediate the struggles between a diverse set of host cells and their pathogenic adversaries. This section presents a few of the better characterized examples in which the mechanisms are beginning to be illuminated.Helicobacter pylori [H. pylori can attack gastric epithelial cells, potentially leading to disease [H. pylori enzyme urease decreases the acidity of the stomach, leading to inflammation, gastritis, and even stomach ulcers in the host .H. pylori by triggering apoptosis (programmed cell death) in a manner that requires the nuclear localization of the p38 MAP kinase [In response to infection, gastric cells limit the spread of P kinase . This kiB. cinerea [A second, more complex example of a SIM/SUMO interaction in a pathogen response is provided by the Jasmonic Acid (JA) pathway in plants. The JA pathway regulates defense against necrotrophic pathogens (pathogens that kill a host cell before consuming it) such as the fungus  cinerea ,66. In tA. thaliana genes encoding the SUMO deconjugating enzymes OTS1 and OTS2 results in high levels of SUMOylated JAZ6, which increases JAZ6 stability by preventing COL1-mediated degradation of JAZ6. This, in turn, interferes with the activation of antipathogen genes in response to the JA signal, rendering the host more susceptible to B. cinerea. Second, B. cinerea infection triggers the degradation of OTS1 and OTS2. Thus, it is possible that rapid degradation of SUMO deconjugating enzymes in response to infection allows for the rapid activation of the antipathogen response even before sufficient levels of the JA-Ile conjugate have built up to trigger this response.A hint that the SUMO pathway may regulate this response comes from the following observations . First, The mechanism by which SUMO conjugation to JAZ6 interferes with COL1-mediated degradation is not clear, but it appears to require binding of the SUMO attached to JAZ6 to an evolutionarily conserved SIM in COL1 (core sequence: VPEV) . This miViral pathogens can also employ SIMs as a way of promoting their own survival and proliferation inside the host. A good example of this concept is provided by Kaposi’s sarcoma-associated herpesvirus (KSHV), the genome of which encodes both a SUMO ligase and a STUbL. Like many SUMO ligases, the KSHV SUMO ligase, K-bZIP, contains a SIM (core sequence: VIDL) . This SIBoth KSHV and herpes simplex virus-1 (HSV-1) encode STUbLs that allow these viruses to circumvent host cell defenses conferred by PML-NBs ,68. WhenIn some ways, SUMOylation is like any reversible post-translational protein modification, in which a covalent change to protein structure serves as an on–off switch that alters protein function. However, unlike modifications such as phosphorylation or acetylation, which involve the addition of a small chemical group to a protein, SUMOylation involves the attachment of one entire protein to another. This added protein can then serve as a platform for the recruitment of diverse SUMO-interacting proteins through SUMO/SIM interactions. SUMO family proteins have evolved a hydrophobic groove that is dedicated to these interactions and which presumably dictates SUMO isoform specificity. This SIM-interacting groove is no doubt part of what differentiates SUMO from other ubiquitin-family proteins, such as ubiquitin or Nedd8.One of the biggest gaps in our understanding of SIM function is the mechanism of interaction specificity. What is it that determines which of the hundreds or thousands of SIM-containing proteins in a proteome will interact with any given SUMOylated protein? This must, at least in part, result from cooperative interactions involving interactions between regions of the SUMOylated protein and the SIM-containing protein outside SUMO and the SIM. Although we have presented a few illustrative examples of this concept, in most cases, the details remain to be determined. Another feature of SUMO that differentiates it from other post-translational protein modifications is the possibility of multivalent interactions that can occur when a protein such as PML is both SUMO-conjugated and able to interact non-covalently with SUMO through a SIM. This can lead to the formation of large protein aggregates resulting in the genesis of membraneless organelles such as PML-NBs via the phenomenon of liquid–liquid phase separation. A number of functions of SUMO  are already known to require these organelles and it seems likely that they will be found to have, as of yet, unappreciated roles in other SUMO functions.


