Single phage proteins sequester signals from TIR and cGAS-like enzymes.

Prokaryotic anti-phage immune systems use TIR and cGAS-like enzymes to produce 1''-3'-glycocyclic ADP-ribose (1''-3'-gcADPR) and cyclic dinucleotide (CDN) and cyclic trinucleotide (CTN) signalling molecules, respectively, which limit phage replication1-3. However, how phages neutralize these distinct and common systems is largely unclear. Here we show that the Thoeris anti-defence proteins Tad14 and Tad25 both achieve anti-cyclic-oligonucleotide-based anti-phage signalling system (anti-CBASS) activity by simultaneously sequestering CBASS cyclic oligonucleotides. Apart from binding to the Thoeris signals 1''-3'-gcADPR and 1''-2'-gcADPR, Tad1 also binds to numerous CBASS CDNs and CTNs with high affinity, inhibiting CBASS systems that use these molecules in vivo and in vitro. The hexameric Tad1 has six binding sites for CDNs or gcADPR, which are independent of the two high-affinity binding sites for CTNs. Tad2 forms a tetramer that also sequesters various CDNs in addition to gcADPR molecules, using distinct binding sites to simultaneously bind to these signals. Thus, Tad1 and Tad2 are both two-pronged inhibitors that, alongside anti-CBASS protein 2 (Acb26-8), establish a paradigm of phage proteins that use distinct binding sites to flexibly sequester a considerable breadth of cyclic nucleotides.

Target RNA activates the protease activity of Craspase to confer antiviral defense.

In the type III-E CRISPR-Cas system, a Cas effector (gRAMP) is associated with a TPR-CHAT to form Craspase (CRISPR-guided caspase). However, both the structural features of gRAMP and the immunity mechanism remain unknown for this system. Here, we report structures of gRAMP-crRNA and gRAMP:cRNA:target RNA as well as structures of Craspase and Craspase complexed with cognate target RNA (CTR) or non-cognate target RNA (NTR). Importantly, the 3' anti-tag region of NTR and CTR binds at two distinct channels in Craspase, and CTR with a non-complementary 3' anti-tag induces a marked conformational change of the TPR-CHAT, which allosterically activates its protease activity to cleave an ancillary protein Csx30. This cleavage then triggers an abortive infection as the antiviral strategy of the type III-E system. Together, our study provides crucial insights into both the catalytic mechanism of the gRAMP and the immunity mechanism of the type III-E system.

Influenza Resurgence after Relaxation of Public Health and Social Measures, Hong Kong, 2023.

Soon after a mask mandate was relaxed (March 1, 2023), the first post-COVID-19 influenza season in Hong Kong lasted 12 weeks. After other preventive measures were accounted for, mask wearing was associated with an estimated 25% reduction in influenza transmission. Influenza resurgence probably resulted from relaxation of mask mandates and other measures.

Epidemiology of SARS-CoV-2 Omicron BA.5 Infections, Macau, June-July 2022.

A SARS-CoV-2 Omicron BA.5 outbreak occurred in Macau from mid-June through July 2022. Out of >1,800 laboratory-confirmed cases, most were mild or asymptomatic; only 6 deaths were recorded. The outbreak was controlled through stringent public health and social measures, such as repeated universal testing and a stay-at-home order lasting 2 weeks.

Biphasic Waning of Hemagglutination Inhibition Antibody Titers After Influenza Vaccination in Children.

We explored the potential for a biphasic pattern in waning of antibody titers after influenza vaccination. We collected blood samples in a randomized controlled trial of influenza vaccination in children and tested them with hemagglutination inhibition assays for influenza A(H3N2) and influenza B/Victoria lineage. Using piecewise log-linear mixed-effects models, we found evidence for a faster initial waning of antibody titers for the first 1-2 years after vaccination and then slower longer-term declines. Children with higher postvaccination titers had faster antibody decay.

Comparison of control and transmission of COVID-19 across epidemic waves in Hong Kong: an observational study.

