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The use of bispecific antibodies (BsAbs) to treat human diseases is on the rise. Increasingly complex and powerful therapeutic mechanisms made possible by BsAbs are spurring innovation of novel BsAb formats and methods for their production. The long-lived in vivo pharmacokinetics, optimal biophysical properties and potential effector functions of natural IgG monoclonal (and monospecific) antibodies has resulted in a push to generate fully IgG BsAb formats with the same quaternary structure as monoclonal IgGs. The production of fully IgG BsAbs is challenging because of the highly heterogeneous pairing of heavy chains (HCs) and light chains (LCs) when produced in mammalian cells with two IgG HCs and two LCs. A solution to the HC heterodimerization aspect of IgG BsAb production was first discovered two decades ago; however, addressing the LC mispairing issue has remained intractable until recently. Here, we use computational and rational engineering to develop novel designs to the HC/LC pairing issue, and particularly for κ LCs. Crystal structures of these designs highlight the interactions that provide HC/LC specificity. We produce and characterize multiple fully IgG BsAbs using these novel designs. We demonstrate the importance of specificity engineering in both the variable and constant domains to achieve robust HC/LC specificity within all the BsAbs. These solutions facilitate the production of fully IgG BsAbs for clinical use. [ABSTRACT FROM AUTHOR]

Studies on root development, soil physical properties, and yield are important for identifying suitable soil management practices for sustainable crop production. Field experiments with winter wheat (Triticum aestivum L.) were conducted in silt loam soil from 2005 through 2007 in arid northwestern China to determine the effects of five tillage systems on soil strength, soil moisture, crop root development, grain yield, and yield components. The five treatments were conventional tillage without wheat stubble (T), conventional tillage with wheat stubble incorporated (TSI), no-tillage without wheat stubble mulching (NT), no-tillage with wheat stubble standing (NTSS), and no-tillage with wheat stubble mulching (NTS). Compared with the T treatment, the NTSS and NTS treatments improved soil water content in the 0- to 130-cm soil depth by 10 to 17% and 15 to 25%, respectively (P < 0.05). The NTSS treatment also increased mean root length density (RLD) by 8 to 40% and crop yield by 13 to 24%, and NTS by 17 to 48% and 17 to 31%, compared with the T treatment. Yield components analysis indicated that thousand-grain weight and spike density considerations helped explain the grain yield increases under conservation tillage systems (NT, NTSS, NTS), while spike length, number of grains per spike, and grain weight per spike failed to contribute to the model. Our results suggest that Chinese farmers should consider adopting conservation tillage practices in arid northwestern China because of benefits to soil strength, water storage, RLD, and wheat yield. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to evaluate the reliability of reconstructing composite defects of the mandible with a local pedicled mandibular osteomuscular flap. Materials and methods: A retrospective study examined patients undergoing secondary mandibular reconstruction following tumour ablation using local pedicled mandibular osteomuscular flaps. The study included five men and three women. The segmental defects of the mandible resulted from oral carcinoma in five cases and mandibular ameloblastoma in three. Results: All of the flaps survived. Proper aesthetics and complete functionality were obtained, and no donor-site problems occurred. The patients were followed for 16–24 months and no recurrence was seen. Conclusions: The pedicled mandibular osteomuscular flap is technically simple, fast to harvest, and has an exceptionally long arc of rotation, which enables the reconstruction of composite segmental defects of the mandible following tumour ablation. [ABSTRACT FROM AUTHOR]

Chronic infections, including Mycobacterium tuberculosis (Mtb)-caused tuberculosis (TB), can induce host immune exhaustion. However, the key checkpoint molecules involved in this process and the underlying regulatory mechanisms remain largely undefined, which impede the application of checkpoint-based immunotherapy in infectious diseases. Here, through adopting time-of-flight mass cytometry and transcriptional profiling to systematically analyze natural killer (NK) cell surface receptors, we identify leukocyte immunoglobulin like receptor B1 (LILRB1) as a critical checkpoint receptor that defines a TB-associated cell subset (LILRB1 + NK cells) and drives NK cell exhaustion in TB. Mechanistically, Mtb-infected macrophages display high expression of human leukocyte antigen-G (HLA-G), which upregulates and activates LILRB1 on NK cells to impair their functions by inhibiting mitogen-activated protein kinase (MAPK) signaling via tyrosine phosphatases SHP1/2. Furthermore, LILRB1 blockade restores NK cell-dependent anti-Mtb immunity in immuno-humanized mice. Thus, LILRB1-HLA-G axis constitutes a NK cell immune checkpoint in TB and serves as a promising immunotherapy target., (© 2024. The Author(s).)

Children's sharing behavior is profoundly shaped by social norms within their society, and they can learn these norms by directly observing how most others share in their immediate environment. Here we systematically investigated the impact of majority influence on the sharing behavior of young Chinese children through three studies (N = 336, 168 girls). Four- and 6-year-olds were allowed to choose 10 favorite stickers and had an opportunity to engage in anonymous sharing. Before making the sharing decision, children were assigned to one of two conditions: watching a video in which three peers all shared 8 out of 10 stickers (i.e., the majority sharing condition) or making their decisions without watching the video (i.e., the control condition). Results showed that both the 4- and 6-year-old children shared more stickers in the majority sharing condition than in the control condition (Studies 1 & 2). Moreover, the influence of the majority had a stronger effect compared to the influence of a single role model. Children shared more stickers after observing three peers sharing, compared to watching one peer sharing three times (Study 2). Furthermore, children were less likely to copy the majority's non-sharing behavior when it came to giving away stickers without prosocial outcomes, which was particularly evident among 4-year-olds (Study 3). The results reveal that majority influence uniquely shapes children's sharing behavior and that children selectively follow the majority based on whether the behavior exhibits prosocial attributes. A video abstract of this article can be viewed at https://youtu.be/8qNNhf9754I?si=7YfpaFpcD&#95;IjlXjJ RESEARCH HIGHLIGHTS: Observing a majority of three peers' unanimous generous sharing promoted sharing behavior in both 4- and 6-year-olds. The influence of three peers on children's sharing was stronger than that of one peer sharing three times. Four-year-olds, but not 6-year-olds, did not copy the non-sharing behavior of the majority as it did not lead to prosocial outcomes., (© 2024 John Wiley & Sons Ltd.)