One adult contact (1/100) tested positive. In 34 index cases, we detected 13 different SARS-CoV-2 Pango lineage variants, with B.1.1.7 being most frequent. In the eight contact-investigations with SARS-CoV-2 positive contacts, four had the same sequence identity as the index, one had no relation, and three were inconclusive. With mitigation measures in place, the spread of SARS-CoV-2 from children in schools is limited. By excluding contact-investigations with adult cases known at the time of enrolment, our data provide a valid estimate on the role of children in the transmission of SARS-CoV-2 in schools.The role of children in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in schools has been a topic of controversy. In this study among school contacts of SARS-CoV-2 positive children in 43 contact-investigations, we investigated SARS-CoV-2 transmission in Norway, August 2020–May 2021. All participants were tested twice within seven to ten days, using SARS-CoV-2 PCR on home-sampled saliva. Positive samples were whole genome sequenced. Among the 559 child contacts, eight tested positive , with no significant difference between primary  and secondary schools ,  Many countries adopted school closures and strict infection prevention and control measures (IPC) to limit the spread of SARS-CoV-2, based on the assumption that transmission among children may augment the spread of the virus in the wider community. The high societal costs related to these interventions have invited questions as to whether they are justified, given that children are mostly mildly affected by the virus and mortality rates are very low ,2.Children of all ages are susceptible to and may transmit SARS-CoV-2 ,4, althoIn Norway, children’s daycare and schools were closed on 13 March 2020, and reopened under strict IPC measures from 20 April 2020. A traffic light model was developed to guide school administrators on IPC strategies . This thWhile high vaccination coverage in adults will limit transmission and disease burden, vaccines for younger children are not yet approved. Understanding children’s role in transmission is therefore still important for future mitigation strategies. Feasibility and high sensitivity and specificity of saliva for detection of SARS-CoV-2 by PCR makes this an attractive means for testing of children . To imprBetween August 2020 and the end of May 2021, we prospectively followed school contacts of 43 children with laboratory-confirmed SARS-CoV-2 (index cases) who had physically been attending school within 48 h prior to symptom onset or the sampling date for asymptomatic cases. The study included primary (1–7th grade) and secondary (8–10th grade) schools in Oslo and Viken counties. We obtained two self-collected saliva samples from all contacts, at least four days apart, within the seven- to ten-day-long mandatory quarantine period. We excluded contact investigations around child cases in schools with known SARS-CoV-2 infected adults at the time of enrolment. The study was conducted in parallel to measures taken by the local health services.Local health authorities identified school contacts as per national guidelines. We used the schools’ digital platform to send study invitations to the same school contacts and the index, with one same-day reminder. The school administrations were not involved in any other study procedures. Contacts outside of school were not included. Consent was obtained from all participants aged 16 years or above, or from both parents for participants aged <16 years. In case of sole parental responsibility, a single consent was sufficient.The index was the child first identified with confirmed SARS-CoV-2 leading to the contact-investigation. A primary case was a contact of the index, who tested positive for SARS-CoV-2 in the first saliva sample. A secondary case was a contact who tested positive for SARS-CoV-2 in the second saliva sample, following a first negative test. A SARS-CoV-2 infected contact was a contact who tested positive in either of the two tests, thus including both the primary and secondary cases. We divided the study-period into before and after the more transmissible Alpha variant (B.1.1.7) was established in the study area  .https://www.fhi.no/en/studies/corona-child-study/, accessed on 1 December 2021).Participants filled a baseline questionnaire including demographic, exposure and clinical information and a form for daily reporting on the presence or absence of symptoms. Non-cases also filled a questionnaire on recent exposure at the study end  and the date of the first saliva sample was four (range: three to six days). The median number of days between the two saliva samples was six (range: three to ten days).https://arctic.network/ncov-2019, accessed on 1 December 2021), run on either the Illumina MiSeq platform , the NanoPore GridIon ; or the Swift Amplicon SARS-CoV-2 Panel  on Illumina NovaSeq  at the Norwegian Sequencing Centre, Oslo University Hospital, according to the manufacturer’s instructions with minor modifications. We used the PANGO lineages nomenclature  to define the SARS-CoV-2 variant [https://github.com/nextstrain/nextclade, accessed on 1 December 2021), and a maximum-likelihood phylogenetic tree was created using IQTREE v.2.0.3  [Samples from all positive cases were whole genome sequenced using two multiplexed amplicon approaches; ARTIC-network nCoV-19 protocol v.3 ,16 (avai variant . Sequencer 2021) . PairwisFor quality assessment purposes we linked the study data with the laboratory results from the national laboratory database in the Norwegian Surveillance System for Communicable Diseases (MSIS) through the participants’ unique national identity numbers. We obtained data from MSIS from the two weeks prior to the date of the first saliva sample and four weeks after the date of the second saliva sample, or the first sample when we did not receive a second sample.We obtained data on the local COVID-19 incidence rate over the last 14 days prior to date of sample collection for diagnosis of the index case in each contact-investigation. To assess possible underestimation of transmission due to non-participation