Background: Hong Kong contained COVID-19 for two years but experienced a large epidemic of Omicron BA.2 in early 2022 and endemic transmission of Omicron subvariants thereafter. We reflected on pandemic preparedness and responses by assessing COVID-19 transmission and associated disease burden in the context of implementation of various public health and social measures (PHSMs). Methods: We examined the use and impact of pandemic controls in Hong Kong by analysing data on more than 1.7 million confirmed COVID-19 cases and characterizing the temporal changes non-pharmaceutical and pharmaceutical interventions implemented from January 2020 through to 30 December 2022. We estimated the daily effective reproductive number (Rt) to track changes in transmissibility and effectiveness of community-based measures against infection over time. We examined the temporal changes of pharmaceutical interventions, mortality rate and case-fatality risks (CFRs), particularly among older adults. Findings: Hong Kong experienced four local epidemic waves predominated by the ancestral strain in 2020 and early 2021 and prevented multiple SARS-CoV-2 variants from spreading in the community before 2022. Strict travel-related, case-based, and community-based measures were increasingly tightened in Hong Kong over the first two years of the pandemic. However, even very stringent measures were unable to contain the spread of Omicron BA.2 in Hong Kong. Despite high overall vaccination uptake (>70% with at least two doses), high mortality was observed during the Omicron BA.2 wave due to lower vaccine coverage (42%) among adults ≥65 years of age. Increases in antiviral usage and vaccination uptake over time through 2022 was associated with decreased case fatality risks. Interpretation: Integrated strict measures were able to reduce importation risks and interrupt local transmission to contain COVID-19 transmission and disease burden while awaiting vaccine development and rollout. Increasing coverage of pharmaceutical interventions among high-risk groups reduced infection-related mortality and mitigated the adverse health impact of the pandemic. Funding: Health and Medical Research Fund.

Advection-Dispersion Behavior for Simulation of H-3 and Pu-238 Transport in Undisturbed Argillaceous Shale of a Near-Surface Repository.

In this study, a column experiment was employed to evaluate the nuclide migration behavior in the surrounding rock medium of a near-surface disposal site in China and to investigate the advection-dispersion behavior of tritium (H-3) and plutonium-238 (Pu-238) in highly weathered argillaceous shale. A reasonable numerical model was selected to fit the experimental breakthrough curves (BTCs) and to obtain the relevant migration parameters. The results show the following: (1) the internal structure of the highly weathered argillaceous shale exhibited heterogeneity, and the nuclide migration BTC showed characteristics of a "curve peak moving forward" and a "tail curve trailing"; (2) compared with other models, the stream tube mode could better fit the BTCs and obtain the average dispersion coefficient , average distribution coefficient , and other parameters; (3) compared to the results of the batch experiment, the distribution coefficient Kd obtained from the column experiment was smaller than that obtained from the batch experiment, which is speculated to be due to the influence of contact time and the contact area between the nuclide and the medium.

Single phage proteins sequester TIR- and cGAS-generated signaling molecules.

Prokaryotic anti-phage immune systems use TIR (toll/interleukin-1 receptor) and cGAS (cyclic GMP-AMP synthase) enzymes to produce 1"-3'/1"-2' glycocyclic ADPR (gcADPR) and cyclid di-/trinucleotides (CDNs and CTNs) signaling molecules that limit phage replication, respectively 1-3. However, how phages neutralize these common systems is largely unknown. Here, we show that Thoeris anti-defense proteins Tad1 4 and Tad2 5 both have anti-CBASS activity by simultaneously sequestering CBASS cyclic oligonucleotides. Strikingly, apart from binding Thoeris signals 1"-3' and 1"-2' gcADPR, Tad1 also binds numerous CBASS CDNs/CTNs with high affinity, inhibiting CBASS systems using these molecules in vivo and in vitro. The hexameric Tad1 has six binding sites for CDNs or gcADPR, which are independent from two high affinity binding sites for CTNs. Tad2 also sequesters various CDNs in addition to gcADPR molecules, inhibiting CBASS systems using these CDNs. However, the binding pockets for CDNs and gcADPR are different in Tad2, whereby a tetramer can bind two CDNs and two gcADPR molecules simultaneously. Taken together, Tad1 and Tad2 are both two-pronged inhibitors that, alongside anti-CBASS protein 2, establish a paradigm of phage proteins that flexibly sequester a remarkable breadth of cyclic nucleotides involved in TIR- and cGAS-based anti-phage immunity.