we obtained aggregated data from the municipal health officer on the number of contacts with confirmed SARS-CoV-2 identified in the routinely performed contact investigation. In the municipalities, testing of all contacts was only routine in the second half of the academic year.An overview of data and sources is presented in Semi-structured phone interviews with school staff about mitigation measures were conducted in parallel with the contact investigations. Two researchers independently categorized the responses into eight broad categories  and scorBox 1Enforced classroom hygiene Defined child cohorts, limited mixing of cohorts Limit shared spaces for children indoors Limit shared spaces for children outdoors Reduce the number of staff involved in each cohort Reduce physical contact between staff Work-from-home policy for staff whenever possibleStay at home policy for all if symptomatic p-value ≤ 0.05). Descriptive measures other than percentages are presented as median (range).We calculated the percentages of the primary, secondary and all SARS-CoV-2 positive contacts among all contacts with 95% confidence intervals, excluding index cases both in the numerator and the denominator. For secondary cases we also excluded primary cases and contacts who did not provide a second saliva sample  from the denominator. Comparison between the groups was made using Fisher’s exact test .The study includes 43 contact investigations in Oslo and Viken counties from August 2020 until May 2021, with 559 child and 100 adult contacts, as seen in Among index cases, 79% (34) consented to participate. At the time of enrolment, 44% (15) reported to have symptoms; six reported fever with at least one other symptom and nine reported other symptoms without fever. Two index cases did not respond to the question. Among those without symptoms at enrolment, two additional indexes reported fever during follow-up.The local incidence rate in the municipality of the Oslo borough over the two weeks prior to the initiation of the contact investigation showed large variation over time and place and ranged from 17–763 cases per 100,000. The corresponding incidence rates for Oslo and Viken counties ranged from 29–471 cases per 100,000, Table A2p = 0.665). Only one primary case and no secondary cases were identified in the lowest grades (1–4th). The percentage infected contacts was higher in secondary than in primary schools, but the difference was not statistically significant (p = 0.229), and the percentage remained low  tested positive in the study with SARS-CoV-2 confirmed in the first saliva sample (primary case) in the pre- Alpha period (5th–7th grade).Among the 34 index cases who consented to participate, whole genome sequencing (WGS) identified 13 different SARS-CoV-2 Pango lineage variants  in 33 inFour of the nine index cases that did not consent to participate were enrolled during the Alpha-period. We assume that these contacts were exposed to the more transmissible Alpha variant, since this was the dominant variant in this period, growing from ~80% in the beginning of March to ~95% by the end of May 2021 .Primary or secondary cases were identified in eight separate contact investigations see . In fourThe phylogenetic analysis showed that SARS-CoV-2 viruses were more similar within than between schools, with some exceptions see . AnalysiLinkage of the study data with national laboratory data revealed that 63% (434) of the participants had test results from testing outside of the study within two weeks prior to the date of the first saliva sample and four weeks after the date of the second saliva sample; 56% (333) in the pre-Alpha period versus 93% (101) in the Alpha-period. The large difference between the periods reflects the change in the recommendations and easier access to and availability of tests in the Alpha period. Concordance of test results from the two sources was high, at 98% (427/434). Among the seven individuals with discordant results, two were index cases with negative saliva tests; one had been drinking milk before the saliva collection, and the other had low viral RNA content in the original sample. Among the five contacts, four had a negative test reported from the study or MSIS 3–10 days prior to a positive result, which may reflect a natural course of the disease or a later exposure. One contact tested negative one month after a positive test result.p-value ≤ 0.05).Data from the municipalities show that they identified five additional SARS-CoV-2 positive cases among contacts who had not consented to participate in the study; four children (primary school) and one adult (secondary school), in total 12 positive cases out of a total of 935  contacts; nine in the pre-Alpha period and three in the Alpha period. It was not possible to distinguish between primary and secondary cases among these. Comparison of infection rates in contacts not enrolled and those enrolled in the study was not significantly different, as determined by using Fisher’s exact test  strain, as well as excluding transmission in one contact investigation. This could have been misinterpreted by solely using PCR-based typing.We did not include consecutive contact-investigations in schools following primary- or secondary cases, which may lead to underestimation of our study findings. The results are not necessarily directly applicable to new variants of SARS-CoV-2, such as the highly transmissible Delta variant (B.1.617.2 and AY.x) and new variants which may emerge. These studies are also important to conduct for new variants, to ensure that the measures to control transmission are well balanced against educational needs for children.We found limited child-to-child and child-to-adult transmission of SARS-CoV-2 in schools, which also holds for the Alpha variant. Since we excluded contact investigations with adult cases known at the time of enrollment, our data provide a valid estimate on the role of children in transmission of SARS-CoV-2 in schools. Looking only at outbreaks in schools in general, without considering contribution of adults in transmission, may overestimate the role of children in transmission.


Cancer patients with COVID-19 have reduced survival. While most cancer patients, like the general population, have an almost 100% rate of seroconversion after COVID-19 infection or vaccination, patients with haematological malignancies have lower seroconversion rates and are far less likely to gain adequate protection. This raises the concern that patients with haematological malignancies, especially those receiving immunosuppressive therapies, may still develop the fatal disease when infected with COVID-19 after vaccination. There is an urgent need to develop Guidelines to help direct vaccination schedules and protective measures in oncology patients, differentiating those with haematological malignancies and those in an immunocompromised state. As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally at an alarming rate, it is having an unprecedented impact on cancer patients . Much ofNature Medicine publications have recently reported that the COVID-19-vaccine efficacy can be linked to neutralising antibody titre [While most cancer patients, like the general population, have an almost 100% rate of seroconversion after COVID-19 infection or receiving mRNA or adenovirus-based COVID-19 vaccines, patients with haematological malignancies, most notably those receiving anti-CD20 immunotherapy, have lower rates of seroconversion and are far less likely to gain adequate protection . In a stThere is now available data demonstrating an improved serological response to a third dose of the mRNA COVID-19 vaccine in select immunocompromised groups, including solid-organ transplant recipients, renal-dialysis patients, and patients with haematological malignancies, most notably those who had not received anti-CD20 therapy within a year . Many coWhile the timing of anti-CD20 therapy impacts the humoral response, it does not modify the T cell response . Given tUnderstanding the impact of immunosuppression on the effectiveness of these vaccines highlights the need for other prophylactic strategies in this immunosuppressed population to mitigate COVID-19 infection or by boosting the immune system response with unique vaccine schedules . UnfortuPosition statements and guidelines for COVID-19 vaccinations in individuals with cancer receiving anti-cancer therapies are frequently released. While many suggest that COVID-19 vaccinations be administered two weeks or more prior to chemotherapy, this recommendation has not been practical. Limited by vaccination availability and the difficulties surrounding the scheduling of chemotherapy around the need for two vaccinations . The pusDecisions surrounding the appropriateness of the COVID-19 vaccine for individuals affected by cancer are currently made on an individual basis by their healthcare team. Patients must be counselled about the unknown vaccine safety profile and effectiveness in immunocompromised populations, the potential for reduced immune responses and the need to continue to follow all current guidance to protect themselves against COVID-19. Therefore, there is a need to develop Policies and Guidelines to help direct vaccination administration schedules in oncology patients, differentiating those with haematological malignancies and those in an immunocompromised state. Interestingly, vaccine-safety information is also absent in the context of therapies that stimulate the immune system, such as the widely available immune checkpoint inhibitors. While the choice of cancer treatment can profoundly impact the rates of seroconversion, currently, there is no evidence that patients receiving these agents are at higher risk of adverse events following the administration of COVID-19 vaccination .While patients with haematological malignancies represent a highly susceptible group with an urgent requirement for effective and available vaccines, with the limited data available at this time, it is critical that these individuals continue to maintain ongoing COVID-19 protective measures after vaccination or infection, including wearing face-masks, social distancing and the screening and vaccination of family members. Testing for seroconversion after vaccination or infection may also be warranted.


Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an unprecedented global crisis. Although primarily a respiratory illness, dysregulated immune responses may lead to multi-organ dysfunction. Prior data showed that the resident microbial communities of gastrointestinal and respiratory tracts act as modulators of local and systemic inflammatory activity (the gut–lung axis). Evolving evidence now signals an alteration in the gut microbiome, brought upon either by cytokines from the infected respiratory tract or from direct infection of the gut, or both. Dysbiosis leads to a “leaky gut”. The intestinal permeability then allows access to bacterial products and toxins into the circulatory system and further exacerbates the systemic inflammatory response. In this review, we discuss the available data related to the role of the gut microbiome in the development and progression of COVID-19. We provide mechanistic insights into early data with a focus on immunological crosstalk and the microbiome’s potential as a biomarker and therapeutic target. Since it was first recognized, Coronavirus Disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), remains a global affliction  is the largest immune organ . The poo4–105 bacteria per millimeter of content in the small intestine, and 1011 bacteria per gram of colonic content  to colonic epithelial cells. In addition, it also regulates mucosal permeability and provides deterrence against pathogenic microbes. More importantly, the microbiota plays an indispensable role in the preservation of intestinal homeostasis by modulating local and systemic immune responses of the host . The micClostridioides difficile enterocolitis, which is associated with prolonged and recurrent broad-spectrum antibiotic usage  outbreak in 2002 showed that diarrhea was a common symptom and occurred in 16%–73% of patients. The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-1) was not only known to infect the lung epithelial cells but also the immune cells, triggering an intense immune response with elevation in Th2 cytokines . It was via circulatory type I interferons  and interleukin-10 (IL-10), are hallmarks of severe COVID-19 infection . These cStreptococcus, Rothia, Veillonella, and Actinomyces), and significantly less diverse symbiotic species. Interestingly, the altered microbial signature in COVID-19 was different from patients with the H1N1 strain.Gu et al. first presented evidence of an altered gut microbiota in COVID-19 patients by using high-throughput sequencing of 16S ribosomal RNA to compare the gut taxa of patients with COVID-19, H1N1 influenza, and healthy controls . CompareIn another study, Zuo et al. analyzed fecal samples of 15 patients with COVID-19 using shotgun metagenomic sequencing . The stuAnother study by Newsome et al. compared microbiota composition from stool samples of 50 COVID-19 patients with uninfected patients . Signifiin vitro transcriptional analysis in a SARS-CoV-2-infected cell model (with samples obtained from stools), the 3’ end of the SARS-CoV-2 genome was detected more than the 5’ end, suggesting active viral replication. Interestingly, majority of the patients had no GI symptoms, suggesting a quiescent GI infection despite active replication of SARS-CoV-2 in the GIT with dysbiosis. Moreover, on functional analysis of the gut microbiota, fecal samples with signatures of high SARS-CoV-2 burden demonstrated high de novo nucleotide and amino acid biosynthesis, correlating with increased bacterial proliferation. Although this was a pilot study comprising only 15 patients, further studies on alterations in the functionality of the gut microbiota may unearth the pathophysiology of COVID-19 illness.Although it was previously believed that gut dysbiosis in COVID-19 was mainly driven by inflammatory mediators from respiratory tract infection, a recent study suggests that active replication of SARS-CoV-2 in the gut may be driving the dysbiosis . Using iOverall, currently expanding evidence suggests that patients with COVID-19 suffer from an alteration in the gut microbiota during and after the illness. Both systemic inflammation and replicative potential of SARS-CoV-2 in the gut may contribute towards dysbiosis.Though limited in number, studies to date have consistently demonstrated gut dysbiosis in patients with COVID-19 Table 1.As previously mentioned, clinical spectrum of COVID-19 ranges from asymptomatic to severe, life-threatening disease . A recenThere is mounting evidence that being elderly and having a chronic inflammatory state  predisposes to a pro-dysbiotic state , 71. It Given the association between gut dysbiosis and COVID-19 severity, the therapeutic potential for modulation of the gut microbiome to modify disease outcomes holds promise. However, there is no microbiota-directed therapy that has demonstrated efficacy in preventing the development or progression of COVID-19 currently.Bifidobacterium and Lactobacillus spp.) while decreasing the proportion of harmful species   . Moreovestridia) . By-prodstridia) . Interesstridia) , 78. AltLactobacillus gasseri SBT2055 in mouse models, prevention of infection with respiratory syncytial virus was demonstrated  have also demonstrated significant improvement in patients with ventilator-associated pneumonia  recommended the use of probiotics to maintain gut microbial homeostasis and prevent secondary bacterial infections . Given tC. difficile enterocolitis  is currently registered at the clinicaltrials.org (NCT04824222), though it has not yet started recruiting patients.FMT is a process of actively transferring colonies of fecal bacteria from a healthy person into the GIT of another individual. The process aims to restore the composition of gut microbiota back to a healthy state. As mentioned