Resurgence of Omicron BA.2 in SARS-CoV-2 infection-naive Hong Kong.

Hong Kong experienced a surge of Omicron BA.2 infections in early 2022, resulting in one of the highest per-capita death rates of COVID-19. The outbreak occurred in a dense population with low immunity towards natural SARS-CoV-2 infection, high vaccine hesitancy in vulnerable populations, comprehensive disease surveillance and the capacity for stringent public health and social measures (PHSMs). By analyzing genome sequences and epidemiological data, we reconstructed the epidemic trajectory of BA.2 wave and found that the initial BA.2 community transmission emerged from cross-infection within hotel quarantine. The rapid implementation of PHSMs suppressed early epidemic growth but the effective reproduction number (Re) increased again during the Spring festival in early February and remained around 1 until early April. Independent estimates of point prevalence and incidence using phylodynamics also showed extensive superspreading at this time, which likely contributed to the rapid expansion of the epidemic. Discordant inferences based on genomic and epidemiological data underscore the need for research to improve near real-time epidemic growth estimates by combining multiple disparate data sources to better inform outbreak response policy.

Study on Tritium and Iodine Species Transport through Porous Granite: A Non-Sorption Effect by Anion Exclusion.

The safety of deep geological repositories is important in the disposal of high-level radioactive waste (HLW). In this study, advection−dispersion experiments were designed to build a transport model through a calibration/validation process, and the transport behavior of tritiated water (HTO) and various iodine species (iodide: I− and iodate: IO3−) was studied on a dynamic compacted granite column. Breakthrough curves (BTCs) were plotted under various flow rates (1−5 mL/min). BTCs showed that the non-sorption effect by anion exclusion was observed only in I− transport because the retardation factor (R) of I− was lower than that of HTO (R = 1). Moreover, equilibrium and nonequilibrium transport models were used and compared to identify the mobile/immobile zones in the compacted granite column. The anion exclusion effect was influenced by the immobile zones in the column. The non-sorption effect by anion exclusion (R < 1) was only observed for I− at 5.0 ± 0.2 mL/min flow rate, and a relatively higher Coulomb's repulsive force may be caused by the smaller hydration radius of I−(3.31 Å) than that of IO3−(3.74 Å).

[Bispecific antibodies in clinical tumor therapy].

Bispecific antibody (BsAb) has two different antigen-binding sites, divided into the "IgG-like" format and the "non-IgG-like" format. Different formats have different characteristics and applications. BsAb has higher sensitivity and specificity than conventional antibodies, with special functions such as recruitment of immune cells and blocking of dual signaling pathways, playing an important role in immune-diagnosis and therapy. With the deterioration of the global environment and the irregular living habits of people, the incidence of tumor is becoming higher and higher. Tumor becomes the most serious fatal disease threatening human health after cardiovascular disease. There are 12 million estimated new tumor cases each year worldwide. The major clinical treatments of tumor are surgical resection, chemoradiotherapy, target therapy. Tumor immunotherapy is a novel approach for tumor treatment in recent years, and activates human immune system to control and kill tumor cells. Although the traditional monoclonal antibodies have already acquired some therapeutic effects in tumor targeted therapy and immunotherapy, they induce drug resistance resulted from the heterogeneity and plasticity of tumors. Binding to two target antigens at the same time, BsAb has been used in the clinical treatment of tumors and obtained promising outcomes. This review elaborates the research progress and applications of bispecific antibody in clinical tumor therapy.