earlier, FMT is an effective therapy for recurrent or refractory ocolitis . Given tocolitis  describeDespite the efficient pace of clinical trials evaluating new and repurposed agents for COVID-19, success has been modest at best. Although still in nascent stages, evolving evidence signals a probable link between gut microbiota and the host’s immune response to COVID-19. However, the exact mechanism and extent of the role of gut dysbiosis in disease severity remain to be elucidated. This is further compounded by the inherent challenges associated with designing microbiome studies. Another possible angle would be to define the state of a leaky gut more clearly with biomarkers and cutoff criteria, to also enable clarification on whether patients who have developed an inflammatory cascade are still amenable to therapeutic gut microbiota modulation.Besides exploration of any potential role in the management of COVID-19, long-term consequences of gut dysbiosis should also be explored with longitudinal follow-up Table 2.The role of resident gut microbiota in other respiratory illnesses has been well recognized. Furthermore, the brunt of unfavorable COVID-19 outcomes has been on elderly patients and those with chronic medical diseases, both scenarios known to have senescence-driven gut dysbiosis. Increasingly, evidence is mounting for gut dysbiosis as a predisposing factor for severe COVID-19, through a leaky gut phenomenon and resultant spillage of bacterial products and toxins. Evidence is emerging that the degree of dysbiosis correlates with the severity of COVID-19 illness. This behooves us to explore potentially preventive and therapeutic targets, such as dietary intervention and probiotics. Several ongoing trials are evaluating various pathogenic routes and therapeutic approaches. While efforts for direct anti-viral agents and vaccines are of prime significance, the gut–lung axis could still hold therapeutic potential.IH and MBA: study concept. IH and MBA: literature search. IH, GY, and MBA: manuscript writing. MAA: critical revisions and intellectual content. MBA: supervision. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Older adults were perceived as a vulnerable group during the COVID-19 pandemic due to the health and mental health challenges they faced. The pandemic was accompanied by an “infodemic” of overabundant and questionable information that has affected older adults’ mental health. As the infodemic and ageist narratives were prevalent online, more anxiety symptoms have been induced among older adults who used social media. Age-friendly communication, advocated by the World Health Organization’s Age-friendly City (AFC) guide, could be an antidote by providing tailored information via appropriate channels for older adults.This study investigated the role of community capacity for age-friendly communication in mitigating anxiety during the pandemic. We hypothesized that age-friendly communication would moderate the effects of infection risks and social media use on anxiety. A double-moderating effect was hypothesized in the context of diminished trust in traditional media.Data were collected from a cross-sectional telephone survey conducted in Hong Kong in 2020. Older adults  were interviewed about their well-being and daily lives. Community capacity for age-friendly communication was measured in a living district–based evaluation. It had 2 components: the reach of appropriate information to older adults (AFC-Information) and the age-friendliness of communication technologies (AFC-Communication Technology) in the community. We tested the hypothesized moderation and double-moderation effects with ordinary least squares regressions.P=.02) and use of social media for COVID-19 information  were associated with more anxiety symptoms. The effect of using social media was moderated by AFC-Information  and AFC-Communication Technology , and the effect of perceived COVID-19 infection risk was moderated by AFC-Information  and AFC-Communication Technology . Lower trust in traditional media exacerbated anxiety symptoms associated with social media use . Higher AFC-Information alleviated this moderation effect .Perceived COVID-19 infection risk (b=0.002, Our findings highlight the role of community age-friendly communication in mitigating anxiety related to the infodemic. Although using social media may have exacerbated the impact of the infodemic on older adults, it has the potential to deliver timely information for an adequate health response. Although the amplifying effects of low media trust was associated with social media use, age-friendly communication determined its strength. Instead of discouraging the use of digital technologies for COVID-19 information, efforts should be made in tailoring information and communication technologies in local communities for older adults. The COVID-19 pandemic challenged older adults’ health and mental health. The threat of the pandemic may generate mental health challenges, such as anxiety, among the older population. Evidence from different countries suggests that higher COVID-19 death rates in the community are positively associated with distress in the population . BecauseThe infodemic associated with the COVID-19 pandemic may have aggravated anxiety among older adults. Older adults obtained COVID-19-related information from more diverse sources than younger adults and were driven to worry more about the pandemic . The infExperts advocated for better media communication for older adults during the COVID-19 pandemic . As in pAccording to the World Health Organization’s (WHO) guide on the Age-friendly City (AFC), “information” and “use of communication and digital devices” are 2 subdomains of age-friendly communication and information . A checkFirst, information directed to older adults at the community level may be particularly helpful in enabling them to manage the “new normal” generated by the pandemic. Complementing information on social media, information disseminated by reliable sources through familiar and preferred channels, such as telephone or information stands in the neighborhood , can serCommunity capacity for age-friendly communication may buffer the amplified effect of reduced trust in traditional media on infodemic-generated anxiety. In a crisis, insufficient or inconsistent information may lower public trust . During Despite the infodemic-amplified anxiety experienced by older adults regarding public health risks during the pandemic, effective age-friendly communication on a community level could ensure they are informed and resilient against problematic information. This study investigated the factors associated with older adults’ anxiety levels and the role of age-friendly communication in moderating the effects on anxiety. We hypothesized that the risk of contracting COVID-19 and the use of social media for pandemic-related information would be associated with increased anxiety levels in older adults, where more community-level age-friendly communication could mitigate the associations. The infodemic challenged the trust in traditional media mainly by way of misinformation in social media. We hypothesized that lower trust in the media would exacerbate anxiety symptoms associated with social media use and the risk of contracting COVID-19. Nevertheless, enhancing community capacity for age-friendly communication may help alleviate the negative impact of lowered media trust. We hypothesized that higher community capacity for age-friendly communication would reduce the effect of lower trust in the media on aggravating anxiety symptoms associated with social media use and the risk of contracting COVID-19. Respondents were recruited to answer a cross-sectional telephone survey aimed to understand the needs and well-being of community-dwelling older adults (age≥60 years) in Hong Kong during the COVID-19 pandemic. The survey protocol is described in a previous study . The surAnxiety symptoms were measured using the validated Chinese version of the 2-item Generalized Anxiety Disorder (GAD-2) questionnaire . Scores Respondents were asked to identify their primary source of COVID-19 information from (1) traditional media or (2) social media. The trust levels toward traditional media and social media were measured on a 5-point scale from total distrust (1) to complete trust (5). A “not applicable” option was available for each item for those who did not use the specified media type. The use of social media for COVID-19 information was captured by a 3-point ordinal scale from 0 to 2: 0, no usage ; 1, used social media ; and 2, used social media as their primary source of information.The local risk of contracting COVID-19 was captured by the number of confirmed cases in the respondent’s district of residence during the week of the survey. The survey covered 12 (67%) of the 18 administrative districts in Hong Kong. This measurement was geographically sensitive and reflected the risk of contracting COVID-19 in communities in the survey period. Data were extracted from daily government reports .Data were extracted from assessments by the Jockey Club Age-friendly City Project in Hong Kong . The asPublic health responses were measured by the Containment and Health Index from the Oxford COVID-19 Government Response Tracker. The index was calculated daily based on the number and strictness of containment and closure policies, such as canceling public events and stay-home requirements, and health system policies, such as contact tracing and public information campaigns . Scores Demographics collected included age in years, gender , district of residence, and service nature. District of residence was not included in the main analysis but was used to match respondents’ community COVID-19 risk and AFC indexes. Service nature was indicated by respondents’ involvement with either community aged care services or a mental wellness center.P<.001), they were included in 2 baseline models separately. The variance inflation factors of all variables in all baseline models were below 2.0, suggesting low multicollinearity between the variables. Second, 4 OLS regression models examined the mediation effects between the independent variables and moderators. The final set tested for moderation and double-moderation effects with trust in traditional media. Graphs of predicted values are provided to illustrate the moderation effects. The Johnson-Neyman technique was used to identify the range of significant moderation effects [Descriptive statistics were computed and appropriately reported. All hypotheses were tested by hierarchical ordinary least squares (OLS) regressions. All models were controlled by the Containment and Health Index and demographic covariates. First, baseline models predicting the GAD-2 score were estimated. Independent variables in the baseline model included community COVID-19 risk and social media use. Since the 2 moderator variables, AFC-Information and AFC-Communication Technology indexes, were substantially correlated  and social media use . A higher Containment and Health Index score, meanwhile, was negatively associated with the GAD-2 score . Female respondents exhibited more anxiety symptoms , but those who received service from a community center for older adults showed less anxiety symptoms . The baseline models with AFC indexes suggested a positive association between anxiety symptoms and AFC-Information  and AFC-Communication Technology .P=.002) and AFC-Communication Technology . P<.001) and AFC-Communication Technology . Nevertheless, the effects of COVID-19 risk and social media use on anxiety level depended on the age-friendliness of community communication. OLS models with interaction terms suggested significant moderation effects by the AFC-Information index and the AFC-Communication Technology index. The effect of social media use on anxiety symptoms was moderated by AFC-Information  but not community COVID-19 risk . The significant moderation slope range suggested by the Johnson-Neyman technique was trust in traditional media<3.93. For older adults with lower trust in traditional media, using more social media predicted more anxiety symptoms. The double-moderation models are consistent with previous findings. In addition, trust in traditional media and AFC-Information exhibited a double-moderation effect with social media use  and community COVID-19 risk . Meanwhile, trust in traditional media and AFC-Communication Technology showed no significant double-moderating effect with social media use  and community COVID-19 risk . When trust in traditional media was considered in the moderated relationships, the 3-way-interaction OLS regression models suggested that AFC-Information is the key to moderating the effects on GAD-2 scores but not AFC-Communication Technology. Study findings suggest that age-friendly communication offers community-level protection on mental health in an unprecedented crisis such as the COVID-19 pandemic by moderating the anxiety associated with COVID-19 infection risk. Although a higher COVID-19 infection risk may generate perceived vulnerability , this stThis study found that the anxiety associated with social media use for COVID-19 information is moderated by age-friendly communication. Although higher social media usage for COVID-19 information was positively associated with anxiety symptoms among older adults, community capacity for age-friendly communication may moderate the association. First, the perception of being better informed may lower pandemic-related anxiety . InformaA key contribution of this study is the demonstration of the double-moderating effect of community-based information for older adults on anxiety during the infodemic. On the one hand, our results suggest that older adults who have lower trust in the media show more anxiety symptoms when they use more social media for COVID-19 information. Distrust in mainstream information may have hindered older adults’ ability to judge the quality of information appropriately. Problematic information thus could impose a stronger anxiety-inducing effect ,9. On thThere are several possible explanations for our findings. First, information from the community possibly overshadowed other information, diluting the effects of media trust on inducing anxiety. Studies on media use suggest that news consumption can be a ritualized and habitual behavior . TherefoThis study provides evidential support for advocating age-friendly communication in local communities. On technology usage, although information delivered offline through key locations and persons is easily accessible for most older adults , approprThe cross-sectional nature of this study means that identified associations should not be treated as causal relationships. The questionnaire was designed to be brief to facilitate expedited completion and extensive reach to older adults. Therefore, the instruments were chosen for their conciseness but provided limited detailed information. For example, social media use for COVID-19 information was constructed as a 3-point measurement. This may have lowered its sensitivity to detect actual usage frequency and hence the estimated effects of social media usage. Data quality could have been affected by the self-reported nature of the survey in terms of memory loss and social desirability bias. Since the survey respondents had established relationships with social services, which may have contributed to the high response rate, they could have utilized more community resources and had higher trust toward the information shared in the community than the general older population. Meanwhile, since the age-friendly communication variables were obtained before the COVID-19 pandemic, community capacity for age-friendly communication could have changed when older adults were later interviewed during the disruption of social life. Age-friendly social services and community resources may be inaccessible for the time being, and hence older adults would not have benefited from them. Although this study suggests the moderation effect of community capacity for age-friendly communication, the measurements did not cover the actual usage of relevant resources. Our findings may underestimate the effect for older adults who fully utilized age-friendly communication opportunities. Lastly, trust in traditional media alone was measured to gauge the influence of the infodemic. This measurement may not fully reflect the impact of the infodemic, and more dimensions of the infodemic are still worth investigating.Although perceived infection risks and social media use during the COVID-19 pandemic may induce anxiety among older adults, community capacity for age-friendly communication alleviates their effects. By lowering trust in traditional media, the infodemic may amplify the effects of perceived infection risks and social media use on anxiety. However, better information circulation in the community for older adults moderates the influence of low media trust. Context-specific age-friendly communication solutions can mitigate the anxiety intensified by the infodemic. Although it is important to curate and deliver age-specific information for older adults, efforts should be made to build older adults' capacity in evaluating and sharing useful information amid the infodemic.